Best from Ksenia


Ksenia is an infamous trans female, she has talked about doing self-surgery (FFS) and can react very badly if someone explain why one of her beliefs are false.

Ksenia: Are you trans?

Zesto: I'm a crossdresser looking to boost my estrogen.

But I want my account deleted because I don't want to post on a jizzy coding forum.

Ksenia: Are you on HRT? I am on estrogen.

Zesto: No, I just drink milk with growth hormones.

I like the way traps look, I think trannies end up looking off.

Ksenia: Disgusting. You are not trans nor non-binary. You are a run of the mill submissive gay man.


u/ksenu on reddit:

In Western countries, women are encouraged for being women in everything they do. They are given scholarships just for being women, etc. At this point crying sexism is just an excuse for poor top performance.

We can eat only starting 7 pm until 3 am I am planning to take 100 mg spiro and 4 mg progynova 7 pm and same dosage 3 am

Thats going to be only during Ramadan month ( 30 days only ) after that i will go back to my previous Regimen
Spironolactone is a duirectic, not suitable for use as an anti-androgen. Taking your HRT in a single dose instead of spreading it will significantly affect the pharmacokinetics because oral E2 has a short half life (few hours). Whether it will affect the end result, there is no way to know for sure. What we do know for sure is that beliefs in a personal god is a delusion. You are possibly impairing your transition results for a delusion.

how could HRT help COVID-19??
Estrogens increase immune response. Davis et al. (2017) found that mice given estrogens recovered faster from influenza than mice deprived of sex hormones. They found progestogens to have the opposite effect.

Has anyone used any supplements or topical creams for breast development? I have substantial chest dysphoria but am not in a place to start my medical transition is there anything on the market or available that I can do or take to help mitigate those feelings and help with a little bit of breast growth?? Has anyone tried anything this? If so how did it effect you when you started HRT?
“supplements” is a vague term in this context. It means nothing concrete. It is used by sellers of pharmaceuticals to try to evade regulations for pharmaceuticals.

Order HRT online and buy it in secret. You can hide the changes. Remember, every day you postpone HRT is one day more of masculinizing on androgens.

There are 3 main types of sex hormones: androgens, progestogens and estrogens. Among those, to feminize it is in practice a sufficient and necessary condition to suppress androgens and you have significant estrogens. This is achieved by administering an anti-androgen and an estrogen or a high dose of an estrogen that will suppress androgens on its own.


She (and Trump) was right about Hydroxychloroquine?
She wrote earlier that studies did show it to help and the following doctor reached the same conclusion.

Update: She was wrong, it didn't actually work.


Ksenia has an interest for programming but she never posted about it on this forum. She has talked about having automized matimatical proofs but i have not looked into her works regarding that.

Our relationship was unstable, eventually she just blocked me completely.


#9 home page#
Use the permalink to bookmark and reference this work.

Flag of Alinism-Ksenism. See description. is an informative web site about transsexualism. The site is focused on scientific information supported by the literature.

This web site is run by the 17beta community which is named after 17β-estradiol (also known as just “estradiol”), the main endogenous estrogen in humans of both sexes.

We make this website for free with the intention that it will be useful for transsex people. However, VPS and domain name costs us money that I (Ksenia) pay out of pocket, money that I would otherwise use for my own transition and other living expenses. If you want to help with paying for the costs of hosting, please donate via Bitcoin to the address 16CcLt78dHAfdAGSmxCnthWemJ42i9eptb. The running cost is approximately 3.15 EUR per month (varies depending on exchange rates).

1 Community and our chat room
We have a XMPP chat room: for the exchange of ideas and experiences and general conversation. If you sympathize with our vision (even if you do not embody it currently), we invite you to join. What sets our community apart is:
  • We approach transsexualism as the choice to transform our bodies to be feminine through the use of female hormones (and optionally surgery). Transsexualism is not a feeling and not about “identifying as a woman”.
  • We are exclusively gynephilic because we appreciate the female form in ourselves and women, and we aim to embody it.
  • We are against gatekeeping and in favor of taking control of our own treatment. We value scientific knowledge that allows us to take our own informed decisions.
  • We see social transition as optional and secondary to physical transition. Those of us who want to be treated as a women by society earn it by passing.
  • We are not a hugbox nor ultraliberals, nor politically correct.
  • Dissent and rational discussion is allowed because it is intellectually enriching.
1.1 XMPP?
XMPP is a decentralized protocol for instant messaging. Register an account in the server of your choice. For a list of public servers, see Alternatively, you can run your own XMPP server. For a client program, I recommend Gajim. For a list of other clients see If you do not want to install any stand-alone program can be used from your web browser.
Although there are centralized instant messaging applications more popular than XMPP, we choose XMPP because it gives users control over their communications, whereas centralized applications put the users at the whim of a company which is free to censor them or invade their privacy as it pleases.

2 Our flag
The meaning of the elements of the flag of Alinism-Ksenism is as follows. The estradiol molecule is the chemical essence of femininity. The sword (a Mainz-type Roman gladius) represents our combativeness in fighting hardship. The drop of blood and the red stripes represents our self sacrifice in improving ourselves and working towards virtue. The pink star and pink stripes represent femininity; the star shape in addition represents our high valuation of femininity. The flag was designed by Ksenia and drawn by Tsarina Effy.

3 Other resources
  • Library Genesis: A digital library for scientific books.
  • Sci-Hub: A digital library for scientific papers.
  • Directory of Open Access Journals: Listing of open access scientific journals and search engine for open access articles.
  • PubMed: Search engine for biology-related papers.
  • PubChem: Database of small molecules with computed and measured properties, and listings of the published literature on the relevant compound.
  • DrugBank: A database of pharmaceuticals and data relevant for their application (commercial names, interactions, et cetera).
  • Binding DB: Data base of binding affinity and related assays.
  • HUGO Gene Nomenclature. In the literature, proteins are often named the same as the gene they are coded in, but note that some genes encode several proteins (e.g.: D2R encodes 2 types of dopamine receptors).
  • Roche Metabolic Pathways (thanks to A. for making me aware of this web site).
  • “Shortcut to female voice”: Recommendations for MTF voice training.
  • Audacity: Free software for editing audio. Can be used to record and analyze one’s voice.
  • The board /lgbt/ in 4channel. It has a running series of /HRTgen/ threads about MTF pharmacology and practical concerns and a list of online pharmacies that sell HRT pharmaceuticals. I can not vouch for nor against any of the online pharmacies listed there because I have not used them.
3.1 Online HRT sellers
I can not vouch for these vendors, as I have not used them.
4 Collaboration
Please contact me if you are skilled in technical writing, you are knowlegdeable in some aspect of transsexualism (pharmacology, surgery, dating or just living as a trans person) and you want to contribute your knowledge to other trans people. I will be glad to add your contributions in this web site if they are of good quality, with due credit.

5 About the author
I am a Mexican MTF transsexual. I started HRT at 22 years of age. I did not start earlier because of ignorance that it could be done. My main interest is mathematics. I also like physics, chemistry and related areas of engineering, especially electrical power systems. I am vegetarian for moral reasons. Occasionally I contribute code to free software projects. I like Eastern Slav culture (Belarus, Russia, Ukraine).

You can reach me via XMPP (Jabber) thorugh the address or e-mail through the address My OpenPGP key is B242 D57F B4EB C57E 7B8C 635C 7CFB 3171 B838 9B66. My OMEMO key fingerprint is 20BE 1803 83DE 631F 5923 4660 32D2 F4CB D982 EFE8 330B 2810 9017 ADE0 C0BD 007B (signed statement).

6 Acknowledgements

Alina Devis/Kožuhova.

We acknowledge the big contribution of Alina Devis/Kožuhova from Russia in publicly speaking about transition as physical improvement for gynephilic males for the first time in history (as far as it is known to the author). She has appeared in Russian-language television and newspapers advancing that biological males can be beautiful too just like women can be, and can benefit from combining the best traits of both sexes. The Huffington Post published an article in English about her.

The pink pill favicon is in the public domain; adapted by Tsarina Effy.

The Alinism-Ksenism flag is in the public domain; concept by Ksenia; drawn by Tsarina Effy.

Copyright © «Ksenia». This work can be used, copied, modified and sold under the terms of the license Creative Commons Attribution-ShareAlike 4.0 International. This work is provided as-is, without any warranty. The reader is solely responsible for the use made of this information.


Pharmacology of transÂsexualism#
First version: 2018-12-04
Last update: 2020-12-27
Persistent link to latest version:
  1. 1 Terminology and concepts
  2. 2 Endogenous sex hormones
  3. 3 Hormone replacement treatment
    1. 3.1 Effects
      1. 3.1.1 Sexual function
      2. 3.1.2 Breast growth
      3. 3.1.3 Immune response
      4. 3.1.4 Other
    2. 3.2 Concrete HRT regimes
      1. 3.2.1 Oral ethynylestradiol
    3. 3.3 Anti-androgens
      1. 3.3.1 Algestone acetophenide
      2. 3.3.2 Cyproterone acetate
      3. 3.3.3 Medroxyprogesterone acetate
      4. 3.3.4 Spironolactone (not suitable)
    4. 3.4 Estrogens
      1. 3.4.1 Ethynylestradiol
      2. 3.4.2 Estradiol esters
    5. 3.5 Selective estrogen receptor modulators
    6. 3.6 Prolactin
  4. 4 Melanogenesis inhibitors (skin, hair and eye whitening agents)
  5. 5 Conversion factors
  6. 6 Hypodermic needles
  7. 7 References
1 Terminology and concepts
We define “transsex†as the people who undergo a treatment to change their sexually dimoprhic features to resemble the other sex. The word “transsexual†is widespread for the same meaning; we prefer the term “transsex†to emphasize that it is about sexual dimorphism, not sexuality. We use the word “transsexualism†to refer to this phenomenon. We refer to people who are not transsex as “cissex†or just “cisâ€. This text concerns exclusively male to female transsex people. Male to female transsex people (MTFs) are also called trans women.

To name substances we use the International Nonproprietary Name if allocated and known. To minimize confusion we refer to esters of steroids by their traditional name; these names correspond to archaic names of carboxylic acids. For example we use “estradiol valerate†instead of “estradiol pentanoateâ€. “valerate†comes from the archaic name of pentanoic acid: “valeric acidâ€. When naming the acids the systematic name must be used. Thus referring to pentanoic acid as “valeric acid†is unacceptable.

2 Endogenous sex hormones
For an overview at the endocrinological level of the signaling pathway responsible for progestogens, androgens and estrogens, see Golan et al. (2017) chapter 30 “Pharmacology of Reproductionâ€; this is required knowledge for any transsexual; only a brief summary is given next.

The main source of endogenous androgens in biological males are the testis. Additionally, in both sexes the adrenal glands secrete androgens. The main androgen produced by testis is testosterone.

The synthesis of androgens in the testicles requires the presence of circulating lutenizing hormone (LH). Lutenizing hormone is a protein secreted by the hypophysis. Lutenizing hormone (LH) and follicle stimulating hormone (FSH) are collectively referred to as the gonadotropins. The production of adrenal androgens is not dependant on gonadoptropins.

In a physiologically normal human, the hypthalamus secretes gonadotrpoin releasing hormone (GnRH) in slow pulses. The pulses of GnRH causes the hypophysis to secrete lutenizing hormone and follicle-stimulating hormone. In both sexes LH and FSH are necessary for the normal functioning of the reproductive system and for fertility. LH stimulates synthesis of testosterone in ovaries and testicles. For details on the chemical structure and pharmacodynamics of GnRH, LH and FSH, see Kleine, Rossmanith (2016).

The enzymes 5α-reductases converts testosterone into 4,5-dihydrotestosterone (common abbreviation: DHT). DHT is a more potent androgen than testosterone, thus the effect of 5α-reductases is to amplify the action of testosterone selectively in the cells where it is expressed and unselectively by increasing circulating DHT. 5α-reductases are highly expressed in cells of the male reproductive system. There are 2 known types of 5α-reductases in humans. 5α-reductase type I (gene SRD5A1) is expressed in the liver and nongenital skin (among other tissues) and 5α-reductase type II (gene SRD5A2) is expressed in the prostate and genital skin (among other tissues). There are other genes classified under the SRD5A family that appear to not to participate in steroid metabolism (Stiles 2010); in specific Chávez (2015) found that the so-called “5α-reductase type III†(gene SRD5A3) does not act as a 5α-reductase in humans, i.e.: does not convert testosterone into DHT.

Stricker et al. (2006) investigated the levels of gonadotrpoins, estradiol and progesterone in normal cis women of reproductive age. We assume measurements of estradiol and progesterone refer to total (not free). The highest level of total estradiol observed is during the lutenizing hormone peak. The amount observed at that time of the menstrual cycle is median: 671Â pmol/l, 95th percentile: 1Â 880Â pmol/l. The highest level of total progesterone observed is during the mid-lutear phase. The amount observed at that time is median: 36.2Â nmol/l, 95th percentile: 54.3Â nmol/l. All quantities reproduced in this paragraph were rounded to 3 significant digits from those reported in the paper, round to nearest with ties to even.

Reference levels of total testosterone in cis females cited in Fung et al. (2017)
CommentMin.Max.Abbott Architect testosterone chemiluminescent immunoassay, pre-menopausal women0.3 nmol/l3.0 nmol/lBeckman Access testosterone chemiluminescent immunoassay0.4 nmol/l2.6 nmol/lRoche Cobas testosterone electrochemiluminescent immunoassay, pre-menopausal women—1.8 nmol/lSiemens Centaur testosterone chemiluminescent immunoassay —2.7 nmol/lMinimum of maximum reference levels above—1.8 nmol/l

3 Hormone replacement treatment
Reviews of the pharmaceuticals used for HRT and its effects include Tangpricha, den Heijer (2016).

Pharmacologically the goals of MTF HRT are:

  • Suppress the activation of the nuclear androgen receptor to prevent further masculinization and partially revert its already-present effects.
  • Activate the nuclear estrogen receptors to cause feminization.
  • Optionally, activate the progesterone receptors. This is speculated to result in increased feminization. As of 2020 the effects of progesterone on feminization are not well characterized.
There are 2 usual ways to achieve this:

  • With a high dose of an estrogen and nothing else. This causes enough activation of the estrogen receptors to decreased production of gonadotropins.
  • With a moderate dose of an estrogen and a separate anti-androgen. (see § Anti-androgens below).
Idrus, Hymans (2014) reported about the HRT regimes and effects of transsex people in Indonesia which self-medicate.

3.1 Effects
3.1.1 Sexual function
In a review about multiple orgasms in biological males Wibowo, Wassersug (2016) mention that ejaculation and exposure to androgens may be at least in part responsible for the post-ejaculatory refractory period and thus the inability to have multiple orgasms in one sexual session in cis men. Kinsey (mentioned in Wibowo, Wassersug 2016) reported that among young males, capacity for multiple penile orgasms are more prevalent in kids and teens. Warkentin et al. (2016) reported a case of a prostate cancer patient who became penile-multi-orgasmic on anti-androgen treatment.

A common side effect of HRT is lowered libido after starting lasting for week to months. Depending on the user this may be a desirable or undesirable effect. In the experience of the author and other transsex people that shared their experience through personal communication, libido rises after some weeks to months on HRT. If the user wishes to increase libido, bupropion can be used. Crenshaw et al. (1987) found bupropion to be effective in raising libido in cis males and cis females. Wibowo, Wassersug (2013) found that estrogens increase sexual interest in biological males.

Schneider et al. (2017) and Jindarak et al. (2019) examined the effects of HRT on testicular tissue and function.

3.1.2 Breast growth
Breast growth in MTF transsex people tends to be different than in cis women. MTFs tend to grow breasts conical in shape that are smaller and firmer than typical breasts of cis women. In the author’s opinion, the typical MTF breasts are more aesthethic and more desirable than the bigger and less firm hemispherical brestas typical of cis women.

Vandenberg (2006) found a non-monotonic response of size of breasts developed as a function of the dose of exogenous estrogen administered to ovariectomized female mice. Size of breasts was smaller in mice administered the highest dose of estradiol than mice administered an intermediate dose. The optimum dose for breast growth in humans can not be extrapolated from this study because metabolization of pharmaceuticals does not scale linearily with body mass and the growth of the human body is slower than that of mice. This result suggests the hypothesis that to maximize breast growth in transsex people it can be appropriate to use a lower dose of the estrogen or increase the dose slowly. However many HRT regimes rely on the estrogen to suppress endogenous androgens; therefore, starting with low dose of an estrogen potentially risks some degree of continued masculinization and sub-optimal feminization.

3.1.3 Immune response
Estrogens appear to increase the strenght of the immune system to disease and progestogens to decrease it. Davis et al. (2017) found that estradiol delays onset of influenza and fastens recovery in mice compared to placebo and progesterone has the opposite effect.

3.1.4 Other
Tebbens et al. (2019) examined quantitatively changes in facial dimensions on HRT with measurements taken over the skin; they found that HRT changes sexually dimoprhic dimensions towards female (see the paper for quantitative data).

Kranz et al. (2014) found that HRT decreases expression of the serotonin transporter in MTF transsexuals. Thus it is inferred, HRT has a similar effect to a serotonin reuptake inhibitor and increases the concentration of available serotonin.

Ulrich et al. (1994) found that high-dose treatment with estrogen and progestogen depot injections quickly improved bone density.

Harrison et al. (2014) found that 17α-estradiol (an isomer of 17β-estradiol with diminished estrogenic potency) prolonges lifespan in a study with mice.

Estrogens are known to be responsible for the cessation of grow in height in both males and females. Therefore, transsexuals should not use estrogens until they reach their desired height or until ephyphyseal plates have ossified (because after ossification, there is no prospect of natural vertical growth). See Chagin, Sävendahl (2007). Transsex people and other people who desire a higher height but have already ossified growth disks can opt for limb lengthening by the method of distraction osteogenesis. This method was pioneered in the USSR by Gavriil Ilizarov. For small increments in height, the procedure can involve exclusively lengthening the femur. For higher increases, the femur, tibia, and peroné are lengthened, and optionally the arms for the sake of proportions. A full discussion of limb lengthening is beyond the scope of this text.

Giltay, Gooren (2000) studied the effect of HRT in production of body hair and skin oil (sebum). They found that “The hair diameter fell sharply within 4 months and remained rather constant thereafter, whereas the median growth rate and density on the cheek and upper abdomen dropped only slowly but progressivelyâ€. In other words, HRT will not make beard and mustache disappear; for that, temporary or permanent hair removal procedures like waxing, plucking, laser, intense pulsed light or electrolysis should be used. The same study found that production of skin oil decreased and was already very little after 4 months of HRT.

3.2 Concrete HRT regimes
The following is a non-exhaustive collection of HRT regimes that the author considers useful. It is up to the reader to decide whether any of these regimes are suitable for her particular case.

3.2.1 Oral ethynylestradiol
Take 2 pills of Diane-35 per day. Take the pills preferentially always at the same time of the day, every 12 hours; timing within a day is not critical. Each pill of Diane-35 contains 35 μg of ethynylestradiol and 2 mg of cyproterone acetate. Any brand of pills with the same active ingredients as Diane-35 is suitable; known alternatives include Mileva-35 and Ginette-35. Missed doses: If the user remembers within the same day, take the pill(s) immediately. If it is more than a day, continue the regime as usual. Do not use this regime for people ≥ 35 years old or with a propensity for thrombosis. References: Lübbert et al. (1992), personal exprience of the author and reports of other transsexuals (through private communication with the author).

3.3 Anti-androgens
Anti-androgens work by interfering with at least one step of the hypothalamus-hypophysis-gonads system or by preventing androgens from acting on the androgen receptor by competitive inhibition (silent antagonist). More specifically their mechanism of action may be classified as follow (categories are not mutually exclusive):
  • Progestogens and estrogens suppress release of gonadotropins by the hypophysis exploiting the natural negative feedback that sex hormones excert upon the hypophysis.
  • GnRH analogues activate GnRH receptors continuously (in contrast to endogenous GnRH which is released intermittently). Initially this causes a surge of testosterone but after approximately 7 days levels reach the same as pre-treatment and thereafter continue to decrease until testosterone is effectively supressed (van Poppel, Nilsson 2008).
  • GnRH receptor antagonists suppress activation of GnRH receptors by endogenous GnRH. Unlike GnRH analogues, GnRH receptor antagonists do not create an initial testosterone flare.
  • Androgen receptor inhibitors inhibit the action of all androgens by binding to the androgen receptors without activating them, thus preventing androgens from binding and activating those receptors. Examples include bicalutamide, flutamide and nilutamide.
In cases other than when using androgen receptor inhibitor the suppression of androgenicity can be evaluated by total testosterone levels. We recommend to aim at a level of free testosterone ≤ 1.0 nmol/l. This is lower than the upper reference value for cis women and achieveable with the regimes mentioned in this aricle. When an androgen receptor inhibitor is used the level of circulating testosterone is not indicative of androgenic activity.

3.3.1 Algestone acetophenide
Algestone acetophenide (a.k.a. dihydroxyprogesterone acetophenide, DHPA) is a progestogen. Like other progestogens it is an anti-androgen through suppression of synthesis of endogenous androgens. The first description of algestone acetophenide seems to be in Fried (1960) where it is referred to as “acetophenone derivative of 16α,17α-dihydroxyprogesteroneâ€. According to Recio et al. (1986), the first to employ algestone acetophenide as an human anticonceptive was Taymor et al. (1964).

Lerner et al. (1961) examined the effect of of algestone acetophenide administered orally and parenterally in rats. They found it to be a strong progestogen without androgenic, estrogenic nor corticoid activity. They found that it has a long duration of action, continued up to 25 days after injection. This study did not invetigate pharmacokinetic parameters. A possible point of confussion is that this paper states that no anti-androgenic activity was found. By this it is meant that algestone acetophenide did not inhibit the direct action of androgens in target tissue, not that it is not an anti-androgen in the sense used in this article.

Newton (1994) reviewed the high-level clinical aspects of algestone acetophenide and other progestogens used as anti-conceptives in cis women.

3.3.2 Cyproterone acetate
Cyproterone acetate (common abbreviation: CPA) is the anti-androgen par excellence for male to female hormone replacement therapy (MTF HRT). CPA is a progestogen. Like other progestogens, it suppresses secretion of gonadotropins and thus of gonadal androgens. Additionally it acts as a partial agonist of the androgen receptor. See Neuman (1994) for an account of the development and pharmacology of cyproterone acetate and of progestogens in general. Another review of the pharmacology of progestogens is Schindler et al. (2013).

CPA must be combined with an estrogen for effective suppression of testosterone. Toorians et al. (2003) found that 100Â mg/d of CPA without an estrogen was not enough to suppress testosterone in biological males (average level in group that received 100Â mg/d of CPA only: 8.1Â nmol/l). Tack et al. (2017) found that after 1 year of treatment with 50Â mg/d of CPA without an estrogen the level of free testosterone was not properly suppressed (average: 7.84Â nmol/l). In a group with dose of oral estradiol increasing up to 1Â mg/d they also found insufficient suppression of testosterone after 1 year at which this was the estrogen dose (average: 5.82Â nmol/l). Fung et al. (2017) found that a dose of 25Â mg/d along with oral estrogens is sufficient to suppress testosterone in MTF transsexuals to below cis female levels. In a group that received 25Â mg/d of CPA with different oral estrogen dose (average ~3Â mg/d) the free testosterone concentration was 0.9Â nmol/l.

Summary of levels of total testosterone achieved with CPA
DescriptionReferenceTotal testosterone100Â mg/d of CPA onlyToorians et al. (2003)8.1Â nmol/l50Â mg/d of CPA only, after 1 yearTack et al. (2017)7.84Â nmol/l50Â mg/d of CPA with increasing oral estradiol up to 1Â mg after 1 yearToorians et al. (2003)5.82Â nmol/l25Â mg/d of CPA with ~3Â mg/d oral estradiolFung et al. (2017)0.9Â nmol/l

3.3.3 Medroxyprogesterone acetate
Medroxyprogesterone acetate (common abbreviation: MPA) is an anti-androgen of the progestogen class. It is commonly available as solutions for depot injections and oral tablets. Johanson et al. (1986) investigated the pharmacokinetics of MPA on humans via oral intake. They found a half-life of 40Â h to 60Â h.

3.3.4 Spironolactone (not suitable)
Spironolactone should not be used as an anti-androgen and is mentioned here only as an advertence.
Spironolactone is a mineralocorticoid duiretic with weak progestogen activity which has been misused as an anti-androgen, especially in the United States. Liang et al. (2018) found that a HRT regime of oral estradiol and spironolactone failed to supress testosterone in the top quartile of biological males per pre-treatment level of testosterone. Leinung et al. (2018) found that estradiol alone suppresses testosterone better than if combined with spironolactone.

3.4 Estrogens
The main estrogens in cis women are estradiol, estrone and estriol, of which estradiol is the most potent. The commonly used estrogens for MTF transsex people are estradiol (17β-estradiol), 17β-esters of estradiol and ethynylestradiol. The reader interested the in pharmacodynamics, pharmacokinetics and structure-activity relationship of estrogens is recommended to consult Oettel et al. (1999a, 1999b).

Leinung et al. (2018) studied the effect of estradiol alone, with spironolactone, and with finasteride on estradiol and testosterone levels. They found that oral estradiol slightly suppresses androgens. However, they found that administering estradiol together with either spironolactone or finasteride increases the level of testosterone compared to the same dose of oral estradiol alone.

3.4.1 Ethynylestradiol
Ethynylestradiol is an estrogen obtained by subtituting an hydrogen atom at the 17α position of estradiol with an ethynyl group. The name “ethinyl estradiol†can also be found in the literature to refer to the same compound; we regard that name as incorrect becuase the name of the functional group is “ethynylâ€, not “ethinyl†and functional groups in subtitutive nomenclature are written without a separating space (example: “chlorobenzeneâ€, not “chloro benzeneâ€).

Kuhl (2005) found that ethynylestradiol is 120 times as potent as estradiol compared on a mass basis, oral administration. Note that an higher potency is not indicative that the substance is more effective, only that a lower dose will be required for a similar effect.

Oral ethynylestradiol is effective in suppressing testosterone. Lübbert et al. (1992) found ethynylestradiol only to be effective in reducing gonadotropins and testosterone to below-castrate levels in an experiment done in a single healthy male. This suggests that when an high-enough dose is used for MTF HRT no additional anti-androgen is needed. Shearer (1973) found that 100 mg/d of ethynylestradiol only, split in 2 doses per day lowered total testosterone to around 2.6 nmol/l in prostate cancer patients; no number is given, this is an estimate of the mean of the data in the graph.

Jain et al. (2006) report Kd(ethynylestradiol-human ERα) = 2.0 nmol/L, Kd(ethynylestradiol-human ERβ) = 8.1 nmol/L. In chapter 35 “Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens†of Oettel et al. (1999b) cite a mean oral availability for ethynylestradiol of 45 % and a half-life after intravenous administration between 6.8 h and 26.1 h varying among the primary studies included. The pharmacokinetics after oral administration are complicated; the chapter says “The time course of EE plasma levels following oral administration can be described, in most cases, by a two-compartment model. A rapid distribution phase is followed by a terminal disposition phase that is characterized by a half-life in the range of about 5 h-30 hâ€. Toorians et al. (2003) compared head to head the effects of CPA alone, CPA with transdermal estradiol and CPA with oral ethynylestradiol on circulating estradiol, testosterone, coagulation factors and gonadotropins.

3.4.2 Estradiol esters
17β-esters and occasionally 3-esters of estradiol are the common active compounds used for depot injection; these are pro-drugs that are convereted to estradiol within the body. The longer the ester chain, the slower the pharmacokinetics (longer time to peak dose and longer half life). Oriowo et al. (1980) compared the pharmacokinetics of 3 esters of estradiol administered as intramuscular depot injections with arachis oil as the carrier. They found the time to peak blood concentration as follows: estradiol benzoate: 1.8 d, estradiol valerate: 2.2 d, estradiol cypionate: 3.9 d. Garza-Flores (2014) compared the pharmacokinetics of 3 esters of estradiol again administered as depot injections. He found the time to peak blood concentration of estradiol to be as follows: estradiol valerate: 2 d, estradiol cypionate: 4 d, estradiol enanthate: 6.5 d, 8.1 d (the 2 numbers are for different medical centers).

In chapter 35 “Pharmacokinetics of Exogenous Natural and Synthetic Estrogens and Antiestrogens†of Oettel et al. (1999b) were reviewed the pharmacokinetics of estradiol via oral administration. The chapter cites a half-life of 1.7 h and 5.5 % bioavailability in young cis women for estradiol administered orally.

3.5 Selective estrogen receptor modulators
In a study on old post-menopausal women (56 to 66 years old) Francucci et al. (2005) found that raloxifene causes a change towards a female pattern of fat distribution.

3.6 Prolactin
Prolactin is an endogenous protein secreted by the hypophysis. Prolactin promotes the secretion of milk. Dopamine receptor agonists like cabergoline, bromocriptine and pramipexole can be used to reduce prolactin.

4 Melanogenesis inhibitors (skin, hair and eye whitening agents)
Statistically, women tend to have a lighter skin color than men. Given that skin color is sexually dimorphic to some degree, and a ligher skin color is more aesthetically desirable, skin whitening is a complement –not a substitute– for manipulaion of one’s primary sex hormones. Anecdotally, many transsexuals (including the author) with light skin report to have experienced further lightening concurrent with starting HRT. It can be conjectured that HRT has overall a skin whitening effect, but it could also be attributed to confounders (i.e.: spending more time indoors and under shadow). See the companion article “Pharmacological control of skin, hair and eye pigmentationâ€.

5 Conversion factors
There are 2 systems in widespread use to express concentration of substance in biological systems. One is mass concentration, expressed in units of mass per unit of volume. The other is amount of substance concentration, expressed in units of amount of substance per unit of volume.

Substance    Molar mass   Equivalence
Estradiol    272.4 g/mol  1 pg/ml ↔ 3.671 pmol/l
Progesterone 314.5 g/mol  1 ng/ml ↔ 3.180 pmol/l
Testosterone 288.4 g/mol  1 ng/dl ↔ 0.034 67 nmol/l
Conversion factors for select sex steroids measured in blood tests

When estradiol or estradiol esteres are administered as depot injections, we assume 100Â % bioavailability and complete cleavage of the ester group in estradiol esters. The relative potency is the total mass of estradiol released divided between the mass of the substance injected. For example, injectiong 10Â mg of estradiol results in 10Â mg of estradiol being released. Injecting 10Â mg of estradiol enanthate results in 7.08Â mg of estradiol being released. Note that this is not a direct equivalence, because the pharmacokinetics are different. This data is not directly applicable to oral delivery because different substances can have different availability.

Comparative potency of estradiol and esters used for depot injections
Substance           Relative potency
Estradiol           1.000
Estradiol Cypionate 0.687
Estradiol Enanthate 0.708
Estradiol Valerate  0.764
6 Hypodermic needles
Gauges of hypodermic needles used for intravenous injections, intramuscular injections, subcutaneous injections, blood extraction and local anesthesia infiltration are listed below. Outer diameters and colors are from Indian Standard IS 16004 which is equivalent to ISO 6004. Thicker gauges are standardized but not commonly used for these purposes; consult the standard for the full list.

Standard outside diameter of hypodermic needles
Outer diameter (mm)  Gauge number  Color
0.30                 30            Yellow
0.33                 29            Red         
0.36                 28            Blue-green
0.40                 27            Medium grey
0.45                 26            Brown
0.50                 25            Orange
0.55                 24            Medium purple
0.60                 23            Deep purple
0.70                 22            Black
0.80                 21            Deep green
0.90                 20            Yellow
1.10                 19            Cream
1.20                 18            Pink
7 References
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  14. N. Jain et al. (2006) “Novel Chromene-Derived Selective Estrogen Receptor Modulators Useful for Alleviating Hot Flushes and Vaginal Drynessâ€. DOI: 10.1021/jm060353u, (supporting information).
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  24. F. Neuman (1994) “The antiandrogen cyproterone acetate: discovery, chemistry, basic pharmacology, clinical use and tool in basic researchâ€. DOI: 10.1055/s-0029-1211261.
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Practical considerations about transsex transitioning

“Am I trans?”
A common question in trans venues is “Am I trans?”. This question is always mislead. Being transsex is defined by undergoing a treatment to alter one’s sexually dimorphic traits towards the other sex. This is a decision one makes, not something one discovers (except for a few possible but very far-fetched scenarios). However, one may discover one’s desire to be or look like a girl/woman. One may also may discover that one has sex-based dysphoria, that is, the dislike of one’s sexually male dimorphic traits.

We will refer to sex-based dysphoria as “dysphoria” for short. Dysphoria is neither a sufficient nor necessary condition to be transsex. One could have sex-based dysphoria and choose to not to transition (that is, repressing), being dysphoric but not transsex. One could strongly desire to look like a woman or be a woman without having any particular dislike of one’s current sexually dimorphic traits. One could choose to transition because of rationally arriving at the conclusion that female sexually characteristics are preferrable.

“B-but I do not feel like a woman”
One does not need to feel like a woman or in some loose sense “be a woman on the inside” to be transsex. If taken as a descriptive statement, it is factually incorrect, as there are many trans women who did not feel like a woman pre-HRT and the vast majority of trans women were males with the usual male anatomy and male physiology previous to transition (that is: had primary and secondary male sexual characteristics). If it is taken as a prescriptive statement, the author strongly disagrees with it. The physical aspect of transition is body modification. It is one’s body what is at stake, so it is one who has the moral right to decide freely on it. We do not require that bodybuilders have a history of feeling dysphoric for not being muscular since they are kids, nor a diagnosis for “wimp dysphoria” before they are allowed to bodybuild. All the justification they need is “I want to be a bodybuilder”, and they only have to justify this endeavor to themselves. Why would physical transition need any more justification? It doesn’t.

All that is needed to transition is to want to transition. The belief that physical transition should be a decision taken by other people based on their opinions instead of taken by oneself based on one’s own judgement is merely a product of brainwashing by the medical establishment (see Gatekeeping and DIY below).

Physical transition and social transition
Social transition is the process of presenting as a woman to society (here “presenting as a woman” means following some or all the customs specific to women). It must be distinguished from physical transition. Many MTFs choose to socially transition but note that it is possible and perfectly fine to physically transition without any type of social transition. The converse is not true.

A few very lucky biological males pass as women without HRT, but those people should take HRT or else they will masculinize in the spawn of a few years, losing their natural femininity. Men that present as women without physically transitioning are not trans women, even if they pass; they are transvestites.

Trans people who do not pass should not socially transition nor present female in any way. First, there is nothing to be gained in demanding that people refers to one as a woman if one does not pass. Being referred as “she” does not make one a woman. Second, there is no point in wearing women’s clothes if one does not look female or at the very least, female-leading androgynous. Women’s clothes are for people with female bodies (i.e.: cis women and passing MTFs).

Women’s clothes complement the person’s femininity but do not compensate for a lack of femininity; they can be thought of as salad dressing: they only make what is good, better. A non-passer wearing women’s clothes or demanding to be referred to as a woman is an extremely unsightly abomination, like foul smelling and tasting food that has a lot of dressing to try to compensate and like an unclean bathroom that has a lot of deodorant added to try in vain to mask the foul smells. Non-passers who present as women contribute to the public perception that trans women are gross transvestite men and thus to transphobia. Worse, they make some people who want to transition, repress, because they infer that this is what they would end up as. For these reasons, trans communities and individual transsexuals should disavow non-passers who present as women.

Gatekeeping and DIY
Imagine you want a particular wall in your house painted green. You hire a painter. He tells you that first you have to pass a test that the current color of your wall causes you distress. Then, you can only have a green draper put over the wall for 1 year as a “real life experience” and only then, grudgingly, he finally paints your wall green, but it is the shade of green he wants, not the one you asked for, even though you’re the one paying and supposedly it is a service for you. If you dare object and say that you can paint your own wall, the painter will get indignated and admonish you for contemplating doing such a thing. “I am a painter, I know what I do and I know what is the best color for this wall; panting your own walls is dangerous. You should only have your walls painted by a painter.”.

Isn’t the above history absurd? Most health care workers are exactly like this hypothetical painter. Every other professional knows that if you hire him, it is to do a job that you have determined you want done, and not to question your motives. Only health care workers wrongly feel entitled to override your decisions and to treat you like their subordinate. Thus, it is generally better to do it yourself (DIY) i.e.: self-medicate and oversee one’s own physical transition. All the required information to physically transition is available in the Internet, mostly in web sites dedicated to sharing academic information. This web site contains various links to such web sites and a compilation of relevant scientific papers and books as a starting point. In any country with sane legislation (which is very few), HRT medication is over the counter. Where that is not the case, HRT can be bought without prescription in many online pharmacies (see links in the main page).

I want to keep using my penis
That is fine. Vaginoplasty (often miscalled “sex reassignment surgery”) is entirely optional. If you want to preserve erectile function, make sure to have a full erection at least once every 7 days; this will preserve voluntary erections and prevent atrophy. Note: The recommendation of 7 days is based on the author’s personal experience and informal reports from other transsex people conveyed via personal communication.

Can I hide that I have breasts?
Yes. Transsex people typically grow small conical breasts. You can hide them easily using loose clothes.


  1. 1 The Alinist-Ksenist Manifesto
  2. 2 The mindset for a smooth and successful transition
1. The Alinist-Ksenist Manifesto
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The sexes are not equal, each has its virtues and flaws. The main virtue of the male sex is its sheer reasoning power. In the past, the strength of the male was an advantage. 1000 years ago, if a rock was to be lifted, all the energy required for lifting it had to come from beasts or –from what amounted to the same– men. Now we have machines stronger than the strongest man or team thereof that can be assembled. In the few activities where human strength is an advantage, this signals the need for more technological development, for it is precisely those activities the ones that should be performed by machines, so that humans are freed for more worthy endeavors. The female body is beautiful with its fine facial features, graceful curves, soft and pale skin, and dainty hands, arms, legs and feet. The male body is ugly and insensitive; indeed, it had to be given the tasks that were required from it before automation. The female body can afford to be delicate and sensitive. It is freed from the duty of physical work, and thus it can afford to be beautiful.

Women’s bodies are made to be admired and pleasured. Men’s bodies are made for physical work.

Machines can be made strong easily, but they are only useful if they can apply force under the right conditions. To design and program them, an intelligent being capable of solving abstract problems is required. Machines are also capable of an immense power of computation when expressed in simple arithmetic and control flow directives. This can be put to applications to perform complex tasks by decomposing them into an unimaginable number of such simple operations (like rendering an HTML document that talks about the philosophy of transsexualism, or prove theorems) but doing so is hard, and requires both creativity and some ability to think rigorously. The contemporary male thus finds herself with a mind perfect for her time, but with a body that is well into its obsolescence and falling into irrelevance. Worse, she find herself charged by the price of a body evolved for tasks that are no longer relevant and she will not perform including among others, the burden of a thick skin that can endure abuse but can not enjoy the orgasmic pleasure of even something as simple as caresses.

But the male is also an inventive and curious creature. Her kind has found an almost magical substance capable to free herself from the slavery of a body designed for work: It is female hormones.

Behold! I teach you the way of the superhuman.

Transsexualism is a form of self-improvement. We are biologically male, or at least, we begin that way. We are attracted to women, but love women and femininity beyond simple sexual attraction. We modify our bodies using modern pharmacology (and sometimes surgery) to adopt the desirable traits of women, in specific, secondary sexual characteristics, while preserving those traits of men that are worth preserving. The sheer intelligence of men, the tact of a woman; the tall and slender body of a man, the graceful features of a woman; the courage of a man, the peacefulness of a woman; the stoicism of a man, the empathy of a woman. Obsolete no more, by means of transsexual transitioning, the now estrogenized male has upgraded herself to the best of both sexes and thus overcomes the weaknesses of both male and female.

We also call the result a trans woman. Men and women, male and female, are in the most strict sense defined by anatomy and physiology, thus “trans women” should be taken as idiomatic or allegorical if we are not to incur in absurdities. Notwithstanding that the upgraded male is still a male according to a rigorous interpretation, we find it appropriate for heuristic purposes to describe and refer to her as a woman. Although not necessary, it is recommendable that the trans woman dresses like any other woman would, using clothes designed to emphasize her new feminine beauty. To say she is a man would be as true as it is misleading. She looks like a woman, she smells like a woman; she behaves like a woman. Indeed, she may adopt the name and voice of a woman as an acknowledgment of her inspiration. She deserves to be treated as a woman at least as much as any other woman does. Indeed, the trans woman has more of a claim to womanhood than those women by birth who neither learn, practice, nor care about femininity and womanhood, because she has earned her femininity several times over with her blood, sweat and tears.

Imitation is the highest form of flattery.

2. The mindset for a smooth and successful transition
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The focus of transitioning should be on changing your secondary sexual characteristics (hormones, surgery, etc.). You should regard it as a body modification similar to “body building”. This is the only sensible approach if you value your social life, integrity, and self-respect.

If you believe that there is an “innate gender” which is unrelated to biology or society then you will inevitably create social problems for yourself. People might understand that one might want to be (or look like) a woman, but almost everyone takes “born in the wrong body” as a joke —especially if you were not previously flamboyant. If you do not look and are socially regarded as a woman, claiming that you are a woman in the inside and that people should respect your innate gender regardless of how you look is meaningless and futile. This at best makes people pity you and at worst makes them mock and bully you. The situation worsens if you dress in women’s clothing but still look like a man. This should be avoided first and foremost out of self-respect, and second out of respect for fellow trannies. You will also hurt yourself for thinking that people do not treat you the way you should be treated.

So what is the solution? Easy, just take your pills. You will eventually start to get weird looks and occasional “ma’am”s. That should be your cue to allow yourself to dress and act more feminine. But if you want to be fully socially regarded as a woman, then you should look like one. For most people hormones might not suffice. At that point you should seek cosmetic facial surgeries (“FFS”). As you look more feminine, dress more feminine, act and sound more feminine, people will regard you as such. You will not have to “come out” and make a fool out of yourself. The transition will be smooth and you will not be going against the grain. Most people in the street will not know anything; they will either see you as a man, feminine male or a woman depending on your stage of transition. Nobody will bother you outside, even if you are not in a liberal country. The only possible problems can come from your family, but that would depend on each person. But regardless, I can assure you that your family will receive “I am working on looking more feminine” much better than “I am a woman inside, my name is Taylor now, pronouns she/her.”.

In conclusion, chemically feminize yourself, dress appropriately at each stage of transition and be honest. Do not be a fool.


Miscellaneous information and links
  1. 1 About 17beta
  2. 2 Technical
    1. 2.1 Units of measurement
    2. 2.2 Electricity
    3. 2.3 Mathematics
    4. 2.4 Other
  3. 3 Wisdom
  4. 4 Entertainment
    1. 4.1 Works of fiction
1. About 17beta
The web site came online 2018-12-03; the first page was the one about pharmacology. On 2019-08-15 we moved most pages to We assign IRIs with care that they will not break and leave dangling links; see

2. Technical

2.1. Units of measurement
Everybody should know the basic principles of the SI –known popularily as the metric system. It is useful to communicate physical quantities day to day, and absolutely necessary in scientific contexts. The SI is not just yet another set of units; instead, it is the rationally designed systems of units of humanity. In specific, it includes a coherent subset of units. Here coherent means that there are no arbitrary conversion factors. The numerical value equations have the same form as the corresponding physical equations. Even the non-coherent units are related to each other and the coherent subset by powers of 10 which makes it trivial to do conversions mentally by shifting the radix point.

British Imperial and US customary units are obsolete and inacceptable. They involve many base units for the same dimensions with arbitrary ratios; for example 1 mile is equal to 5280 foot; the number 5280 has no physical significance. Moreover, composition of the named units with algebra results in units that conflict with the named ones. E.g.: 1 horsepower is equal to 550 foot-pound-force per second. Once again, the number 550 has no physical significance. These arbitrary conversion factor add clutter to formulas, distract from the physical meaning (especially among laypeople) and have to be memorized without any benefit.
2.2. Electricity
We speak of electric charges, electric currents, and so on. What is electricity? In the times of Maxwell, it referred to what we now call electric charges. Now it is used as a prefix to describe concrete concepts, but there is no single concrete physical phenomenon called “electricity”. The flow of charge is electric current. The separation of charge in a capacitor is called its charge.

2.3. Mathematics
  • “Introduction to Mathematical Logic”, 5th edition by Bert Mendelson can be recommended by the author. It is suitable for mathematicians new to formal logic (incl. set theory) and very motivated laypeople.
  • “Foundations of Analysis”, 3rd edition by Edmund Landau constructs the real numbers from the natural numbers (which is a part of the foundation of mathematics often handwaved by analysis books). It is a remarkable book for being very basic and having no formal prerequisites and at the same time very dense and impossible to understand intuitively without mathematical rigor.
  • “A course in number theory and cryptography”, 2th edition by Neal Koblitz: Exactly what it says on the title. It focuses on public key cryptography and includes a chapter on elliptic curves.
  • Metamath is a very simple proof assistant. It includes proofs with absolute rigor of a non-trivial part of mathematics. Most proofs are manually-generated and suitable for human reading.
  • HOL4 is a fully-fledgled proof assistant based on higher order logic, on which significant theories have been mechanized. It is highly extensible and suitable for use with automated theorem provers.
  • “Thousands of problems for theorem provers” (TPTP) is a collection of problems for automated theorem provers in a standard format. Associated with TPTP are regular competitions of automated theorem provers, under the name of CASC.
  • “The international SAT Competitions web page” contains links to the yearly competitions of boolean satisfiability solvers, which is a specific and solvable case of automated theorem proving.
  • “The Quantified Boolean Formulas Satisfiability Library”: Similar to the previous, but about solvers of quantified boolean formulas.
  • “E”: An automated theorem prover. As of 2019, it is overall the best free software prover for first order logic.
  • A home page for New Foundations set theory.
  • Information about overlooked and commonly misexplained physical phenomenon.
2.4. Other
3. Wisdom
“Poor are those people that only have money.” —Spanish-language proverb.

There once was a factory of shoes that wanted to expand their market. They sent a shoe seller to an undeveloped country in Africa. The seller immediately returned back and reported total failure; nobody here wears shoes”. The company manager fired him, and sent his best shoe seller who did not disappoint. He reported back in a telegram “Excellent news! Nobody here wears shoes yet. I will be selling these in a heartbeat. Ship more crates of shoes!”.

4. Entertainment
4.1. Works of fiction


Glossary of transsexualism
Unless otherwise stated, all the terms below are given definitions valid in the context of MTF transsex.
  • AGP: Autogynephilia.
  • Alinism: The philosophy of choosing to be transsex as a form of self-improvement along with the pursuit of virtue by combining the best traits of the female sex and the male sex and acknowledging with pride that one is a male who has improved herself and lives in the image of a woman (if applicable), not a woman in the literal sense. Named after Alina Devis/Kožuhova. The philosophy of this web site.
  • analloerotic: (morphemes: an-allo-erotic, NOT anall-o-erotic!) A person who does not experience sexual attraction to other people. This says nothing of whether the person has a libido, masturbates, etc.
  • androphilic: A person (of any sex) attracted towards men or people who look like men. This tells nothing of whether the person is attracted to women.
  • asexual: A person who has no interest in participating in any sexual activity and does not experience sexual desire nor attraction. Note: The term is often misused as a synonym of analloerotic. This is incorrect. From the etymology, a-sexual, “asexual” describes somebody who is not sexual, which is a stronger condition that not experiencing sexual attraction to other people (analloerotic).
  • autogynephilia: (1) The propensity of a biological male to be sexually aroused at the thought of herself as a woman. (2) A category of transsex people in the Blanchard’s pseudoscientific typology. Note: The use of this term is discouraged because of its association with Blanchard’s pseudoscientific typology. Instead use FESF or self-eroticism when appropriate.
  • bica: Bicalutamide, an anti-androgen of type competitive androgen receptor inhibitor.
  • boymoder: A MTF who presents like a man (that is, with men’s or unisex clothes, a male voice, using male grammar, et cetera). Sometimes humorously spelled “boymodding” (with 2 ‘d’s) or even “boy modding”.
  • cishon: A cis woman who looks more like a hon than a woman.
  • clocking: Discovering that a person is a trans woman (if she tells that she is trans, that does not count as clocking).
  • conetits: Breasts with a conical shape as opposed to a rounded shape resembling an hemisphere.
  • CPA: Cyproterone acetate, a progestogen and anti-androgen.
  • Diane-35: A brand name of pills of ethynylestradiol and cyproterone acetate. The same active ingredients are available under other brands like Mileva-35 and Ginette-35.
  • E: (1) Estradiol. (2) Any estrogen.
  • E1: Estrone.
  • E2: Estradiol.
  • E2V: Estradiol valerate.
  • EE: Ethynylestradiol.
  • egg: Informal term for a cis person who desires to transition but is not fully aware of this desire and is repressing it.
  • FESF: Female embodiment sexual fantasy. A sexual fantasy centered around the person being a woman. Can be used to describe a person of any sex.
  • gatekeeper: A person who has the power to control, authorize or deny access to a product or service (usually HRT) and uses that power to enforce access according a standard. The term “gatekeeper” is usually used with the connotation that such a standard is unjustified. In more mundane words: A gatekeeper is somebody who controls access to something you want and demands that you meet his personal standard in order to give it to you.
  • girlgasm: An orgasm that is felt through a big fraction of the body or through the whole body instead of the sensation being localized in the genitals or stimulated area.
  • girlmoder: A MTF who presents like a woman (that is, wearing women’s clothes, using a female voice, using female grammar, et cetera).
  • GRS: “gender reaffirmation surgery”, a misnomer for vaginoplasty in case of MTFs
  • girl pills: Informal and affectionate term for HRT pills.
  • gynephilic: A person (of any sex) attracted towards women or people who look like women. This tells nothing of whether the person is attracted to men.
  • hon: (1) Informal term for a man who dresses as a woman and demands to be referred and treated as a woman despite looking patently as a man in women’s clothes. (2) Informal term for any trans person who does not pass, used with a depreciationg connotation.
  • hugboxing: (1) Telling a non-passing MTF that she passes compliments not based on reality. Example: Telling a hon “You go girl; you look gorgeous!”. (2) In general, telling nice things that are not justified on reality.
  • hurtboxing: Opposite of hugboxing. Telling a passing MTF that she does not pass or telling her anti-compliments not based on reality.
  • HRT: Hormone replacement treatment. In the context of transsexualism: Using pharmaceuticals to cause feminization in biological males or masculinization in biological females.
  • informed consent: A model of gatekeeping trans people where they are given HRT or trans-related surgery under the condition they sign legal paperwork and follow the treatment prescribed by a doctor instead of allowing them to buy the medication directly and to take care of their own physical transition.
  • Lupron: Brand name of leuprorelin, an anti-androgen of type GnRH receptor agonist.
  • MTF: (1) A male to female transsex person, i.e.: a biological male who takes female hormones to resemble women. (2) male-to-female as an adjective. Example: “MTF HRT”.
  • non-op: A transsex person who desires to keep her genitals unaltered, and thus not undergo vaginoplasty.
  • orchie: Orchiectomy, removal of the testicles.
  • P: Progesterone.
  • Pinkpill: To pinkpill somebody is to convice a cis biological male of taking HRT to improve her body or mind with female secondary sexual characteristics.
  • PIV: Penis-in-vagina sex.
  • psychopath: A person that does not feel empathy. Note that in the literature, the term “psychopath” is used in a very loose sense of psychopathy cluster.
  • psychopathy cluster: A loosely defined set of psychological traits that correlate with psychopathy and reinforce psychopathy or are reinforced by psychopathy.
  • post-op: A transsex person who underwent vaginoplasty.
  • pre-everything: A person who wants to be trans but has not begun transitioning. Pre-everythings are not trans yet, and should not be referred as such.
  • pre-op: A transsex person who has not undergone vaginoplasty. Used with the connotation that the person desires to have vaginoplasty in the future.
  • ralox: Informal name for raloxifene, a SERM.
  • RPM: Routine penis maintenance. Any procedure that causes a full erection with the purpose of preventing penile atrophy.
  • SERM: Selective estrogen receptor modulator. SERMs are a class of pharmaceuticals that act as nuclear estrogen receptor agonists in some tissue and nuclear estrogen receptor antagonists in other tissue.
  • spiro: Spironolactone, a duiretic with weak anti-androgenic action often misused as an anti-androgen.
  • SRS: “sex reassignment surgery”, a misnomer for vaginoplasty in case of MTFs.
  • stealth: A transsex person who presents to society pretending she is a cis woman. In other words, a trans woman whose social live is as if she were a cis woman instead of telling she is trans.
  • T: (1) The group of all transsex people. Example: “T does not belong with LGB because T is not about sexual orientation”. (2) Testosterone.
  • titty skittles: Informal and affectionate term for HRT pills.
  • tranny: Affectionate shortening of “transsexual”. Analogous to “Australian”→“Aussie”.
  • transmedicalism: The posture that transsexualism is a mental illness and should be treated within institutionalized medical care (not the view of this web site!).
  • transbian: Informal term for “trans lesbian”. A MTF who is exclusively gynephilic.
  • transgender: A delusional person who identifies (sic) as something different that the sex he/she is. Whereas transsexualism is about changing one’s sexually dimorphic features to actually resemble the other sex, transgenderism is about the notion that one can be a woman in an extremely vague sense of “gender” disconnected from factual reality that instead depends only on feelings. Some transgender people are also transsex, but the concepts should not be confused and any similarity is only superficial.
  • trans woman: Affectionate term for MTFs. As used in this web site, the term “trans woman” does not carry the implication that the person is literally a woman.
  • twinkhon: Informal term for a MTF who does not pass but nonetheless looks youthful, feminine and cute. When used to refer to others, usually it has neutral or affectionate connotations. When used to refer to oneself, usually it has self-depreciating connotations.


Pharmacological and physical control of skin, hair and eye pigmentation#
First version: 2019-10-13
Last update: 2020-08-21

Persistent link to latest version:



The main substance responsible for skin, hair and eye pigmentation is melanin. We review the biochemical pathways of the endogenous synthesis of melanin and agents known to target these pathways. We address both common agents present in commercially available skin whitening creams and agents that despite not being in widespread use for this purpose have been found to decrease pigmentation, often serendipitously as a salient side effect.

Keywords: skin whitening, skin lightening, skin bleaching, hair lightening, eye depigmentation, eye lightening.

  1. 1 Overview
  2. 2 Discovery and design
  3. 3 Mechanism of action
    1. 3.1 Inhibition of the activity of tyrosinase
      1. 3.1.1 Irreversible tyrosinase inhibitors
      2. 3.1.2 4-Butylbenzene-1,3-diol
      3. 3.1.3 Thiazolylresorcinol-based compounds
    2. 3.2 Inhibition of the expression or activation of tyrosinase
      1. 3.2.1 The MC1R receptor and cAMP
    3. 3.3 Preventing the transfer of melanosomes to keratinocytes
      1. 3.3.1 Protease-activated receptor 2 (PAR2)
      2. 3.3.2 Keratinocyte growth factor receptor (KGFR)
    4. 3.4 Chemically-induced vitiligo
      1. 3.4.1 Benzene-1,4-diamine
      2. 3.4.2 4-(Benzyloxy)phenol
      3. 3.4.3 4-tert-Butylphenol (4-TBP) and 4-tert-butylbenzene-1,2-diol
      4. 3.4.4 Imiquimod
      5. 3.4.5 4-Methoxyphenol
      6. 3.4.6 Olapatidine
      7. 3.4.7 Rhododendrol
      8. 3.4.8 Other agents
    5. 3.5 Inhibition of tyrosine kinases
      1. 3.5.1 Cabozantinib
      2. 3.5.2 Dasatinib
      3. 3.5.3 Imatinib
      4. 3.5.4 Masitinib
      5. 3.5.5 Pazopanib
      6. 3.5.6 Sunitinib
    6. 3.6 Directly destroying existing melanin
    7. 3.7 Serotonin signaling
  4. 4 Other agents causing hair lightening
    1. 4.1 Green hair
  5. 5 Eye lightening
  6. 6 Notes
  7. 7 References
1 Overview
Variation between individuals in skin color, hair color and eye color are mostly due to varying amounts of the dark-colored polymers called generically “melanin”. Pigments acquired through food and embedded within the skin and also blood vessels play a minor role.
There exists a big set of substances known to inhibit the pigmentation of skin with melanin which we call “melanogenesis inhibitors”. There are several mechanism of actions of melanogenesis inhibitors. The molecular pathway of melanogenesis is well-understood; a detailed treatment is outside the scope of this article. For a review of inhibitors of melanogenesis, see Pillaiyar et al. (2017), Chang (2012), Callender et al. (2011), Ebanks et al. (2009), Briganti et al. (2003) and Searle, Riley (1990).
Several products are commercially available for skin whitening; some are taken orally or injected and have a systemic effect; others are topical. Only agents known to be commercially available for systemic effect are mentioned in the following list.
Higa et al. (2000) found that very high doses of the tyrosinase inhibitor kojic acid increases thyroid function in an assay with rats.

2 Discovery and design
Melanogenesis inhibitors have been discovered and developed through several methods, including: screening of synthetic chemical libraries (high throughput screening is occasionally used), screening of plant extracts (Chang et al., 2009a) computational (in silico) search (Choi et al, 2016; Ai et al., 2014), found as a side effect of previously known drugs (Baek, Lee, 2015; Choi, Jee, 2015; Wang et al., 2014; Espín, Wichers, 2001) and exploration of structural analogues of previously known tyrosinase inhibitors (Quing et al., 2015; Yongfu et al., 2013) based on knowledge (in varying degrees) of their structure-activity relationship. Thus, the development and discovery of melanogenesis inhibitors illustrates many of the methods used in drug design. Laijis, Ariff (2019) reviewed the methods used to discover melanogensis inhibitors with a less detailed review of the mechanism of action. Some of the most potent competitive reversible tyrosinase inhibitors are synthetic compounds with a potency hundreds of times that of kojic acid.

3 Mechanism of action
Melanin is the main substance responsible for the color of the skin. Melanin is class of dark polymers generated by the body through the process of melanogenesis. Among the melanin pigmenting the skin and hair, 2 types can be distinguished based on its chemical composition and biological route of synthesis: the black/brown eumelanin and the red/yellow pheomelanin. The variation of skin color among individuals is mostly because of variation of the content of melanin in the skin. Skin with little or no melanin is almost white. Other factors influence skin color in a lesser degree, including the amount of blood in blood vessels (because of the color of blood), skin thickness and content of carotenoids in skin (Whitehead et al., 2012; Pezdric et al., 2015).

Melanin in synthesized in melanosomes which are organelles produced in melanocytes. Melanocytes are cells dedicated to this function that are present in the skin, hair follicles, and other structures of the body. The synthesis of melanin (also called "melanogenesis" and "melanization") involves a chain of enzyme-catalyzed chemical reactions and non-enzyme-catalyzed reactions. The chemical pathways of the synthesis of melanin has been described by many papers; however, it is often oversimplified. The following references are suggested: Kondo, Hearing (2011), Chang (2009) and Slominski et. al. (2004). The main precursor to melanin is L-tyrosine. The first step of melanogenesis is the conversion of L-tyrosine to L-DOPA; this is the first and rate-limiting step and is catalized by the enzyme tyrosinase (TYR) (Slominski et al. 2004, p. 1163). Other enzymes involved in the synthesis include tyrosinase-related protein 1 (TRP1) and tyrosinase-related protein 2 (TRP2); TRP2 is also known as “dopachorome tautomerase” (DCT). L-tyrosine is taken by the melanocytes from the intercellular medium, then transported to the melanosomes. L-tyrosine is also synthesized within the melanocytes from L-phenylalanine by the enzyme phenylalanine hydroxylase (PAH) (Slominski et al. 2004, p. 1164).
Melanosomes are transferred to keratinocytes (the most abundant cell type in the skin). Most of the melanin of skin is found in keratinocytes. Additionally, melanocytes interact with keratinocytes through chemical signaling. See § Preventing the transfer of melanosomes to keratinocytes.
Skin whitening agents work by reducing the presence of melanin in the skin. To accomplish this, there are several possible mechanism of actions (Ebanks et al. 2009) [1]:
  • Inhibition of the activity of tyrosinase: The catalytic action of tyrosinase is inhibited (slowed or nearly stopped) by the skin whitening agent.
  • Inhibition of the expression or activation of tyrosinase: The antimelanogenic agent causes that less tyrosinase is generated or that tyrosinase is not activated to its functional form.
  • Scavenging of the intermediate products of melanin synthesis.
  • Preventing the transfer of melanosomes to keratinocytes.
  • Directly destroying existing melanin.
  • Destroying melanocytes.
3.1 Inhibition of the activity of tyrosinase
Many tyrosinase inhibitors have been discovered or developed. Very many inhibitors of tyrosinase are known; most are of the reversible type [2]. For a review of tyrosinase inhibitors see Chang (2009a). Reviews of patents on tyrosinase inhibitors have been published (Sultan et al. 2016, Pillaiyar et al. 2015).

Upregulation of tyrosinase caused by tyrosinase inhibitors: Several skin whitening agents including some which are tyrosinase inhibitors have been found to cause an increase in the expression of tyrosinase (which by itself would increase melanin synthesis) (Gruber, Holtz 2013, Chang 2013).

3.1.1 Irreversible tyrosinase inhibitors
There are irreversible inhibitors of tyrosinase described in the literature. These have the potential to be very effective for skin whitening and hair lightening, to the point of virtually complete elimination of melanin. Some irreversible inhibitors are listed below.
3.1.2 4-Butylbenzene-1,3-diol
4-Butylbenzene-1,3-diol is a simple compound more often referred to in the pharmacological literature by the names “4-butylresorcinol” and “4-n-butylresorcinol”; these are systematic names. The preferred IUPAC systematic name is 4-butylbenzene-1,3-diol.
Kolbe et al. (2012) compared 4-butylbenzene-1,3-diol with hydroquinone and arbutin in in vitro human reconstructed skin and human subjects; they found that 4-butylresorcinol to be a far more potent inhibitor of melanogenesis than the other examined compounds. Garcia-Jimenez et al. (2016) found that 4-butylbenzene-1,3-diol is a substrate of mushroom tyrosinase. Lee et al. (2016a) found that 4-butylbenzene-1,3-diol increases proteolytic degradation of tyrosinase in vitro in an assay with B16F10 mice cells. Kim et al. (2005) found that 4-butylbenzene-1,3-diol reduces melanogenesis in Mel-Ab mice melanoma cells via direct inhibition of tyrosinase in concentrations at which it is not cytotoxic. Chaudhuri (2015) reviewed the safety and commercial uses of 4-hexylbenzene-1,3-diol, an analogue of 4-butylbenzene-1,3-diol that differes only in the length of the alkyl group. Astra, Oja (2019) determined experimentally the Antoine constants (from which the boiling point follow) for 4-butylbenzene-1,3-diol and related compounds.

3.1.3 Thiazolylresorcinol-based compounds
Mann et al. (2018a) screened a library of compounds for inhibition of human tyrosinase. They found thiamidol (PubChem CID: 71543007) was the most potent inhibitor among those examined of the competitive and reversible type, with a Ki of 250 nmol/l. Arrowitz et al. (2019) found that a cream with thiamidol was effective and well-tolerated in subjects with melasma. Mann et al. (2018b) examined the structure-activity relationship of Thiazolylresorcinol-based compounds.

3.2 Inhibition of the expression or activation of tyrosinase
Microphthalmia-associated transcription factor (MITF) is the master transcription factor that controls the expression of TYR, TRP1 and TRP2, MART1, PMEL17 and many other important proteins involved in the function of melanocytes [3]. Downregulation of MITF decreases melanogenesis and is a mechanism of action of some skin whitening agents (Chang 2012, Smit et al. 2009). As an heuristic rule, agents acting through downregulation of MITF are more likely to have side effects that selective tyrosinase inhibitors [4] Various signaling pathways and genetic mutations influence the expression of MITF [5].
Inhibitors of melanogenesis whose mechanism of action includes reducing the genetic expression of melanogenic enzymes include caffeoylserotonin (Kim et al. 2012), AP736 (Shin et al. 2015), pomegranate extract (Kang et al. 2015), betulinic acid (Jin et al. 2014) and finasteride (Seo at al. 2018). Yokoyama et al. (2008) found that some histone deacetylase inhibitors lower pigmentation in mice via supression of MITF expression.

3.2.1 The MC1R receptor and cAMP
The melanocortin 1 receptor (MC1R) is a transmembrane and G-protein coupled receptor expressed in melanocytes. MC1R is an important target for the regulation of melanogenesis (Chen at al. 2014; Rodríguez, Setaluri 2014; Yamaguchi, Hearing 2009). Agonism of MC1R increases the ratio of eumelanin to pheomelanin and increases the generation of melanin overall. Loss of function alleles of MC1R are correlated with pale skin, freckles and red hair. We conjecture that pharmacological inhibition of MC1R will increase the proportion of pheomelanin to total melanin thus giving hair a lighter and more reddish color.

MC1R/cAMP signaling pathway[6]: Activation of MC1R causes activation of adenylyl cyclase (AC), which produces cyclic adenosine monophosphate (cAMP), which activates protein kinase A (PKA), which activates (by protein phosphorylation) cAMP response element-binding protein (CREB), which upregulates MITF (CREB is a transcription factor of MITF). Whitening agents that interfere with the MC1R/cAMP signaling pathway have been reviewed by Chang (2012).
cAMP is degraded by phosphodiesterases (PDE). The PDE5 inhibitors sildenafil and vardenafil, the cAMP-promoter IBMX and 8-CPT-cGMP (a cyclic guanosine monophosphate (cGMP) analogue) increase melanin synthesis Zhang et al. (2012).
MC1R ligands. alpha-melanocyte stimulating hormone (α-MSH), beta-melanocyte stimulating hormone (β-MSH) and adrenocorticotropic hormone are endogenous agonists of MC1R (Slominski et al. 2004, p. 1175). According to Yamaguchi, Hearing (2009), agouti signaling protein (ASIP) is the only endogenous antagonist of MC1R. Synthetic MC1R agonists have been designed; examples include the peptides afamelanotide and melanotan II (Chen 2014a). Cain et al. (2006) found several non-peptide small-molecule antagonists of MC1R.

3.3 Preventing the transfer of melanosomes to keratinocytes

Keratinocytes in the skin. Within the skin, melanocytes are present in the basal layer of the epidermis; from these melanocytes originate dendrites that reach keratinocytes [7]. Keratinocytes are the most abundant cell type in the epidermis [8]. In the skin, there are approximately 36 keratinocytes per melanocyte [7]. Keratinocytes are continuously generated in the basal layer of the epidermis and displace older keratinocytes of the skin towards the surface. Le Poole et al. (1993) found that melanocytes are capable of phagocytosis and demonstrated it with latex beads 10 μg in diameter. The literature does not appear to have studied the significance of melanocyte phagocytosis in melanosome transfer.

Melanosome transfer. Melanosomes along with the melanin they contain is transferred from melanocytes to keratinocytes when keratinocytes are low in the epidermis [9]. Keratinocytes carry the melanosomes with them as they move towards the surface. Keratinocytes contribute to skin pigmentation holding the melanin originated in melanocytes and induce melanogenesis through chemical signals directed at melanocytes [5]. The transfer of melanosomes to keratinocytes is a necessary condition for the visible pigmentation of the skin (Wu, Hammer 2014). Blocking this transfer is a mechanism of action of some skin whitening agents (Smit et al. 2009, Ebanks et al. 2009). Skin whitening agents that block melanocyte transfer include niacinamide, heparin (Makino-Okimura et al. 2014), madecassoside (Jung et al. 2013), soybean (Leyden, Wallo. 2011) and Saccharomyces cerevisiae (a species of yeast) (Lee et al. 2015).

3.3.1 Protease-activated receptor 2 (PAR2)
The protease-activated receptor 2 (PAR2) is a transmembrane and G-protein coupled receptor expressed in keratinocytes and involved in melanocyte transfer [10][11]. Antagonists of PAR2 inhibit the transfer of melanosomes and have a skin whitening affects. Agonists of PAR2 have the opposite effect, as expected [11]. The common endogenous agonists of PAR2 are serine proteases which irreversibly activate PAR2 by cleaving a part of the extracellular terminal of this receptor thereby exposing a part of it that subsequently works as a ligand tethered to the reset of the receptor at the molecular scale. Some synthetic agonists of PAR2 are short peptides that imitate the aforesaid tethered ligand but do not cleave the extracellular terminal.

3.3.2 Keratinocyte growth factor receptor (KGFR)
Keratinocyte growth factor receptor (KGFR), UniProt ID: P21802-3, is a receptor tyrosine kinase present in keratinocytes involved in transfer of melanosomes. It is part of the FGFR (fibroblast growth factor receptors) family. It is also known as FGFR2b and FGRF2-IIIb. KGFR was determined to be a splicing variant of FGRF2 by Miki et al. (1992). Cardinali et al. (2005, 2008) found that KGF (keratinocyte growth factor) and ultraviolet radiation promote transfer of melanosomes from melanocytes to keratinocytes. Chen et al. (2009) found that ultraviolet irradiation increases secretion of KGF and KGF without UV irradiation increases amount of tyrosinase and pigmentation. Belleudi et al. (2011) found that increased KGFR expression promote phagocytosis of microscopic latex beads and melanosomes by keratinocytes. Based on the aforementioned studies it would be expected that a KGFR inhibitor causes depigmentation of skin or hair in vivo. Contrary to this, Borad et al. (2014) reported no depigmentation in subjects that received the “pan-FGFR inhibitor” ponatinib; it is possible that a higher dose would achieve a depigmenting effect.

3.4 Chemically-induced vitiligo
Some melanogenesis inhibitors are toxic to melanocytes. These agents can cause permanent depigmentation. They cause well-defined patches of depigmented areas that become bigger with more exposure until they cover the whole area under treatment. The patchy appearance is aesthetically very unfavorable. At least while the patchy phase lasts, the skin in depigmented areas tends to have a notoriously pinkish color instead of a white color. It is recommended that these agents are used with much care or not at all. See Harris (2017) and Gupta et al. (2012). for a review of these agents. See Boissy, Manga (2004) for a review of the mechanism of action. See Ghosh (2010) for a review of the clinical aspects of chemically-induced vitiligo. A non-exhaustive list of agents that induce vitiligo is presented below:
Toosi et al. (2012) examined the mechanism by which 4-TBP and 4-(benzyloxy)phenol cause an autoimmune response. Hariharan et al. (2010) examined the differences of the cytotoxicity towards melanocytes of 4-TBP and 4-(benzyloxy)phenol. They found that 4-TBP causes apoptosis and 4-(benzyloxy)phenol causes non-apoptotic cell death. Both compounds were cytotoxic to fibroblasts in the concentrations that they are toxic to melanocytes.

Hariharan et al. (2011) found that 250 mmol/l (↔ 50 mg/ml) of 4-(benzyloxy)phenol increased the amount of Langerhans cells 2.4 times w.r.t. control and 250 mmol/l (↔ 38 mg/ml) increased it 2.4 times w.r.t. control. In same article, application of 4-(benzyloxy)phenol reduced pigmentation of hair in mice by 20.5 % and reduced pigmentation of skin; application of 4-TBP reduced the same by 2.8 % and increased pigmentation of skin. The experiments in this article compared 4-(benzyloxy)phenol and 4-TBP on the basis of the same amount of substance which gives a 33 % higher dose of 4-(benzyloxy)phenol by mass.

Menter et al. (1993) found that intradermal injections of 4-tert-butylbenzene-1,2-diol (4-TBC) or 4-hydroxyphenol produced depigmentation of skin and hair in mice and that 4-hydroxyphenol but not 4-TBC caused depigmentation away from the site of injection.
3.4.1 Benzene-1,4-diamine

Bajaj et al. (1996) reported a case of depigmentation of the scalp hair and the surrounding skin caused by application of a hair dye with benzene-1,4-diamine (called “paraphenylenediamine” in the paper). Depigmentation persisted 1.5 years after the event with slight repigmentation. The persistence of the depigmentation and the patchy appearance strongly suggest that the mechanism was chemically-induced vitiligo.

3.4.2 4-(Benzyloxy)phenol
4-(Benzyloxy)phenol is used in medical practice in vitiligo cases to extend it to all the skin, thus avoiding the patchy appearance of incomplete vitiligo after the treatment is complete (Grimes, Nashawati 2017). Van den Broon et al. (2011) reviewed the autoimmume response caused by 4-benzyloxyphenol. Several papers [12] attribute the discovery of the chemically-induced vitiligo effect of 4-(benzyloxy)phenol to Oliver et al. (1939).
In an experiment with black guinea pigs Kasraee et al (2006) found that a combination of 4-(benzyloxy)phenol with retinoic acid was more effective in depigmenting skin and reducing the number of melanocytes than 4-(benzyloxy)phenol alone and retinoic acid alone. Samples of a control skin zone had an average of 76 melanocytes; comparable samples treated with 4-(benzyloxy)phenol had an average of 6 melanocytes (7.9 % of control). Pigmentation of hair (fur) was not affected in any treatment. The authors of that study propose the combination of 4-(benzyloxy)phenol alone with retinoic acid for the complete depigmentation of people with vitiligo.

Denton et al. (1962) found that mouse tyrosinase does not directly oxidize 4-(benzyloxy)phenol. In the same article it is presented several experiments with 4-(benzyloxy)phenol in mice. 76 days of oral administration of of 4-(benzyloxy)phenol in an increase dose relative to body mass from 40 mg/kg to 160 mg/kg resulted in visible hair lightening in 3 of 5 mice (60 %). This paper also studied the effects of benzene-1,4-diol and 1-(4-hydroxyphenyl)prop-1-one. They found that subcutaneous injections of 1-(4-hydroxyphenyl)prop-1-one resulted in systemic depigmentation of hair and subcutaneous injections of benzene-1,4-diol resulted in depigmentation of hair in the site of injection.
The stimulator of immume response imiquimod (see below) enhances the depigmenting effect of 4-(benzyloxy)phenol. Webb et al. (2014) examined the combination of 4-(benzyloxy)phenol with imiquimod. Van den Boorn et al. (2010) investigated the combination of 4-(benzyloxy)phenol with imiquimod and cytosine-guanine oligodeoxynucleotides in mice.

3.4.3 4-tert-Butylphenol (4-TBP) and 4-tert-butylbenzene-1,2-diol
In an in-vitro assay Kroll et al. (2005) found that 250 μmol/l (↔ 37.6 μg/ml [13]) of 4-TBP reduces the number of melanocytes in culture of 2 different immortalized cell lines to 59.1 % and 37.5 % of control; the viability of fibroblasts was not affected at 250 μmol/l; it was affected significatively only at 1 000 μmol/l (↔ 150 μg/ml). 4-TBP increased the concentration of HSP70 in cultured melanocytes up to 6.3 times at a TBH dose of 500 μmol/l (↔ 75.1 μg/ml). This study also found that 4-TBP increased the killing of melanocytes mediated by dendritic cells.
Yang et al. (2000) investigated the cytotoxicity of 4-TBP to human melanocytes in culture as a function of their tyrosinase activity. They found that 4-TBP is cytotoxic to human melanocytes including a culture with oculocutaneous albinism type 1, which have a loss of function mutation in the gene that encodes tyrosinase. Thus they conclude that activity of tyrosinase is not neccessary for the cytotoxicity of 4-TBP. This study found that 4-TBP is selectively cytotoxic against melanocytes and fibroblasts compared to keratinocytes. The viability w.r.t. control of melanocytes treated with 500 μmol/l (↔ 75.1 μg/ml) of 4-TBP was ~40 % and treated with 750 μmol/l (↔ 113 μg/ml) was ~15 % (visual estimation from figure 1). This article contains many highly relevant references for the reader interested in the mechanism of action of 4-TBH. Curiously, this study used a compound of uranium in their assays.

Yang, Boissy (1999) found that 4-tert-butylphenol inhibits the activity of tyrosinase in a cell lysate and decreases the expression of tyrosinase in a monoculture of melanocytes.

Manga et al. (2006) found that the cytotoxicity of 4-TBP is mediated by TRP1.
Yang, Boissy (2006) found that 4-TBP is an inhibitor of tyrosinase.

3.4.4 Imiquimod
Imiquimod is a small molecule stimulator of immune response. Topical application can cause depigmentation of skin; the mechanism is apparently through an autoimmune response (chemically-induced vitiligo) and apoptosis of melanocytes. Kim et al. (2010) found that imiquimod causes apoptosis in a culture of normal human melanocytess. Brown et al. (2005) reported a case of local vitiligo-like depigmentation apparently caused by application of imiquimod to male genitals and reviewed previous reports; they found 68 reports of pigmentary changes attributed to imiquimod of which 43 reported depigmentation, 17 reported hyperpigmentation, 7 reported vitiligo and 1 reported hypopigmentation. Jacob, Blyumin (2008) reported a case of topical imiquimod causing a patch of depigmentation in a 65 year old male that persited for at least 18 months.

3.4.5 4-Methoxyphenol
In a non-randomized non-controlled trial in humans with sufferers of vitiligo, Njoo et al. (2000) found that 4-methoxyphenol is effective for the depigmentation of the leftover pigmented areas. The compound was applied as a cream with 25 % (we assume mass fraction) of 4-methoxyphenol. Depigmentation was achieved after 4 months to 12 months of use; this is longer than MBEH. 25 % of the subjects reported mild burning or itching that disappeared when the treatment was stopped.
Riley (1969a) applied a cream of 20 % (we assume mass fraction) 4-methoxyphenol to the skin of guinea pigs; this resulted in depigmentation of skin and later hair. Discontinuation of the treatment resulted in very slow repigmentation from the edges of the depigmented area, suggesting gradual resurgence of melanocytes into the treated area from the untreated area. The same study found that treatment with 2-methoxyphenol did not have a depigmenting effect and 3-methoxyphenol has a very weak depigmenting effect.
Riley (1969b, 1970) found that 4-methoxyphenol is directly cytotoxic to melanocytes.

3.4.6 Olapatidine
Suchi et al. (2008) reported 2 cases of inflammation and depigmentation of the skin around the eye apparenly cauased by olapatidine eye drops in humans that also contain benzalkonium chloride (BAC). The depigmentation persisted months after stopping use of the eye drops; this in indicative of chemically induced vitiligo. Note that no depigmentation of the irises was reported.

3.4.7 Rhododendrol
In an experiment with brown guinea pigs Kuroda et al. (2014) found that rhododendrol reduced the pigmentation in skin and reduced the density of melanocytes in skin from 99 mm−2 to 2.2 mm−2 after 21 days of treatment. After 69 days of non-treatment, this figure increased to 24 mm−2. Ito, Wakamatsu (2018) and Sasaki et al. (2014) examined the mechanism of cytotoxicity of rhododendrol.

3.4.8 Other agents
Bonchak et al. (2014) found that the 5-HT2A agonist 8-DPAT destroys stem cells of melanocytes, which are concentrated around hair follicles.
Denman et al. (2008) found that mice which were treated with a gene gun system to express HSP70 and TRP-2 developed loss of melanocytes and depigmentation of fur including in non-treated areas; this paper attributes the depigmentation to induced immune response against TRP-2 and enhancement of this response by HSP70.

3.5 Inhibition of tyrosine kinases
Tyrosine kinase inhibitors (not to be confused with tyrosinase inhibitors) can cause depigmentation of skin and hair. The mechanism of action is through inhibition of SCFR (Mast/stem cell growth factor receptor Kit; a.k.a. c-Kit, Kit, CD-117. Encoded by gene KIT). See Moss et al. (2003). Dai et al. (2017), Ricci et al. (2016), Galanis, Levis (2015), Robert et al. (2012) reviewed the effects reported in the literature of changes in pigmentation in skin and hair caused by use of tyrosine kinase inhibitors. Martinez-Anton et al. (2018) reviewed the effect of SCFR inhibitors on physiological function including melanogenesis. Botchkareva et al. (2001) examined the importance of SCFR for the pigmentation of hair in mice. Grichnik (2006) reviewed the important role of SCFR in melanogenesis. Some inhibitors of SCFR also inhibit platelet-derived growth factor (PDGF). Karlsson et al. (1999) examined the role of PDGF on normal hair and skin physiology. TKIs that inhibit VEGFR (vasal endothelial growth factor) impair wound healing [14].

Karaman et al. (2008) determined the binding constants of TKIs to tyrosine kinases and computed their main targets and selectivity.
Lee et al. (2014) found that diosmetin (5,7,3’-trihydroxy-4’-methoxyflavone) found in Chrysanthemum morifolium inhibits melanogenesis in vitro through inhibition of SCFR.

Shin, Lee (2013) found that glyceollins, a family of compounds found in soy beans, suppress melanogenesis via inhibition of SCFR.
Nilotinib is a tyrosine kinase inhibitor with activity for SCFR that counter-intuitively increases melanogenesis (Kim et al. 2018, Chang 2018).

3.5.1 Cabozantinib
Zuo et al. (2019) report that cabozantinib caused depigmentation of hair and/or skin in 18 of 41 subjects (44 %) given 60 mg per day; dose was adjusted in some subjects.

3.5.2 Dasatinib
Davis et al. (2011) does not list SCFR among the main targets for dasatinib. Dasatinib can cause hair depigmentation. Compared to other TKI that cause hair depigmentation, dasatinib seems more likely to cause hair whitening (as opposed to a yellow/blond color) and hair loss.
Case reports (not exhaustive):
  • Brazzelli et al. (2012) reported a case of complete depigmentation of scalp hair, eyelashes, eyebrows and partial depigmentation of skin in vitiligo-like patches in a Caucasian male with relatively dark skin treated with 100 mg of dasatinib 2 times per day.
  • Samimi et al. (2013) reported a case of whitening of the scalp hair, eyebrow and eyelashes in a 27 year old woman that received 100 mg per day of dasatinib on regrowth of hair after initial loss (“During her protracted disease course, she experienced an initial anagen effluvium followed by chronic telogen effluvium”).
  • Fujimi et al. (2015) reported a case of depigmentation of scalp hair, eyebrows and eyelashes in a 56 year old woman treated with 90 mg of dasatinib twice daily.
  • Alharbi et al. (2018) reported a case of a 12 year old boy treated with 70 mg per day of dasatinib with localized skin depigmentation.
3.5.3 Imatinib
Cairo-André et al. (2006) found that a concentration of 1 μmol/l of imatinib decreased the number of dendrites and melanogenic activity of melanocytes in vitro and 10 μmol/l caused melanocytes to migrate upwards in in vitro reconstructed epidermis.

3.5.4 Masitinib
Masitinib is a multi-targeted inhibitor of tyrosine kinases with high activity for SCFR. Despite this, we could not find a case report of hair depigmentation caused by masitinib. Pala et al. (2020) reported a case of vitiligo apparently induced by masitinib in a female subject.

3.5.5 Pazopanib
In some papers pazopanib is referred to as GW786034, its research name.
Kobayashi et al. (2014) reported that pazopanib caused hair to grow depigmented in a woman. In the photography they present it can be observed that the natural color of the woman’s hair is black and there are whites and blond stripes corresponding to the time span in which she took pazopanib. Šeparović et al. (2018) reported a similar case of hair depigmentation with pazopanib. Routhouska et al. (2006) reported a case of intense hair depigmentation (from black to white) in a 69 year old woman treated with 1 400 mg of pazopanib. Hurwitz et al. (2006) reported that 6 of 14 subjects (43 %) given a dose ≥ 800 mg per day of pazopanib showed hair depigmentation. Falvre et al. (2006) reported hair depigmentation in 18 of 28 subjects (64 %) among those who received ≥ 50 mg per day and a yellow coloration of skin (prevalence not state) in the same group.
Hurwitz et al. (2009) write that for doses of ≥ 800 mg per day the half-life of pazopanib is 31.1 hours and the most frequent side effects are hypertension, diarrhea, hair depigmentation and nausea.
For a review of the pharmacokinetics of pazopanib, see Verheijen et al. (2017).

3.5.6 Sunitinib
Sunitinib is commonly encountered as the maleate salt. Sunitinib maleate is a yellow powder; the free base is orange (Kassem et al. 2012). In some papers sunitinib is referred to as SU11248, its research name.
Brzezniak, Szabo (2014) reported a case of hair depigmentation in a woman caused by 50 mg of sunitinib per day. Hartmann, Kanz (2008) reported a case of depigmentation of hair caused by 50 mg of sunitinib per day. Bansal et al. (2014) reported a case of partial depigmentation of body hair and a simultaneous adverse cutaneous reaction in an Indian man treated with 50 mg per day of sunitinib. Davis et al. (2011) examined the pharmacodynamics of several tyrosine kinase inhibitors; they found that sunitinib and masitinib are the only compound among the compound examined whose main target is SCFR and rated sunitinib as the most selective inhibitor for SCFR. Rosenbaum et al. (2008) reviewed clinical trails of sunitinib; among studies that used a dose of 50 mg per day, they found a prevalence of hair depigmentation in any degree of 16 %; they found that yellow pigmentation of the skin is a common effect of sunitinib; this pigmentation goes away in the span of weeks after discontinuation of sunitinib.

3.6 Directly destroying existing melanin
Several species of fungi produce enzymes that reduce pigmentation by degrading melanin. These enzymes often require the presence of hydrogen peroxide and sometimes the presence of Mg+2 ions to work. Nagasaki et al. (2008) proposed melanin-degrading enzymes as a safer alternative to hydrogen peroxide for cosmetic direct hair depigmentation.
The enzyme lignin peroxidase produced by the fungus Phanerochaete chrysosporium has been studied as an ingredient suitable for skin-whitening: In a double-blind placebo-controlled split-face randomized study Tess et al. (2011) found this enzyme to be effective and superior to hydroquinone in skin whitening. In a non-controlled study Zhong et al. (2015) applied this enzyme to volunteers with facial melasma during 8 weeks; the treatment was found effective in reducing pigmentation in both skin affected by melasma and skin unaffected by melasma.

3.7 Serotonin signaling
Melanocytes express serotonin receptors and are capable of producing serotonin. Pharmacological interference with the serotonin system of melanocytes can result in either increased or decreased melanin synthesis. Serotonin itself is a weak inhibitor of tyrosinase (Yamazaki et al. 2009) with 0.11 times the potency of kojic acid [15]. Nonetheless, serotonin increases synthesis of melanin when its overall effect on melanocytes (as opposed to isolated tyrosinase) is evaluated (Zhou et al. 2016). Activation of 5-HT2B receptors with BW-723C86 inhibits melanogenesis (Oh et al. 2016) while activation of 5-HT2A receptors with DOI promotes melanogenesis (Lee 2011). The serotonin reuptake inhibitor 6-nitroquipazine inhibits melanogenesis in-vitro (McEwan, Parsons 1987).

4 Other agents causing hair lightening
Shimshek et al. (2016) found that the compound NB-360 caused fur depigmentation in mice and reduced melanogenesis in a culture of human melanocytes.

Chloroquine and hydroxychloroquine further lighten hair in people who already have light hair. Bubblin, Thompson (1992) reviewed case reports of hair lightening caused by chroloquine and hydroxychloroquine. According to Bubblin, Thompson (1992), the first paper to report the hair lightening efect of chloroquine was that of Alving et al. (1948).

Plonka et al. (2006) found that oral administration of a high dose of zinc sulfate caused depigmentation of fur in mice to a light brown-yellow color. This paper also includes a review of the opposing roles of zinc in melanogenesis.

Mephenesin can make hair grow blond in people with dark hair during the duration of its use. Spillane (1963) reported 6 such cases with total daily doses around 5 g-10 g. Turner (1963) reported 3 further cases of hair depigmentation with mephenesin with daily doses between 4.5 and 8 g. Both case reports mention that skin did not change color.

Schoental (1971) found that the DNA disruptor methyl N-methyl-N-nitrosocarbamate (a.k.a. N-methyl-N-nitrosourethane) causes fur depigmentation in mice and rabbits; this paper says: “Similar permanent depigmentation of hair was observed in pigmented mice also after s.c. injections of N-ethyl-N-nitrosourethane and of elaiomycin.”.

Jimbow et al. (1974) found that subcutaneous injections of hydroquinone cause hair depigmentation in mice.
Schoental et al. (1978) found that intraperitoneal injections of calcium pantothenate (vitamin B5) caused hair depigmentation in mice. lists some studies about drugs known to cause color changes in hair.

Hair removal with incoherent intensed pulsed light (IIPL) or laser often causes white depigmentation of the remaining hair in the affected area. Radmanesh (2004) reported a case where IIPL caused blond depigmentation of facial hair in a woman.

4.1 Green hair
Exposure of light hair to water with a high concentration of copper ions occasionally results in the hair acquiring a greenish color (Roomans, Forslind 1980).

Pulos et al. (2019) and Callander et al. (1989) reported cases of green hair apparently caused by systemic use of propofol in people with light hair (natural in one case, dyed in another). The conjectured mechanism is the deposition of a green metabolite of propofol in the hair.

5 Eye lightening
The eyes are harder to depigment than the skin and hair because the melanin in the eyes is persistent. The melanin in hair and skin is removed with normal hair growth and skin renewal.

Doyle, Liu (1999) reported a case of depigmentation of the irises apparently caused by levobunolol eye drops.
Pulsed laser can disrupt the melanin of the iris and elicit a response where the body body removes the melanin through the span of weeks, leaving the eye in its structural color; this can be blue, purple or gray; the most common structural color is blue. This technique appears to be already in use, elective and for correction of heterochromia (irises of eyes of different color). However there is scarse research in the literature. Yildirim et al. (2016) tested this technique on rabbits; they used a frequency-doubled neodymium-doped yttrium aluminum garnet laser (Nd:YAG) to depigment the irises with good restults. Basoglu, Çelik (2017) used a Nd:YAG laser on a human subject with heterochromia with blue and brown to even the color to blue.

6 Notes
  1. Chang (2009a) writes:
    In addition to inhibition of tyrosinase catalytic activity, other approaches to treat hyperpigmentation include inhibition of tyrosinase mRNA transcription, aberration of tyrosinase glycosylation and maturation, acceleration of tyrosinase degradation, interference with melanosome maturation and transfer, inhibition of inflammation-induced melanogenic response, and acceleration of skin turnover. Accordingly, a huge number of depigmenting agents or whitening agents developed by those alternative approaches have been successfully identified and deeply reviewed in many articles [references omitted]​
  2. Chang (2009a) writes:
    In contrast to the huge number of reversible inhibitors has been identified, rarely irreversible inhibitors of tyrosinase were found until now. These irreversible inhibitors, which are also called specific inactivators, can form irreversibly covalent bond with the target enzyme and then inactivate it.​
  3. Ebanks et al. (2009) write:
    The transcriptional level is the first stage by which the expression of tyrosinase and related melanogenic enzymes may be modulated. Influential in this process, the microphthalmia-associated transcription factor (MITF) is a basic helix-loop-helix leucine zipper transcription factor that regulates melanocyte cellular differentiation as well as the transcription of melanogenic enzymes (tyrosinase, TYRP1 and TYRP2) and melanosome structural proteins (MART-1 and PMEL17) [references omitted].​
    Chang (2012) writes:
    In addition to being involved in the survival, proliferation, and differentiation of melanocytes, MITF is the master regulator of melanogenesis in melanocytes via binding to the M box of a promoter region and regulating the gene expression of tyrosinase, TRP-1, and TRP-2 [references omitted]. The up-regulation of MITF activity activates the expression of the melanogenesis-related enzymes, thus stimulating melanogenesis. In contrast, the down-regulation of MITF activity depresses the expression of the related enzymes, thereby inhibiting melanogenesis.​
  4. Chang 2012 writes:.
    Because tyrosinase is produced only by melanocytic cells, tyrosinase inhibitors have highly specific targeting to melanogenesis in the cells without other side effects. In contrast, those melanogenesis inhibitors targeting to the tyrosinase gene expressions or protein degradations are rarely used as clinical hypopigmenting agents, due to their non-specific and global effects via intracellular signaling pathways.​
  5. Many papers have described the signaling pathways affecting melanogenesis and other functions of melanocytes. The following reviews are suggested reading (all of which are available online at no cost): For a description with emphasis on the relation with skin whitening, see Chang (2012) or Smit et al. (2009). For a description with emphasis on physiology, see Yamaguchi, Hearing (2009) or Kondo (2011). For a description of intra-melanocyte signaling pathways, saee Imokawa, Ishida (2014). An extensive and detailed review was written by Slominski et. al. (2004). See also Ho-Sung et al. (2015), Hideki et al. (2015).
  6. Chang (2012) writes:
    Alpha melanocyte-stimulating hormone (α-MSH), a peptide derived from proopiomelanocortin (POMC), regulates melanogenesis via a cyclic adenosine monophosphate (cAMP)-dependent pathway [references omitted]. When binding to its receptor, melanocortin receptor 1 (MC1R), on the membrane of melanocytes, the hormone activates adenylate cyclase (AC) to produce cAMP as an intracellular second message via a G-protein-coupled receptor (GPCR)-type activation. cAMP activates protein kinase A (PKA), which then activates the gene expression of MITF via phosphorylation of the cAMP response element-binding protein (CREB). Finally, MITF efficiently activates the melanogenesis-related enzymes and stimulates melanogenesis. Once α-MSH binds to MC1R, up to a 100-fold increase in melanogenesis attends. In addition to α-MSH, other POMC-derived peptides, such as β-MSH and adrenocorticotropic hormone (ACTH), also stimulate melanogenesis via the same pathway.​
    D’Orazio et al. (2013) writes:
    α-MSH binding to melanocortin 1 receptor (MC1R) on melanocytes in the basal epidermis generates the second messenger cAMP via interactions between MC1R and adenylyl cyclase, and leads to activation of protein kinase A and the cAMP responsive binding element (CREB) and microphthalmia (Mitf) transcription factors. CREB and Mitf directly enhance melanin production by raising levels of tyrosinase and other melanin biosynthetic enzymes. Thus, MSH-MC1R signaling leads to enhanced pigment synthesis by melanocytes and accumulation of melanin by epidermal keratinocytes.


    The MC1R is found on the surface of melanocytes where it binds to α-melanocyte stimulating hormone (MSH) and transmits differentiation signals into the cell through activation of adenylyl cyclase and generation of cAMP [references omitted]. cAMP signaling leads to activation of the protein kinase A (PKA) cascade which, in turn, leads to increased levels and/or activity of many melanogenic enzymes to enhance production and export of melanin by melanocytes [>references and figure omitted].​
    See also Chen 2014a, Rodríguez 2014 and Lee 2013.
  7. Smit et al. (2009) write:
    In the skin, melanocytes are situated on the basal layer which separates dermis and epidermis. One melanocyte is surrounded by approximately 36 keratinocytes. Together, they form the so-called epidermal melanin unit. The melanin produced and stored inside the melanocyte in the melanosomal compartment is transported via dendrites to the overlaying keratinocytes.​
    Ebanks et al. (2009) write:
    Each melanocyte resides in the basal epithelial layer and, by virtue of its dendrites, interacts with approximately 36 keratinocytes to transfer melanosomes and protect the skin from photo-induced carcinogenesis. Furthermore, the amount and type of melanin produced and transferred to the keratinocytes with subsequent incorporation, aggregation and degradation influences skin complexion coloration [reference omitted].​
    Wu, Hammer (2014) describe the number of keratinocytes per melanocyte as above 40.
  8. D’Orazio et al. (2013) write:
    Keratinocytes are the most abundant cells in the epidermis and are characterized by their expression of cytokeratins and formation of desmosomes and tight junctions with each other to form an effective physicochemical barrier.​
  9. Research about the mechanism of melanosome transfer has been reviewed by Wu, Hammer (2014).
  10. Jung et al. (2013) write:
    Protease-activated receptor (PAR)-2 is a member of a novel G-protein-coupled seven-transmembrane receptor family. In epidermis, PAR-2 is expressed in keratinocytes [references omitted], but not melanocytes [references omitted]. A central role for PAR-2 in keratinocyte uptake of melanosomes has been established [references omitted]. PAR-2 has been linked to the upregulation of COX-2 and the release of arachidonic acid and secretion of PGE2 and PGF2α [references omitted]. Several reports have suggested that PAR-2 mediates cutaneous pigmentation through increased uptake of melanosomes by keratinocytes and by the release of PGE2 and PGF2α that stimulate melanocyte dendricity [references omitted].​
  11. References about PAR2 and its role in skin pigmentation: Kim et al. (2016), Choi et al. (2014), Makino-Okamura (2014), Wu, Hammer (2014), Ando et al. (2012), Ando et al. (2010).
  12. For example, van den Boorn et al. (2010) write (other references omitted):
    Monobenzone is the most potent skin depigmenting agent, discovered by Oliver et al. in 1939.​
  13. Mass concentration computed using a molar mass of 150.22 g/mol for 4-TBP, then reported rounded to 3 digits.
  14. Macdonald et al. (2015) write (references elided):
    Inhibition of the VEGF pathway can disrupt wound repair and result in delayed wound healing in a dose-dependent fashion and fistula formation. This becomes a consideration for surgical nplanning in both the adjuvant and neoadjuvantsettings.​
  15. Computed from the data reported by Yamazaki et. al. (2009): IC50(serotonin)=550 µmol/l. IC50(kojic acid)=68 µmol/l.
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Notes about psychopharmacology#
First version: 2019-11-06
Last update: 2021-01-09
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This article contains assorted notes about psychopharmacology. These notes are not comprehensive about any subtopic. Currently, SSRIs are covered with the most detail. These notes are written from a scientific viewpoint as much as possible; this implies objectivity and value-neutrality. An important question about any psychoactive compound is how it feels like. E.g: Does a psychopharmaceutical considered “antidepressant†cause the depressed person to feel relieved of depression? Since current techniques do not allow this to be answered objectively, we allow ourselves a departure from a purely scientific approach in answering it subjectively in the form of anecdotal reports and results of questionnaires filled by human subjects. In addition to psychopharmaceuticals, some activities with relatively well-characterized psychological effects are included.

  1. 1 Background
    1. 1.1 What is there to learn?
    2. 1.2 On psychiatry
    3. 1.3 No categorical difference
    4. 1.4 The inscrutability of the brain
    5. 1.5 On classification
  2. 2 QT interval prolongation
  3. 3 Outline of psychoactive compounds
  4. 4 Antiadrenergics
    1. 4.1 Clonidine
    2. 4.2 Prazosin
    3. 4.3 Propranolol
      1. 4.3.1 Cardiovascular effects
      2. 4.3.2 Psychological effects
      3. 4.3.3 Pharmacokinetics
  5. 5 Antimuscarinics
    1. 5.1 Biperiden
      1. 5.1.1 Pharmacokinetics
    2. 5.2 Scopolamine (hyoscine)
    3. 5.3 Trihexyphenidyl
      1. 5.3.1 Pharmacokinetics
      2. 5.3.2 Psychological effects
  6. 6 Antihistamines
    1. 6.1 Diphenhydramine
    2. 6.2 Hydroxyzine
  7. 7 Caffeine and other methylxanthines
  8. 8 Cholecystokinin tetrapeptide (CCK-4)
  9. 9 Gabapentinoids
  10. 10 Dopamine receptor agonists
    1. 10.1 Aripiprazole
    2. 10.2 Pramipexole
  11. 11 Dopamine receptor antagonists
  12. 12 Melatonin receptor ligands
    1. 12.1 Melatonin
  13. 13 Mirtazapine
  14. 14 Selective serotonin reuptake inhibitors (SSRIs)
    1. 14.1 Effect on startle response
    2. 14.2 Effect on critical flicker fusion threshold
    3. 14.3 Effect on anxiety
    4. 14.4 Causation of apathy
    5. 14.5 Effect on psychopathy cluster traits
      1. 14.5.1 Increase in callosity-unemotionality
    6. 14.6 Effect on sexual function
      1. 14.6.1 Reduced genital sensitivity
    7. 14.7 Effects at biochemical level
    8. 14.8 Other effects
    9. 14.9 Fluoxetine
  15. 15 Non-SSRI SERT inhibitors
    1. 15.1 Vortioxetine
  16. 16 Valproic acid
  17. 17 Activities with psychological effect
    1. 17.1 Physical exercise
    2. 17.2 Low blood glucose (hypoglycemia)
  18. 18 Other related works
  19. 19 Acknowledgements
  20. 20 Notes
  21. 21 References
1 Background
For a description of the basic biochemistry of the nervous system see Nestler et al. (2015) chapters 1 “Basic Principles of Neuropharmacology†to 4 “Signal Transduction in the Brainâ€.

1.1 What is there to learn?
There are 3 facets of information available about psychoactive compounds:
  • Objective parameters that can be measured about psychoactive compounds, like binding affinity, intrinsic efficacy for each receptor, half-life, products of metabolism.
  • Psychophysiological parameters. Psychophysiology is a little-known discipline whose goal is to find and describe the objective parameters that give rise to subjective experiences. One of its greater success is in relating color perception to the spectrum of light emitted by the stimulus. In psychopharmacology, psychopharmacology parameters include amplitude of startle response, heart rate, heart rate variability. Unfortunately the subjective experience elicited by a psychoactive substance does not bear a simple relation to physical parameters, like color perception does.
  • Subjective experience not related to objective parameters. This answers the question: “how does taking [a particular] compound feels likeâ€.
The first 2 points are often examined in the literature, especially in academic papers examining a particular compound. Many such papers are listed in this article. The matter of subjective experience is rarely addressed in the literature. Online forums are a valuable resource to find reports written by users of a particular compound. Some such reports are listed in this article. Thus, learning about a psychoactive compound should involve consulting peer reviewed articles and anecdotal reports in online forums; there resources are complementary rather than mutually competing.

Knowledge about the pharmacodynamics of a substance and how these pharmacodynamics helps us to make some inferences about its possible effects. Effects attributed to a particular compound only in isolated cases (either in the literature or in online forums) and that are not consistent with the known pharmacodynamics of a compound should be considered with reserve. These may be a spurious event not related to the substance in question, an artifact of perception on the part of the subject (e.g.: confirmation bias), purely psychogenic somatization of an effect expected a priori by the subject, a genuine effect that is uncommon (e.g.: because the subject has an uncommon genetic composition), intentional exaggeration or lies.

1.2 On psychiatry
The present article is about psychopharmacology. In the literature and in practice there is a great degree of overlap between psychopharmacology and psychiatry, therefore a short comment about psychiatry is due: A necessary condition for a discipline to be science is that it makes objective observations. Psychiatry is a discipline based around the concept of mental illness. What is and is not a mental illness is subjective, a matter of opinion. These opinions are embodied in the Disorders and Statistics Manual and the International Classification of Diseases. Psychiatry abuses the language of science and medicine to present these opinions as if they were objective: “this patient has bipolar disorderâ€. The conclusion is that psychiatry is a pseudoscience.

As is typical of pseudoscience, in psychiatry a few scientifically sound concepts are mixed with the more abundant unsound ones. For example: grand mal seizures are a phenomenon with electroencephalography measurements as an objective marker; Parkinson’s disease has an objective component in loss of dopaminergic activity and involuntary tremors.

Note that from the above critique of psychiatry does not follow that one should not judge people (positively or negatively) based on their mind, only that such judgements are not within the scope of science and that the terminology of science should not be abused to lend them false credibility.

Some concepts used in psychiatry can be useful despite being scientifically unsound. For example, a person may describe himself/herself as having agoraphobia. This enables an interested party to recommend psychoactive substances that would help the person to find relief per his/her own evaluation. This should not be an excuse to present these concepts in the language of science. Intellectual honesty dictates that they are presented as what they are: useful heuristics.

The present article focuses on the effects of psychoacative substances while avoiding to classify mental states as diseased and healthy. We have included some anecdotal reports on the basis that they are useful and duly noted that these are intrinsically subjective.

Thomas Szasz made an extensive criticism of psychiatry and the concept of mental illness through several books and articles. E.g.: Szasz (1974) denounces the concept of mental illness; Szasz (2011) comments on the deprivation of individual freedoms by the state under the guise of health care.

1.3 No categorical difference
Psychopharmaceuticals usually have a similar effect among people. This is different to pharmacology of non-psychoactive substances where many of them target a categorical anomaly and will not result in any improvement if this anomaly is absent. For example: Antibiotics will only cause an improvement of symptoms if there is an infection with a bacteria succeptible to that antibiotic. In psychopharmacology, caffeine will virtually always reduce sleepiness and benzodiazepines will virtually always increase it because there is no categorical difference between being sleepy and being well awake like there is between having an infection with Staphylococcus aureus and not having it. SSRIs will always cause unemotionality after ~90 days of continous use because there is no categorical difference between having depression and not having depression.

Most psychopharmaceuticals do not treat any disease. They change subjective aspects of the mind along a continuum. The erroneous idea that psychopharmaceuticals treat a categorical anomaly like antibiotics treat a bacterial infection comes from psychiatry. Psychopharmacology is often discussed in the context of the pseudoscience of psychiatry. Therefore the litearture is plagued by the pseudoscientific conept of mental ilnesses. This leads to the error of treating mental conditions as if they were a disease.

There is no categorical biological difference between depressed people and “normal†people. For diseases there exists an objectively measurable anomaly. For example, in Hashimoto thyroiditis there is destruction of the thyroid by the immune system. Decreased levels of triiodothyronine and anatomically visible destruction of the thyroid gland are objective markers that validate Hashimoto thyroid as a scientific conept. In psychiatry, the concept of major depressive disorder has no scientific basis. So-called “diagnose†of MDD is entirely subjective judgement.

Fallacious studies of a biochemical basis for so-called mental illnesses. In these studies a sample of subjects deemed to have a particular mental disease is compared to a sample of people considered healthy, matched for some demogrpahical parameters. A statictical difference in some biological parameter is found among the “ill†and normal groups. The study postulates that the biological difference is responsible for the illness. This is a fallacy because:
  • The observations do not establish a causal relationship. An observational study can not rule out confounders.
  • The study fails to establish a mechanism with scientific rigor. There is inevitably a gap in knowledge between the observed biochemical anomaly and the mental condition. Contrast with the assertion that an anomaly in the enzymes that synthesize melanin causes albinism. This is established with scientific rigor. The enzymes that participate in melanogensis is known. The chain of chemical reactions by which tyrosine is transformed into melanin is known. Their activities can be measured. When the enzymes whose loss of function cause albinism are inhibited in a normal subject they cause a lighter skin color.
  • The relationship is merely a statistical trend. There is no hard relationship betwen the biological anomaly and the mental condition. If the mental condition had a causal relationship with the biological anomaly then every subject with the biological anomaly would have the mental condition. For comparison: A loss-of-activity allele in the TYR gene always results in oculocutaneous albinism. Loss-of-activity in the F11 gene always results in hemophilia. Severe iron deficiency always results in anemia.
  • Homozygous twin studies are especially fallacious. When homozygous twins are raised together the fact that they live with a sibling with almost the same physique as them is itself a salient aspect of their lives which is a confounder. When homozygous twins are separated early in their lives that is itself a confounder. Most people are not separated early from their siblings. Despite sharing the genome and the aforementioned conditions in their living only a statistical correlation is found. This is evidence against a cause-effect relation between the biochemical anomaly and the mental condition. If the mental condition is caused by genetics then homozygous twins would have perfect correlation. In real genetic illnesses, homozygous twins both have it or do not. That is the case with non-autoimmune hemophilia, daltonism, albinism, etc.
1.4 The inscrutability of the brain
The brain is unique in that it most of its complexity is in the heterogenous fine structure of the connectome. The connectome has no analogy in the rest of the body. This is different from saying that the brain has complexity at the microscopic level. All the body shares this property. What makes the brain unique in complexity is that the details of which neuron connects to which other neurons is meaningful. In other organs the microscopic structure is homogeneous in the sense that it is repeated among functional units and the macroscpic function is the aggregate of the microscopic contribution of every functional unit. For example:
  • In the circulatory system there are capillary blood vessels. Its function is to exchange oxygen, hormones, cytokines and nutrients with the rest of the body. It makes no difference which exact artery irrigates a particular part of the body since all of them have the same function.
  • In the lungs there are alveolus. The precise bronchiole to which an alveolus is connected makes no difference. All alveolus exchange gases with the atmosphere.
  • In the muscles there are sarcomeres in parallel. The force exerted by the muscle is the sum of the force exerted by each sarcomere.
In the brain the mind is encoded in the fine detail in the connection between neurons and the fine detail in their biochemistry: epigenetics, expression of receptors and enzymes, phosphorylation status of proteins. The function of the brain is not the aggregate of the function of neurons. For example, if the precise axons to which cone cells were scrambled then the image would be scrambled and vision would not be possible. By contrast, skin can be transplanted from one part of the body to another. The precise connection of the blood vessels is not important as long as the grafted skin has a sufficient blood supply in its new place. The working of other organs can be elucidated by examining at most a few functional units which are representative of the rest. The working of the brain can not be elucidated in that way.

Functional magnetic resonance imaging studies (FMRI) studies commit the fallacy of assuming that the brain is homogeneous at the level of detail studied and can be studied in the same way as other organs. The resolution is several orders of magnitude inferior of that required to observe the details of the connections. Postulated working of the brain based on FMRI studies is broken science, the current-day equivalent of phrenology.

It is possible to study the activity of individual neurons with several types of neuronal clamps to measure the voltage of the cystol with respect to interstitial fluid. In this way action potentials are monitored with the precision that is the rule in physics and engineering. This technique yields scientifically rigorous observations about the low-level working of the brain. It does not yield information about how behavior arises from the low-level details for the brain because of practical limitations. Neuronal clamps are invasive. Every clamp requires time to place and remove and space around the neuron. Since the brain has in the order of 1010 neurons the time to place the clamps makes impossible to monitor a significant fraction of the brain.

1.5 On classification
In the literature, psychopharmaceuticals are referred to by their (correctly or erroneously) perceived clinical function. This is is misleading because compounds with very different pharmacology are often grouped under the same functional label. For example, both bupropion (a noradrenaline reuptake inhibitor) and escitalopram (a serotonin reuptake inhibitor) are labeled “antidepressantsâ€; both haloperidol (a dopamine receptor antagonist that has a sedative effect) and aripiprazole (a dopamine receptor partial agonist with some activity on serotonin receptors, that has a slightly stimulating effect on normal arousal) are labeled “antipsychoticsâ€.

2 QT interval prolongation
The QT interval is a caradiac parameter, the time between 2 specific features observable in an electrocadiogram. Many psychoactive drugs prolong the QT interval (Mistraletti, Iapichino 2016).

3 Outline of psychoactive compounds
We present below a rough classification of psychoacive compounds by pharmacological targets and psychological effects. Some compounds fit in several categories. Structural similiary is intentionally ignored in this classification.

  • Dopaminergic stimulants. Cause increased arousal. Counter sleepiness. In low to moderate doses, aid in focusing in intellectually demanding tasks.
    • Dopamine uptake inhibitors. Include methylphenidate.
    • Dopamine releasing agents. Include amphetamine.
  • D2 dopamine receptor agonists Cause nausea, increased libido and sexual function, decreased secretion of prolactin. Used as a treatment of Parkinson’s disease and hyperprolactinemia.
  • Inhibitors of the serotonin transporter (SERT).
    • Selective serotonin reuptake inhibitors (SSRIs). This is the sub-category whose psychological effect is most representative of the effect of inhibition of SERT.
    • Serotonin and noradrenaline reuptake inhibitors (SNRIs). e.g.: venlafaxine, reboxetine, imipramine, clomipramine.
    • Miscellaneous compounds (not a sub-category) A few compounds with atypical pharmacodynamics have SERT inhibition as a secondary mechanism of action. These compounds have little relation with each other. E.g.: tianeptine, dextrometrophan.
  • 5-HT2A agonists. Also known as psychedelic hallucinogens. Include LSD, 2C-B, psilocybin (active compound of “magic mushroomsâ€).
  • Serotonin releasing agents. Most compounds of this family are called empathogens/entactogens because they produce an increase in empathy in most subjects. Although the “tact†in “entactogen†referes to a metaphorical touch, it can also be interpreted in terms of physical touch; entactogens produce pleasurable tactile sensations.
  • Inhibitors of the noradrenaline transporter. Include bupropion. Mild stimulant activity. Anxiogenic. Cause increased libido in some subjects.
  • Antiadrenergics. Some of these compounds have an anti-anxiety and anti-aggressivity effect.
    • α-adrenoreceptor antagonists. Used primarily to lower blood pressure.
    • β-adrenoreceptor antagonists. Used primarily to lower heart rate pressure.
  • Monoamine oxidase inhibitors (MAOIs). Increase levels of dopamine, noradrenaline or serotonin by inhibiting the enzymes that inactivates them. Uncommon in modern use. Formerly common use in the treatment of Parkinson’s disease.
  • μ-opioid receptor agonists. In this article and most treatises these are also called “opioidsâ€. Note that there exist other types of opioid receptors whose activation has different effects. Include morphine, oxycodone, fentanyl. Opioids produce pain relief and are used as analgesics in subjects with intense pain. In high doses opioids produce respiratory depression which can lead to death. Easily produce physical dependence with strong withdrawal symptoms.
  • μ-opioid receptor partial agonists and antagonists. Include naloxone, naltrexone, suboxone. Partial agonists are used to diminish withdrawals symptoms of opioids. Antagonists are used to counteract respiratory depression caused by opioids.
  • NMDA receptor antagonists. These substances cause hallucinations, dissociation and general anesthesia. They are used as general anesthetics in high doses, recreatively in intermediate doses and as anti-depresants and treatment for obsessive-compulsive condition in low doses.
  • Antihistamines. Used mainly to reduce inflammation in allergy. They have a sedating and anxiolytic effect. In high doses, they can produce mild hallucinations.
  • GABAergics. Produce sedation, have anxiolytic effect. Include benzodizepines, barbiturates and ethanol. GABAergics have varying propensity to cause respiratory depression. High doses of barbiturates can easily cause fatal respiratory depression. Used as sleeping aid, anxiolytics and to counter overdose of stimulants.
    • Positive allosteric modulators of GABA receptors. Include most benzodiazepines.
    • Agonists of GABA receptors. Include barbiturates and ethanol.
  • Adenosine receptor antagonists. Include caffine. Have a stimulant effect.
  • Melatonin receptor agonists. Produce sedation. Force the phase of the circadian rhythm. Include melatonin itself which is used as a sleeping aid and occasionally as an anxiolytic.
  • Cannabinoid receptor agonists. Include tetrahydrocannabinol (the main active compound in psychoactive cannabis) and synthetic cannabinoids. Produce relaxation and acutely impair short-term memory. Can produce hallucinations.
  • Cannabinoid receptor antagonists. Include rimonabant, used experimentally as an anorexigen and intellectual aid.
  • Anticholinergics. In high doses cause hallucinations experienced as reality. Include atropine, scopolamine, diphenhydramine (non-selecive).
4 Antiadrenergics
Keller, Frishman (2003) reviewed the psychological effect of cardiovascular medication including clonidine, prazosin and propranolol.

β-antagonists decrease normal production of tears (Singer et al. 1984, Samochowiec-Donocik et al. 2004).

4.1 Clonidine
Clonidine is an antagonist of the α2A, α2B and α2C adrenoreceptors. Neil (2011) gives the half-life of clonidine as 12 h-16 h, prolonged up to 24 h with chronic oral administration. The main physiological effect is decreasing blood pressure. Clonidine has been used to lower blood pressure during surger to reduce bleeding (Degoute 2007). Psychologically, clonidine has been used to enhance concentration in subjects deemed to have attention deficit hyperactivity disorder and to treat post-traumatic stress disorder (Naguy 2016).

4.2 Prazosin
Prazosin is an antagonist of the α1 receptors. It is used to lower blood pressure in hypertension and as an uncommon treatment for people deemed to have post-traumatic stress disorder (Huffman, Stern 2007).

4.3 Propranolol
Propranolol is an antagonist of the β-adrenoreceptors. For a short review of its medical use see Srinivasan (2019).

Woods, Robinson (1981) found that propranolol has the highest octanol to water partition coefficient among the examined β-blockers (acebutolol, atenolol, labetalol, metoprolol, nadolol, oxprenolol, pindolol, propranolol, sotalol and timolol) with labetalol a close second. Therefore, it can be inferred that propranolol and labetalol cross the blood-brain barrier much better than the other compounds examined.

Le Mellédo et al. (1998) found that an infusion of 0.2 mg/kg reduced self-rated anxiety in response to CCK-4.

Alexander, Wood (1987) found that propranolol binds to 5-HT1A, 5-HT1B and 5-HT1C in rats. Tsuchihashi et al. (1990) found that propranolol binds to 5-HT1B in rats.

4.3.1 Cardiovascular effects
Antagonists of β-adrenoreceptors like propranolol cause a reduction in heart rate through inhibition of the sympathetic signal. The effect is much greater on the heart rate during aerobic exercise than on the resting heart rate (Carruthers et al. 1976). Chidiac et al. (1993) reported that propranolol is an inverse agonist of the β-adrenoreceptors. In a non-controlled open-label trial with people with hyperthyroidism Taneku et al (2018) found that acute administration of 80 mg/d of propranolol split in 2 doses per day reduced heart rate from 91 min−1 to 79 min−1. Root mean square of the first difference of inter-cardiac period (RMSSD) was not significantly reduced, from 22.3 ms to 25.2 ms. Ernst et al. (2017) found that an acute dose of 40 mg of propranolol did not change heart rate to a meaningful extent after 90 min of the dose, from 66 min−1 to 65 min−1 (here rounded to 2 digits).

Fernández et al. (2000) found that propranolol did not counter the vasoconstriction caused by serotonin.

4.3.2 Psychological effects
Propranolol has anxiety-lowering effects reviewed by Steen (2015). Steen (2015) attributes the discovery of this effect to Turner et al. (1965). Propranolol was already established in medical use to treat cardiac diseases before the discovery of its anxioloitic effect. Davis et al. (1979) found that injections of propranolol decreases the magnitude of potentiated startle in rats compared to saline.

Propranolol can be used to reduce aggressivity and egodystonic generalized anger. London (2020) found that propranolol lowered aggressivity in subjects demed to have autism spectrum disorder; in addition the same paper reviewed the literature on studies where propranolol is used to lower aggressivity. Newman, McDermott (2011) reported a case of a subject with a history of aggressiveness (having to change school, arrests) and who expressed feeling angry all the time given 20 mg of propranolol 2 times per day and then 40 mg propranolol 2 times per day. The subject missed more than half the doses, self-reported improvement in his temper and that propranolol “Takes the edge off.â€. Sagar-Ouriaghli et al. (2018) reviewed the use of propranolol to treat various adverse psychological conditions commonly found in people deemed to have autistic spectrum disorder. Silver et al. (1999) used propranolol to treat aggressivity in subjects interned in psychiatric centers; they started with a low dose and increased gradually; the mean dose was 1 336 mg per day. All subjects except one received a dose of at least 640 mg per day of propanolol.

The literature has conflicting reports on whether β-antagonists like propranolol cause depression. See Steffensmeier et al. (2006) for a review.

4.3.3 Pharmacokinetics
For a review of the chemical properties and pharmacokinetics of propranolol see Al-Majed et al. (2017). In a review, Ã…gesen et al. (2019) concluded that the pharmacokinetics of propranolol are highly variable between individuals. In a review, Routledge, Shand (1979) found that propranolol has non-linear pharmacokinetics in a single oral dose below 30Â mg and linear pharmacokinetics at an higher dose; this review gives the time to peak blood concentration after oral administration as approximately 2Â h and half life as 3.9Â h.

Kaila, Marttila (1993) estimated the receptor occupacy of β1 and β2 by propranolol in humans. The methodology was indirect: Propranolol and other pharmaceuticals were administered to the subjects, samples of blood and cerebrospinal fluid (CSF) were taken at various times after dosing, then tissue from rabbits and rats that expresses β1 and β2 were immersed in the blood and CSF. They found that estimated receptor occupancy peaked at 2 h after dosing 40 mg.

5 Antimuscarinics
Antimuscarinics have been used for the treatment of Parkinson’s disease. In low dose they work as anxiolytics. In high dose they impair memory and cause delirium. Antimuscarinics include atropine, biperiden, diphenhidramine (covered under antihistamines), scopolamine (a.k.a. hyoscine) and trihexyphenidyl.

Traub, Levine (2017) described the physiological effects of antimuscarinics and the treatment in overdose.

Physostigmine is a cholinesterase inhibitor often used as an antidote for overdose of anticholinergic agents. Its use was reviewed by Watkins et al. (2014).

A common hypothesis presented in the literature is that years-long administration of antimuscarinics increase the risk of dementia in old people. Studies on the matter are plagued by confounding factors and the fallacy of inferring a causal relationship when only a correlation has been observed. For a review see Andrade (2019).

Kimura et al. (1999) examined the binding profile of biperiden and trihexyphenydyl in rats. They found that trihexiphenydyl is a reversible inhibitor of muscarinic receptors and biperiden binds to the same in a partly irreversible manner. This study found that biperiden but not trihexiphenydyl resulted in apparent lasting memory impairment in rats.

Lustig et al. (1992) examined the effects of several psychoactive compounds used for the treatment of Parkinson disease on NMDA neurotoxicity; they found that benztropine amplified NMDA neurotoxicity and was toxic by itself; trihexyphenydyl had no effect and amantadine (not an antimuscarinic) protected against NMDA neurotoxicity.

5.1 Biperiden
Fleischhacker et al. (1987) evaluated the psychological and physiological effect of an acute dose of 5Â mg of biperiden administered intravenously to healthy volunteers. They write:

The acute signs and symptoms observed immediately after the administration of biperiden were headache, nausea, dryness of mouth, blurred vision, weakness, apathy and dizziness. [...] Later, some of them also developed further symptoms like increase of drive, euphoria, disinhibited and contact seeking behavior, depersonalization, derealization, visual hallucinations and disturbances of time perception. Biperiden frequently induced an impairment of cognitive functions characterized by disturbances in concentration, a deterioration of short-term memory and a lossening of associations. [...] There were 2 two cases of visual hallucinations [among 28 subjects, 7.1Â %]: one woman was very concerned about her hair turning gray, whereas another one amusdely told everybody that her hands had turned yellow.​
Martinez et al. (2012) reported a case of a subject who used increasing doses of biperiden up to 50Â mg per day. This subject arrived at an hospital with delirium.

5.1.1 Pharmacokinetics
Hollman et al. (1984) examined the pharmacokinetics of biperiden on oral administration. They found a time to peak concentration of 1.5Â h. They found that pharmacokinetics followed a 2-compartment model with terminal half-life of 18.4Â h

5.2 Scopolamine (hyoscine)
Scopolamine (also called hyoscine, PubChem CID: 5184) is an antimuscarinic. Furey, Drevets (2006) examined the potential of scopolamine to counter depression. Drevets et al. (2013) found that scopolamine administered intravenously at a dose relative to body mass of 4 μg/kg produced relief of depression the following day and did not produce hallucinations. For a review on the anti-depressant effect of anticholinergics see Wiktin et al. (2019).

5.3 Trihexyphenidyl
Trihexyphenidyl (PubChem CID: 5572) is an antimuscarinic. It is also referred to as benzhexol especially in very old articles. As a medication it is produced in pills of 2Â mg and 5Â mg.

5.3.1 Pharmacokinetics
He et al. (1995) examined the pharmacokinetics of trihexyphenidyl; they found a mean time to peak concentration of 1.32Â h; they found that elimination follows a biexponential model with half-lives of 5.33Â h and 32.7Â h. Burke, Fahn (1985) examined the pharmacokinetics of 5Â mg to 12.5Â mg of trihexyphenidyl administered orally. They found that it has linear pharmacokinetics, a time to peak concentration of 1.3Â h and an elimination half-life of 3.7Â h.

5.3.2 Psychological effects
Pomara et al. (2010) found that an acute dose of 2Â mg of trihexyphenidyl facilitated recall of information acquired prior to the administration of trihexyphenidyl in healthy old people.

6 Antihistamines
6.1 Diphenhydramine
Diphenhydramine is a pharmaceutical with many biochemical targets. Its main targets are the H1 receptor where it is an inverse agonist and muscarinic cholinergic receptors where it is an antagonist. In low doses, diphenhydramine causes sleepiness and reduction of anxiety. In higher doses it causes delirium.

Gengo et al. (1989) evaluated the pharmacokinetics of an acute dose of 50Â mg of diphenhydramine in healthy volunteers. They found that the time to peak concentration is between 1.5Â h and 2.5Â h and the half-life is 4.8Â h (computed from elimination rate constant of 0.144Â h given in the paper). In the same study, they found that diphenhydramine produced self-rated sleepiness and an impairment in reaction time assessed with simulated driving and in a test involving mapping symbols to other symbols according to a displayed arbitrary association. Kay (1997) administered diphenhydramine, loratadine or placebo to healthy volunteers; the diphenhydramine group was given a total of 100Â mg of diphenhydramine each of 5 consecutive days; this study found that diphenhydramine resulted in higher self-rated sleepiness and fatigue and lower self-rated motivation than placebo; diphenhydramine caused increased erroneous answers and timeouts in tests compared to placebo.

Thomas et al. (2008) give the dose as 50Â mg for an hypnotic effect and 300Â mg-700Â mg for an hallucinogenic effect. Sicari, Zabbo (2019) give the dose as 25Â mg-50Â mg for an hypnotic effect.

Radovanovic et al. (2000) examined the effects of high doses of diphenhydramine.

Prolonged administration of diphenhydramine produces physical dependence. Nolen, Dai (2019) presented a case report and reviewed previous reports of diphenhydramine dependence. Daily doses ranged from 50Â mg to 3000Â mg.

6.2 Hydroxyzine
Hydroxyzine is an anti-histaminic with minor activity for serotonin and muscarinic acetylcholine receptors. It has an onset of action of 10Â min to 30Â min. It potentiates opioids. It is suitable for use as anxiolytic and sleep aid (Dowben et al. (2013) for paragraph).

Stahl (2017) gives the usual dose as 50Â mg-100Â mg 4 times per day as an anxiolytic. Guaiana et al. (2010) reviewed the use of hydroxyzine as an anxiolytic.

7 Caffeine and other methylxanthines
Caffeine, theacrine, theobromine and theophiline are structurally similar compounds of the chemical group of methylxanthines.

Lara et al. (2019) examined the time course of effects of caffeine on aerobic physical performance in a double-blind controlled study. They found that 20 days of administration of ~200Â mg/d of caffeine resulted in partial tolerance to the performance-enhancing effects. Robertson et al. (1981) found tolerance to changes in blood pressure, heart rate, increase in blood adrenaline and noradrenaline is developed quickly after 4 days of administration of ~250Â mg/d caffeine.

Caffeine appears to decrease resting heart rate (Colton, 1968; Hajsadeghi et al., 2016).

8 Cholecystokinin tetrapeptide (CCK-4)
Cholecystokinin tetrapeptide (abbreviation: CCK-4) is a structural analogue of the endogenous peptide cholecystokinin. Administration of CCK-4 to humans generally produces intense dysphoria, anxiety or fear. Details of the psychological effect differ between subjects; they are always negative and related to anxiety.

De Montingny (1989) investigated the effect of intravenous administration of CCK-4 in healthy voulunteeres. He found that a dose of 100 μg or lower caused a panic-like attack in 7 of 10 subjects (70 %) and increased heart rate (64.9 min−1 to a peak of 92.1 min−1). In a limited second round, he found that pretreatment with 4 mg total of lorazepam split in 3 doses (1 mg and 2 mg the preceeding day and 1 mg in the day of the experiment 1 hour before the CCK-4 stimulus) inhibited the panic-like attacks in 2 subjects that had previously shown this response.

In addition to their own results this study reports on previous self-experimentation by different workers: “Rehfeld [reported] that he and one of his colleagues injected themselves intravenously with 70 μg of CCK-4 and both experienced within one minunte after the injection “a very unplesant anxiety†and a feeling that the “world was sliding awayâ€â€.

De Montingny (1989) also administered the related compound sulfated cholecystokinin octapeptide (CCK-8S) to healthy volunteers in increasing doses; the dose escalation was discontinued becuase of intense gastrointestinal upset before any intense psychological effect.

Zwanzger et al. (2002) found that pretreatment with 1 mg of alprazolam 1 hour in advance reduced the panic response to a stimulus of 50 μg of CCK-4 in healthy subjects.

9 Gabapentinoids
Gabapentinoids are ligands of the α2δ subunit of the L-type voltage-gated calcium channels. Gabapentinoids available for medical use are gabapentin, pregabalin and mirogabalin. The name “gabapentinoid†is a reference to gabapentin; gabapentinoids are not necessarily GABAergic. For an overview of the pharmacology of gabapentinoids, see Calandre et al. (2016).

10 Dopamine receptor agonists
Dopamine receptor agonists include bromocriptine, cabergoline, pergolide, pramipexole, ropinirole. Among these, bromocriptine, cabergoline and pergolide are structural analogues of ergoline.

Dopamine receptor agonists are used as a treatment of hyperprolactinemia, restless leg syndrome (RLS) and symptomatic treatment of Parkinson’s syndrome. Some of the research of the effects on subjects with these conditions may be not generalizable to healthy subjects. In special, subjects with Parkinson’s syndrome have a significantly disrupted dopamine system both because of the disease and because of treatment.

Some cis male bodybuilders that use anabolic steroids that are partially metabolized to estrogens use dopamine receptor agonists to prevent breast growth by inhibiting the increased release of prolactin that could reduce from the estrogenic activity. See chapter “Dostinex (cabergoline)†in Llewelyn (2011).

In a laboratory setting, dopaminergics tend to impair learning of arbitrary associations. E.g.: In a randomized controlled experiment with healthy volunteers Gallant et al. (2016) found that pramipexole impairs learning of pictures of abstract 3D items to numbers.

Dopamine receptor agonists cause impulsiveness and hypersexuality in some users. See Bostwick et al. (2009) for a review. Krüger et al. (2005) reviewed the effect of prolactin and dopamine receptor agonists on orgasmic function. Hollande et al. (2016) found that 0.5 mg of cabergoline 2 times per week improved subjective orgasmic function in andrological patients. Krysiak et al. (2018) found that 5 mg-10 mg per day of bromocriptine increased self-rated sexual function including desire and lubrication in a group of females with hyperprolactinemia; notably 1 among 32 subjects that received bromocriptine dropped from the study because of hallucinations (presumably induced by bromocriptine; although this is not stated in the paper). Krüger et al. (2003) found that an acute dose of 0.5 mg of cabergoline increased subjective sexual performance in healthy male subjects.

10.1 Aripiprazole
Aripiprazole is a partial agonist of dopamine and serotonin receptors. Functionally it is an antipsychotic and mood stabilizer. Almost all other antipsychotics in common use are full antagonists of dopamine and serotonin receptors. See § Dopamine receptor antagonists.

10.2 Pramipexole
Belluci et al. (2020) found that in a test to assess trust (briefly: subjects were are given money, the option to send an amount to money to a stranger, which is triped from what they have, and the stranger has the option to share a part or all of it back to the subject) pramipexole increased trust in women using anticonceptives and decreased trust in women not using anticonceptives as evaluted by the amount of money sent to the stranger.

Wright et al. (1997) examined the pharmacokinetics of pramipexole in healthy volunteeres including an analysis of the difference of its pharmacokinetics between the sexes. They found that the mean half-life was 11.6Â h in men and 14.1Â h in women. Putri et al. (2016) examined the pharmacokinetics of pramipexole in healthy males in Indonesia; they found the time to peak concentration was 2Â h or 1.8Â h (depending on formulation) and the mean half-life was 8.9Â h. We believe the faster pharmacokinetics compared to the previously cited study are because this study was performed in an Southeast Asian population.

Hall et al. (1996) found that pramipexole protects against ischemia-caused and methamphetamine-caused neurological damage in mice.

In a controlled trial in subjects having Parkinson’s disease and given pramipexole escalated to a dose up to 4.5 mg per day Shannon et al. (1997) found that the most common side effects of pramipexole were nausea in 39 %, insomnia in 25.6 %, somnolence in 18.3 % fatigue in 14.6 % and hallucinations in 10 %.

Micallef et al. (2009) found that a single dose of 0.5Â mg of pramipexole decreased latency to sleep in healthy volunteeres compared to placebo; there was no increase in subjective self-rating of sleepiness.

Samuels et al. (2007) found that 0.5Â mg of pramipexole acutely increases growth hormones (GH) but not thyroid stimulating hormone (TSH) in healthy volunteers.

Pramipexole has a direct antidepressant activity. This is in contrast to serotonin transporter (SERT) inhibitors, which cause apathy. Bennett et al. (1994) attribute this effect to D3 activity.

11 Dopamine receptor antagonists
In a study with monkeys Dorph-Petersen et al. (2005) found that prolonged administration to olanzapine and risperidone caused a reduction in brain volume. In a randomized controlled trial on humans Voineskos et al. (2020) found that “the mean reduction in cortical thickness caused by 36 weeks of exposure to olanzapine is equivalent to loss of approximately 1.2 % of a person’s cortexâ€.

Dopamine receptor antagonists are often used as antipsychotics. Given the evidence for permanent neurological harm and the existence of alternatives free from this harm like benzodiazepines and aripiprazole, we consider that use of dopamine receptor antagonists as a first line treatment is gross negligence.

Avoid the term “atypical antipsychotic†because it is vague. Mailman, Murthy (2010) write:

A great deal of research was devoted to the discovery of drugs that were “atypical†– although there was no convention about the meaning of the term “atypical.†In its broadest sense, it was used to refer to drugs that had at least equal antipsychotic efficacy to the “typical†drugs, without producing EPS or sustained prolactin elevation [references elided]. With time and after the development of drugs that could be called “atypical,†the definition was often expanded to include compounds that might have superior antipsychotic efficacy (e.g., in treatment resistant patients) or have beneficial effects against negative symptoms and/or cognitive deficits.​
12 Melatonin receptor ligands
12.1 Melatonin
Melatonin is an endogenous ligand of melatonin receptor 1 (MT1) and melatonin receptor 2 (MT2). Melatonin receptors are part of the biological control pathway of the circadian rhythm.

Melatonin is available as a pharmaceutical. Tordjman et al. (2017) reviewed the pharmacology of melatonin. Di et al. (1997) found that melatonin has a mean oral bioavailability of 33Â % (range: 10Â %-56Â %) and a half-life of 47Â min.

13 Mirtazapine
Mirtazapine is a ligand of serotonin, adrenaline/noradrenaline and histamine receptors. It does not act as a serotonin reuptake inhibitor. For a review of its pharmacokinetics and pharmacodynamics, see Anttila, Leinonen (2001) and Timmer et al (2000).

Timmer et al (2000) gives the elimination half-life as between 20Â h and 40Â h depending on sex and age.

In administering mirtazapine to subjects deemed to have depression, Sitsen, Zivkov (1995) found that:
Only drowsiness, excessive sedation, dry mouth, increased appetite and weight increase occurred significantly more frequently with mirtazapine than with placebo. These complaints were typically mild and transient in nature, and they decreased in intensity and frequency over time despite increased dosages of mirtazapine.​
14 Selective serotonin reuptake inhibitors (SSRIs)
Selective serotonin reuptake inhibitors are the compounds that block transport of serotonin from extracellular space to the cistol by the serotonin transporter (encoded by gene SLC6A4) and do not significantly block the dopamine transporter nor adrenaline transporter. Thus the main effect at the biochemical level is raising the concentration of serotonin in synapses thereby increasing activation of serotonin receptors.

The SSRIs that are commercially available as medication are: citalopram, dapoxetine, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline. Unlike the others, dapoxetine is a short-acting SSRI is not customarily used for any psychological effect; instead it is used to delay orgasm; note that all SSRIs have this effect.

SubstaceED50 for SERT inhibition[1]Usual dose[2]Citalopram3.4Â mg/d20Â mg/d-40Â mg/dFluoxetine2.7Â mg/d20Â mg/d-80Â mg/dParoxetine5.0Â mg/d20Â mg/d-50Â mg/dSertraline9.1Â mg/d50Â mg/d-200Â mg/dVenlafaxine (extended release)5.8Â mg/d75Â mg/d-225Â mg/d

There are subtle differences in pharmacodynamics among SSRIs which have consequences in their perceptible psychological effect; for a revew see Sanchez et al. (2014) and Carrasco et al. (2005).

14.1 Effect on startle response
Harmer et al. (2004) examined the effects of administration of 20Â mg per day of citalopram after 7 on the blink startle response to loud noise. The subjects were given bursts of loud noise either without additional stimulus or while observing a human face showing positive, neutral or negative affect. They found that in the placebo group faces with negative affect potentiated the blink reponse. In the citalopram group there was no difference in the blink response when noise was delivered while showing a face with negative affect compared to no face shown. Thus citalopram inhibited the potentiation effect of showing a face with negative affect in the blink in reponse to noise.

Capitão et al. (2015) performed an experiment with an acute dose of 20 mg of fluoxetine with a design very similar to that of Harmer et al. (2004) mentioned above. They found that acute administration of fluoxetine slightly decreased blink startle response to noise (opposite of citalopram) and inhibited the potentiation of this startle response by faces with negative affects. They conjecture that the opposite effect of fluoxetine compared to escitalopram on startle response may be because fluxoetine is a 5-HT2C antagonist.

Browning et al. (2006) reported than an acute dose of 20Â mg of citalopram increased blink startle response to loud noise.

Grillon et al. (2008) performed an startle-based experiment that attempts to distinguish between anxiety (long-term and dependant on vague context) and fear (shot-term and dependant on specific clues). They found that a administration of 10Â mg per day of citalpram for 2 days followed by 20Â mg per day for 12 days reduces anxiety but not fear.

14.2 Effect on critical flicker fusion threshold
When a light is cycled between on and off fast enough, the human visual system perceives it as if it was continously on at an intermediate brightness. For a given set assay conditions (light intensity, spectrum, viewing conditions, duty cycle, etc.) the critical flicker fusion threshold (CFFT) is the least frequency at which a cycled light is perceived as continous. The CFFT is a psychophysiological correlate of psychological arousal. Stimulants generally increase it while hypnotics decrease it. At face value the CFFT is an indicator of bandwidth which is in turn an indicator of how fast the neurological system is capable to process information. This can be seen applying the concepts of Fourier transform and amplifier bandwidth. The light intensity of a light that turns on and off periodically can be expressed as the sum of the average intensity, a sine wave at the frequency of cycling (fundamental frequency) and sine waves at integer multiples thereof (harmonics); that is its Fourier series. Given that the human visual system is an active system, it is expected to have a finite bandwidth. At the CFFT, the visual system has a gain of ~0 for all non-zero frequency components.

Schmitt et al. (2002) contend that pupil diameter should be controlled for in experiments that evaluate CFFT because a higher pupil diameter causes a brighter image in the retina which causes a higher CFFT, everything else being the same; thus a higher CFFT is not necessarily indicative of CNS stimulation. In particular, SSRIs increase pupil diameter (see paper for references). Schmitt et al. (2002) evaluated the effect of citalopram and sertraline on CFFT on healthy volunteers with and without control for pupilar diameter. They found that acute but not chronic (at day 15) administration of citalopram and sertraline reduced CFFT with control for pupilar diameter enough to achieve statistical significance.

Kerr et al. (1993) found that 20Â mg per day of fluoxetine increases the critical flicker fusion frequency threshold in humans through 2 weeks of chronic use from 25.5Â Hz to 27Â Hz (approximate data from the graph in the paper).

14.3 Effect on anxiety
In an assay with rats Bagdy et al. (2001) found that acute administration of fluoxetine increases indicators of anxiety and that this was reduced by a 5-HT2C antagonist, suggesting that SSRI-induced anxiety is mediated by activation of 5-HT2C.

Inhalation of a mixture of carbon dioxide (CO2) and diatomic oxygen (O2) causes a sensation of asphyxiation in humans. An assay to test the effect of psychoactive drugs on anxiety consists of comparing the self-reported anxiety when given CO2 after a pharmacological treatment and when given before pharmacological treatment. Bertani et al. (2001) found that 10Â mg per day of citalopram decreases anxiety caused by CO2. According to Bertani et al. (2001), Pols et al. (1996) found that fluvoxamine reduced anxiety caused by CO2 after 6 weeks and Bertani et al. (2001) found that paroxetine, sertraline and fluvoxamine reduced the anxiety caused by CO2; we could not access the paper Pols et al. (1996) nor Bertani et al. (2001).

Cholecystokinin tetrapeptide (CCK-4) causes a panic-like dysphoric response in human subjects. This has been used as a probe for anxiety-countering effects similar to administration of breathable air with high concentration of CO2. Several studies have examied whether SSRIs attenuate the panicogenic response to CCK-4. Van Megen et al. (1997) found that fluvoxamine lowers the dysphoric response to CCK-4 in subjects deemed to have panic disorder. Kellner et al. (2009) found that treatment with 10Â mg/d of escitalopram for 42 days did not reduce the dysphoric response to CCK-4 in healthy subjects.

Anxiety sensitivity is the condition of physical signals related to anxiety causing further anxiety. Reiss et al. (1986) presented the Anxiety Sensitivity Index, a 16-item questionnaire to evaluate anxiety sensitivity. In a non-controlled trial, Romano et al. (2004) found that citalopram decreased score in ASI from 26.6 to 23.3 after 7 days and 17.2 after 42 days of administration; subjects were given 10Â mg daily for 7 days, then 20Â mg daily for 4 days, then 30 mg per day for 3 days, then 40 mg daily for the rest of the trial.

14.4 Causation of apathy
Sansone, Sansone (2010) wrote a short compilation of case reports of SSRI-induced apathy. Price et al. (2009) described anhedonia caused by SSRIs based on users’ reports.

Hoehn-Saric et al. (1990) is one of the first (if not the first) case reports of apathy induced by SSRIs; 2 cases of apathy induced by fluvoxamine and 2 cases induced by fluoxetine were reported. The subjects became indifferent towards their duties: work and child-caring. The apathy was severe to the point that one of the subjects stopped paying the bills for 3 months.

In a non-randomized trial with subject selected among people considered to have major depressive disorder and previously selected for a study on SSRI-induced sexual dysfunction, Opbroek et al. (2001) found that SSRIs decrease self-reported of emotionality in a heterogeneous group treated with fluoxetine, paroxetine and sertraline. The items in the questionnaire with the largest decrease were sexual desire and ability to cry. This study conclues with the following utterance: “We speculate that insome patients, rather than representing a side-effect, blunting of emotions may be the central therapeutic effect of SSRIs.â€.

14.5 Effect on psychopathy cluster traits
Knutson et al. (1998) found that 20 mg/d of paroxetine results in reduced negative affect. Rütgen et al. (2019) found that open-label non-randomized treatment with serotonergics of people considered to have major depressive disorder resulted in decresaed empathy, specifically reduced self-reported distress when seeing videos of which they were told, depicted a person experiencing pain during a treatment for tinnintus. Knutson et al. (1998) mentions evidence from animal studies and observational studies in humans that sertraline decreases aggressivity.

Berman et al. (2009) and Fanning et al. (2014) found that an acute dose of 40Â mg of parxoetine reduced provoked aggression. In both studies, subjects were told they would compete against an opponent (which was fictitious) on reaction time conducted as follows: Prior to each round, each participant would select a level of electric shock to be given to the opponent. After each round, the loser would be given the level of electric shock chosen by the winner and the winner would be told the level chosen for him by the loser. The provocation stimulus consisted in the ficicious adversary choosing high shock levels. The response was evaluated according to the intensity of shock chosen by the subject to be ostensibly given to his adversary after the provocation stimulus.

Dunlop et al. (2011) examined the effect of sertraline and triiodothyronine (T3) in the components of the Psychopathic Personality Inventory (PPI). They found that sertraline increases score in component PPI-1 (fearless dominance) and decreases score in component PPI-2 (self-centered impulsivity). They found that treatment with T3 did not cause a change in PPI scores.

Crockett et al. (2015) found that an acute dose of 30Â mg citalopram increases aversion to giving and receiving electric shocks in exchange of receiving a monetary reward. Crockett et al. (2010) using the same acute dose of citalopram found that it decreases the proportion of subjects that answered that causing personal harm in specific hypothetical situations is acceptable in order to avoid a common harm. These results softly contradicts the results above by which we would expect that citalopram would decrease aversion to giving electric shocks.

14.5.1 Increase in callosity-unemotionality
There is significant evidence from anecdotal reports that prolonged administration of SSRIs increase the callous-unemotional component of personality. Users of SSRIs often describe this change as becoming a psychopath. Users of SSRIs usually ignore the possibility of this effect when they start.

The author’s observation is that SSRI users who rely on reason over emotions prior to starting a SSRI tend to either like the increase in callosity-unemotionality or passively accept it while users who take their emotions on prima facie value and give them more importance than reason tend to be very averse to this effect, to the point of it being a cause to discontinue SSRIs. Thus, there is a self-selection bias where people who already have a cold personality are more likely to continue use of SSRIs.

“Worried [fluoxetine (Prozac)] has turned me into a psychopath†is a self-report of fluoxetine causing a person with high empathy to become completely undisturbed by videos of extreme violence towards humans. From that report:

I was put on [fluoxetine] for my OCD in late 2014 and was kept on throughout 2015, upping my dosage from [20 mg per day] to [40 mg per day] at some point, I can’t remember when exactly. During that time I noticed a sense of emotional blunting e.g. no empathy, constant boredom and apathy, no motivation, felt no rush during dangerous situations.
Around April of 2016 I got on Sertraline to try and combat this and it has seemed to be doing some good but lately I’m starting to wonder if that’s all in my head. [...]​
From “I feel like Zoloft (sertraline) is turning me into a psychopathâ€:

If I saw some one in pain or struggling on classwork, I would drop what I was doing and put 100% of my attention on them. Up until 11th grade (when the [sertraline] started working) I always was thinking about asking girls out, who I had a crush on... etc. I was completely grossed out by blood of any kind, If I saw even a bloody cut or something like that on the internet it would give me chills and sometimes even nightmares.
Now I feel like all of those feelings are almost gone. I have no problem looking at mangled corpses, car crash victims, or even beheadings. Hell, looking at some of those images and videos actually kind of excites me, in the way that it releases adrenalin, [...] If I personally see someone get injured or struggle on their school work, I just don’t care about helping them anymore. I have no problem lying, manipulating or breaking the rules to get my way. I mean in high school I never broke any rule, I would always tell the truth even if I knew it would get me in trouble.​
From “Developing sociopathy through pharmaceutical meansâ€:
[...] As soon as I started the fluoxetine, I’ve become much less inclined to avoid conflict. I won’t budge [a centimeter] now. I used to care what people think. Now I don’t give a rat’s ass. I’ve almost completely lost my ability to feel affective empathy. I wasn’t always deficient in this area, but now my best ‘friend’ could break his leg and I wouldn’t feel a thing. I’d do all the things a best friend is supposed to console them, but I wouldn’t feel a thing. When my mother cries, I feel nothing except for annoyance. I used to never lie. Now I lie whenever it suits me. I used to have self esteem issues. Now I think people who dislike me can die for all I care. I don’t feel any regret, guilt or shame when I fuck up, just annoyance.​
From “I feel like [escitalopram (Lexapro)] (20mg) is slowly turning me into a sociopathâ€:

[...] when I’m on [escitalopram] I become apathetic to those feelings so when I do something shitty/selfish/assholish/stupid/embarassing/etc. I just don’t really care and my behavior stays the same (or worsens...). I will admit that I was definitely selfish when I was off [escitalopram] prior, but it was something I was struggling to fix. Now I have no incentive to though and I feel like I’m hurting the people all around me and just use them with no regard to their emotional well-being.​
From “SSRIs destroyed my emotions and empathyâ€:
So I’ve been taking [sertraline ...] I’ve quit it recently.
The reason of quitting was not being able to normally feel emotions (they basically felt detached (dissociated?) and flat, like I was spectator rather than a participant, and I felt like I’m faking them), I was sorta ok with it at first but then I started hating this “feelingâ€, I basically started to feel indifferent, like if my house was burnt or some shit like apocalypse began I’d just yawn a lil (actually a lot) and not care at all. Alongside that my empathy suffered aswell, it’s just not there anymore.​
“Sociopathy and [SSRIs]†is a self-report of instrumental aggression and anti-social behavior attributed to paroxetine.

I think their [(SSRIs’)] effect on a person who doesn't really need them is fearlessness.
My first experience with [paroxetine] didn’t only relieve my anxiety, it made me basically fearless and kind of unleashed me and my impulsiveness, the latter got me in trouble. I did all sorts of things that I knew I was capable of, but just wasn’t ballsy enough to do before (nor now).​
14.6 Effect on sexual function
Banov (1999) reported that in his experience, administering fluoxetine to other people caused less sexual disruption that other SSRIs. Nafziger et al. (1999) wrote an epistemological critique of Banov’s paper.

Atmaca (2019) reviewed sexual dysfunction caused by SERT inhibitors and its attempted treatment. Massand (1994) reported success in treating SSRI-induced sexual dysfunction with amantadine (not a controlled trial). Users of SSRI affected by this phenomenon were given up to 600Â mg of amantadine given as 3 doses of 200Â mg every day. Of the 5 users to which amantadine was given, 2 reported mild side effects (one rash, which is not clearly attributable to amantadine and the other slight nausea), 2 reported no side effect and 1 was lost to follow-up. Zahiroddin et al. (2017) examined separately amantadine and bupropion to restore sexual functioning in subjects receiving various SSRIs; they found that bupropion increased self-reported sexual functioning; amantadine increased it too to a lesser extent. Costa et al. (2006) reviewed the literature for treatments of antipsychotic-induced sexual dysfunction; this can be applicable to SSRI-induced sexual dysfunction too.

The web forum discusses the phenomenon of persisting sexual impairment caused in some cases by use of SSRI.

14.6.1 Reduced genital sensitivity
Reduced general sensitivity is an uncommon effect of SSRIs. In some extreme cases this is referred to as “genital anesthesiaâ€. Following is a list of case reports.
  • Michael, Andrews (2002) reported a case of “complete loss of sexual, touch, and pain sensation†in the vagina of a 30 year old woman treated with paroxetine. The problem stopped after cessation of SSRIs.
  • Bolton et al. (2006) reported a case of a 26 year old man treated with sertraline that developed reduced penile sensitivity, subjectively delayed orgasm (apparently according to the user’s own judgement) and absence of a pleasurable feeling coincident with ejaculation.
  • Waldinger et al. (2015) reported a case of 20Â mg per day of paroxetine causing loss of sense of taste, smell and general decreased skin sensitivity in a 43 year old man that had a very poor baseline penile sexual response. After discontinuation of paroxetine skin sensitivity was recovered but not in the penis. Penile sensitivity partially recovered with low-power laser irradiation therapy on the glans.
  • Ellison, DeLuca (1998) reported a case of a 37 year old woman developing reduced sensitivity with treatment to fluoxetine, 10 mg-60 mg per day. They write: “she noted altered sensation in her vagina, vulva, and clitoris such that touch was perceptible but reduced in intensity and “not stimulating.â€â€. Treatment with yohimbine while continuing fluoxetine did not result in relief. Treatment with 180 mg to 240 mg of the Ginkgo biloba extract EGb 761 while continuing fluoxetine resulted in relief of the symptons. It is not clear whether relief was complete.
  • Deisenhammer, Trawöger (1999) reported a case of lack of energy and decreased genital sensitivity caused by sertraline. “Mr. A was prescribed sertraline, 50 mg/day, and after 3 days he noticed decreased sensation of his penis upon any form of stimulation. Erectile function remained unaffected.â€. Discontinuation of sertraline caused the problem to disappear. One year later, reexposure to the same dose of sertraline cause the problem to reappear.
  • Patacchini, Cosci (2019) reported a case of anhedonia and loss of libido apparently caused by administration of 100 mg per day of sertraline to a subject that persisted for years after discontinuation. The subject was described as having “premature ejaculationâ€. This is opposite to the usual effect of SSRIs which is to delay ejaculation and orgasm.
14.7 Effects at biochemical level
In an experiment with rats Bymaster et al. (2002) found that all the SSRIs they tested (fluoxetine, citalopram, fluvoxamine, paroxetine and sertraline) increased extracellular concentration of serotonin in rats and that fluoxetine but not other SSRIs increases the extracellular concentration of dopamine in the prefrontal cortex. Perry, Fuller (1992) found that fluoxetine did not increase extracellular concentration of dopamine in the striatum of rats. Di Mascio et al. (1998) found that paroxetine, sertraline and fluvoxamine reduced the firing rate of dopaminergic neurons in the ventral tegmental area and the firing rate of serotonergic neurons in the dorsal raphe nucleus; this paper also examined the effects of tertatolol combined with the aforementioned SSRIs.

14.8 Other effects
SSRIs have an effect on sexual function, almost entirely negative: Decreased libido, increasing latency and amount of stimulation needed to reach orgasm, in some cases decreased genital sensitivity, anorgasmia. Some of these effects can persist after discontinuation in a phenomenon known as post-SSRI sexual dysfunction (PSSD). Bala et al. (2018) reviewed the literature on PSSD. Haberfellner, Rittmannsberger (2004) reported spontaneous improvement in delay of orgasm caused by SSRIs after 6 months including complete remission of that effect in 31Â % of users.

Moore et al. (2010) found that the SSRIs fluoxetine, paroxetine, sertraline, escitalpram, citalopram and duloxetine have a disproportionate number of case reports of being suspected of causing violent behavior. Note that this is a purely observational study and therefore it is subject to many confounders.

SSRIs have a mild estrogenic effect. Hansen et al. (2017) investigated the effects on steroidgenesis of citalopram, escitalopram, fluoxetine, fluvoxamine, paroxetine and sertraline in vitro in an adrenal cell line. They found that in high enough concentration, all these pharmaceuticals reduced production of androgens and increased production of estrogens. Munkboel et al. (2018) found that sertraline decreases concentration of androgens and of enzymes involved in steroidgenesis in rats. Despite the overall incrase in estrogens Jacobsen (2015a) found that citalopram, fluoxetine, fluvoxamine, paroxetine and sertraline act as aromatase inhibitors with IC50 varying across 2 orders of magnitude.

SSRIs decrease the blood concentration of 5-hydroxytryptophan (5-HTP), a precursor in the biological synthesis of serotonin. Grillon et al. (2008) report that 14 days of administration of citalopram (10 mg per day for 2 days, then 12 mg per day for 12 days) resulted in 5-HTP levels below 50 μg/l (↔ 227 nmol/l).

Fleischhacker (1991) wrote a case report of fluoxetine-induced akathisia treated with 20 mg/d of propranolol. He writes: “Propranolol [...] led to immediate relief which started on the second day of treatment and reached a maximum by day 3. [...] Stopping propranolol for 2 days was followed by a recurrence of akathisia, treatment had to be taken up again.â€. Basu et al. (2014) wrote a case report of escitalopram-induced akathisia treated with 60 mg/d of propranolol and 1 mg/d of clonazepam.

SSRIs and tricyclics reduce neuralgia (a.k.a. neuropathic pain; related keyword: neuritis); this effect appears to be caused in part by use-dependent blockage of voltage-gated sodium channels and in the case of tricyclics, stimulation of adrenergic receptors. Tricyclics are generally considered more effective than SSRIs for this purpose (Dick, 2007). See Obata (2017) for a review on the mechanism of action. Huang et al. (2016) identified the SSRIs paroxetine, sertraline, fluoxetine, fluvoxamine; the tricyclics amitriptyline, desipramine, doxepin, protriptyline, trimipramine and other compounds from other pharmacological classes as voltage-gated sodium channel blockers.

Kemp (2010) examined the association between heart rate variability (HRV) and psychoactive drugs used to treat depression including SSRIs and tricyclics. Agorastos et al. (2015) examined the change in heart rate variability in healthy volunteers caused by CCK-4 with or without treatment with escitalopram for 42 days in healthy volunteers. This article includes a review of the effect of SSRI on heart rate variability.

14.9 Fluoxetine
Fluoxetine (PubChem CID 3386) was the first SSRI to be discovered. It was discovered by the pharmaceutical company Lilly and presented in Wong et al. (1974); 2 of the same authors subsequently wrote an account of the discovery of fluoxetine in Wong et al. (1995).

Catterson, Preskorn (1996) give the half-life of fluoxetine as 2Â d to 3Â d. The same paper mentions that norfluoxetine (PubChem CID 4541) is a metabolite of fluoxetine with comparable SERT inhibition potency and a half-life of 7Â d-15Â d.

As mentioned in § Effect on critical flicker fusion threshold, fluoxetine increases the critical flicker fusion threshold in humans.

As mentioned in § Effect on startle response, fluoxetine decreased magnitude of startle response, opposite of citalopram (which is a more specific SSRI).

Kokotos et al. (1996) report that fluoxetine inhibits MAO-B with a IC50 of 50Â nmol/l and fluvoxamine does not significantly inhibit MAO-A nor MAO-B.

15 Non-SSRI SERT inhibitors
15.1 Vortioxetine
Vortioxetine is a SERT inhibitor and ligand of several serotonin receptors. See Sowa-Kućma et al. (2017) for a review of its pharmacodynamics.

In a review Chen et al. (2017) stated that vortioxetine has a t1/2 of 66Â h and time to peak concentration of 7Â h-11Â h.

Several trials found that vortioxetine has a lesser negative impact on sexuality than SSRIs. In a randomized blind comparision Jacobsen et al. (2015b) found that subjects rated higher their sexual functioning with a dose of 10Â mg/d-20Â mg/d of vortioxetine compared to 20Â mg/d of escitalopram. The same study found that vortioxetine caused generalized itching in some subjects.

16 Valproic acid
Valproic acid is a simple chemical compound with systematic name 2-propylpentanoic acid. In medical use it is commonly found as a salt, thus referred to as X valproate where X is the counter-ion.

Valproic acid serves as an anti-epileptic and mood stabilizer. Its mechanism of action is less well characterized than that of most other psychoactive substances (SSRIs, opioids, benzodiazepines, etc.). Peterson, Naunton (2005) reviewed the effects of valproic acid.

17 Activities with psychological effect
17.1 Physical exercise
Heart rate is influenced by sympathetic stimulation (increases) and vagal stimulation (decreases). Heart rate variability (HRV) is a strong indicator of vagal stimulation and cardiac health. The higher the vagal stimulation, the higher the HRV.

Physical exercise and in particular aerobic exercise have been found to decrease resting heart rate, increase HRT and decrease and other quantitative correlates of cardiovascular pathologies (Reimers et al. 2018; Kang et al., 2016; Goldsmith et al., 2000).

17.2 Low blood glucose (hypoglycemia)
Eating foods with a high proportion of carbohydrates results in an increase in glucose within minutes followed by a decrease of glucose that lasts hours. Low blood glucose (hypoglycemia) has adverse physical and psychological effects: Impaired ability to concentrate, dysphoria (i.e.: opposite of euphoria), somatization, tiredness, sleepiness, decreased energy. See Aucoin, Bhardwaj (2016) for a case report and short review.

18 Other related works
  • Stahl (2017) contains information on individual psychoactive compounds organized in one section per compound.
  • Reviews of products commercialized as “supplements†with a claimed psychological effect.
  • A web site about the side effects of psychoactive drugs including a monetary prize for a cure of post-SSRI sexual dysfunction.
19 Acknowledgements
Thanks to A. and E. for bringing several of the studies cited herein to my attention.

20 Notes
  1. Meyer et al. (2002) give the ED50 for receptor occupacy of SSRIs and venlafaxine (also a SERT inhibitor) in humans
  2. Stahl (2017)
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Cases of self-surgery#
First version: 2019-12-21
Last update: 2020-12-27
Persistent link to latest version:

We present a compilation of case reports of self-surgeries. In each case only a very short description is presented. The reader is referred to the case reports for a more extensive description.
Inclusion criterion: We attempt to list only procedures that are remarkable in their good preparation, good technique or good results. Emergency surgeries done in the field without any proper equipment nor preparation like amputations of trapped limbs and similar are not considered. Cases of self-cutting without an intention to perform a well-defined surgical procedure are not considered.
  1. 1 Overview
  2. 2 List of reported cases
    1. 2.1 Removal of kidney stone of Maldigny, 1824
    2. 2.2 Operation of inguinal hernia of Alexandre Fzaicou, 1909
    3. 2.3 Appendectomy of Evan O’Neil Kane, 1921
    4. 2.4 Cardiac cathetherization of Werner Theodor Otto Forßman, 1929
    5. 2.5 Operation of inguinal hernia of Evan O’Neil Kane, 1932
    6. 2.6 Appendectomy of Leonid IvanoviÄ Rogozov, 1961
    7. 2.7 Denervation of adrenal glands reported by Kalin (1979)
    8. 2.8 Removal of bone fixators reported by Moholkar et al. (2000)
    9. 2.9 Operation of carpal tunnel syndrome by Henry David Nava Dimaano, 2010
    10. 2.10 Release of trigger finger by Henry David Nava Dimaano, 2010
    11. 2.11 Lipectomy by de Freitas Sobrinho, 2012
    12. 2.12 Operation of umbilical hernia by Aytekin, 2013
    13. 2.13 Excision of cosmetic defect in arm by Castelán Castro, 2020
  3. 3 Acknowledgements
  4. 4 References
1 Overview
Szabó, Brockington (2013) reviewed instances where a self-caesarean section was attempted.

Self-orchiectomy appears to be relatively common. We conjecture most cases go unnoticed by the medical establishment as it is a simple surgery unlikely to result in complications that would prompt the self-surgeon to seek help.

We recommend that professional and amateur surgeons document their experiences in the literature. To amateurs that do not want or can not pay for the publishing fee for open access we recommend to make use of e-print servers where papers can be published without cost to the author nor the reader.

2 List of reported cases
Individual cases self-surgery are listed below in chronological order. This is not an exhaustive list.

2.1 Removal of kidney stone of Maldigny, 1824
M. Clever Maldigny, miltary surgeon in the French Royal Guards had received 5 renal lithotomies (by other personnel) before he successfully performed the 6th himself (Nwaogbe et al., 2017).

2.2 Operation of inguinal hernia of Alexandre Fzaicou, 1909
In 1909 Alexandre Fzaicou operated his own left inguinal hernia using strychnine and amylocaine (a.k.a. stovaine) as an anesthethic (Nwaogbe et al., 2017).

2.3 Appendectomy of Evan O’Neil Kane, 1921
In 1921 Evan O’Neil Kane performed part of an appendectomy on himself in an hospital setting using local anesthetic. A stated motivation was to prove the suitability of local anesthetics for major surgery. Closing the wound was left to assistants (Rennie, 1987).

2.4 Cardiac cathetherization of Werner Theodor Otto Forßman, 1929
Forßman performed the first cardiac cathetherization on himself to prove its viability and safety. He presented the plan to the chief of surgery and was rejected. Without authorization he asked for the help of a nurse. The nurse accepted and offered herself as the subject. While keeping the guise of preparing to operate on the nurse, Forßman inserted the cathether in his own arm then revealed this to the nurse. They proceeded to the X-ray room to complete the procedure and take X-rays photographs. After contacting the chief of curgery about his success, Forßman was admonished and allowed to apply the procedure in patients (Nwaogbe et al., 2017).

2.5 Operation of inguinal hernia of Evan O’Neil Kane, 1932
In 1932 the previously mentioned Evan O’Neil Kane operated himself an inguinal hernia he acquired during horseback riding (Nwaogbe et al., 2017).

2.6 Appendectomy of Leonid IvanoviÄ Rogozov, 1961
The Soviet medic Leonid IvanoviÄ Rogozov performed appendectomy on himself in an improvised setting in an Antarctic research station. Members of his team without medical training served as assistants (Rogozov, Bermel, 2009). Depsite that Rogozov used a mirror, he chose to operate without gloves because given the sub-optimal visibility part of the operation had to be performed by tact.

2.7 Denervation of adrenal glands reported by Kalin (1979)
A 22-year old unnamed natal male attempted to denervate his adrenal glands. The surgeon had previously performed a removal of both of his own testicles and started taking MTF HRT. The motivation was to become asexual. In the case report he is quoted as saying “I’m no homosexual or transsexual. I still want a hugging and kissing relationship with a woman.â€. We interpret this as that he had no intention to present as a woman. Note that since was taking cross-sex hormones he was transsex per the definition of “Pharmacology of transsexualismâ€.

The operation took place in the surgeon’s dormitory. He had previously cleaned it with spray disinfectant and covered an area (presumably of his bed) with sterilized sheets. He took barbiturates per oral for analgesia (the report is not more specific). He took cortisol and prepared a canister of aerosolizable adrenaline (case report says “vaporized†adrenaline) in preparation for a possible hypovolemic shock. A surgical mask, sterile gloves, scalpel and retractors were used. The outer incision was 14 cm incision from the end of the sternum to around the navel (case report does not specify if this was made in a single cut). Lidocaine was injected as he proceeded deepening the cut. For hermostatsis, sterile cotton thread for ligating blood vessels and gelatin powder was used. After 8 h there was no significant blood loss. The surgeon could not reach the target nerves. He closed the wound with bandages and went to a hospital. The personnel irrigated with antiseptic solution and closed the wound without terminating the surgery (Kalin, 1979).

2.8 Removal of bone fixators reported by Moholkar et al. (2000)
A 27 year old male attempted to remove the fixation of his fractured fibula. At the time he performed the self-surgery he was awaiting for removal of the fixator. The fixators were causing pain. The fixation consisted of a metal plate and 6 screws. An alcoholic beaverage per oral was used for analgesia. He removed 5 screws, then he went to emergency room of an hospital where the removal was completed. The article where this case was reported states that the subject was a university student; it is not stated whether he was a student of a medical field. We suppose his field was not medicine becuase of the improvised instruments employed (Moholkar et al. 2000).

2.9 Operation of carpal tunnel syndrome by Henry David Nava Dimaano, 2010
Henry David Nava Dimaano operated his carpal tunnel syndrome in the left arm. A video is available; unfortunately it does not show the suture.

2.10 Release of trigger finger by Henry David Nava Dimaano, 2010
Henry David Nava Dimaano performed a release of trigger finger affecting his ring finger of the left hand with heavy help of an assistant. A video is available; again it does not show the suture. The sutured wound of his previous carpal tunnel surgery is visible.

2.11 Lipectomy by de Freitas Sobrinho, 2012
Brazilian plastic surgeon Luiz Américo de Freitas Sobrinho performed a lipectomy on himself with the help of assistants. A self-archived recording is available. A translation of the text at the start of the video by the author of this article follows.
This film is about a self-surgery in the lower abdominal region performed by plastic surgeon Dr. Luis Américo de Feritas Sobrinho, whose challenge has as a main goal an improvement of his technique by feeling in his own body what his patients have felt over the course of 3 decades of his professional activity.​
The video was published with the following description, again translated by the author of this article.
Self-surgery of my lower abdomen.​
I pondered for around 2 years about the pros and cons of this self-surgery. Some colleagues supported me, other suggested me [psychological] therapy and fortunately some challenged me. I say “fortunately†because the latter contributed to my decision, taking into account that I like challenges very much.​
When I read the story of Soviet medic Leonid Rogozov that extracted his appendix to save his own life during a mission to antarctica (in the article “The 10 most incredibles self-surgeries in the world†in HypeScience) I received the impulse I was missing to what on myself what that valiant collegue did on himself.​
The surgery.
The surgery lasted around 2 hours. In the operating room as supporting team there was present a plastic surgeon, a general surgeon and a general practitioner. I used local anesthesia for the self-surgery, as I usually do in surgeries of minor and medium size in my clinic. Local anesthesia and muscular sedation are preferrable to general anesthesia or venous sedation because the risks are smaller.​
With a mass of 92Â kg and height of 1.70Â m I performed the operation well above the ideal weight. It is important to note that when people are operated within the ideal mass future corrections to remove leftover tissue as a consequence of post-surgical shrinking can be avoided.​
The surgical procedure included removal of skin and of fatty tissue in an ellipse shape, but in chunks (technique used normally by me) I removed several segments of around 10Â cm each, cauterizing and suturing. I forgot to weight it, but I think I have not removed more than 1Â kg of fat tissue because it weights little.​
I feel happy for having accomplished another challenge, of the many that remain to heppen.​
Luiz Américo de Freitas Sobrinho specialist in plastic surgery.​
The self-surgery of de Freitas Sobrinho was itself featured in HypeSpace, the web site from which an article inspired him to do a self-surgery.

2.12 Operation of umbilical hernia by Aytekin, 2013
Oygar Aytekin (web page) published a video (in YouTube) where he successfully operates his umbilical hernia with help of an assistant. Proper surgical instruments were used. The year given here is the year of publication of the video.

In an interview with newspaper Hürriyet (picture), Aytekin said (translation by Tsarina Effy):

The surgery was indicated. Regarding why I self-performed it, we can say that it was out of boredom. Imagine having to get off your butt and visit a colleague for it [...] I already had everything I needed there, so I just operated. Assistant nurse and I not only performed the surgery, but also had fun doing it.​
I sat down reclined. I administered local anesthesia. Now that I have experienced it, I do not believe anyone saying ‘local anesthesia hurts’. I did not feel anything. I belive confidence comes from knowledge. You know that you cannot harm yourself. Because you know the layers, tissues, where everything is situated, and how exactly to operate. I told myself ‘I cannot be bothered to visit another doctor, I will do it myself.’ I do not find it extraordinary. Any surgeon can do it. The hard part of the operation is the position. In reclined position, it is harder to see the surgical site and to separate the layers. Also, the position applies pressure to the abdomen which pushes the fats outwards.​
2.13 Excision of cosmetic defect in arm by Castelán Castro, 2020
In 2020 the author of this article removed a small cosmetic defect in the arm with one hand. A self-report with extensive details was written (Castelán Castro 2020).

3 Acknowledgements
Thanks to Tsarina Effy for bringing the self-surgery of Aytekin to my attention and translating the text and for bringing to my attention both surgeries of Nava Dimaano. Thanks to the persons who have performed self-surgery thus demonstrating in practice the right to self-determination over one’s body even when it goes against common orthodoxy. Thanks to the persons who have experimented with novel procedures of technical value (surgery or otherwise) on their own bodies thus leaving a technical contribution to humanity’s collective knowledge and an example of courage.

4 References
  1. M. X. Castelán Castro (2020) “Cosmetic self-surgery in the armâ€. ARK:
  2. K. Moholkar et al. (2000) “Self-surgery: removal of ankle surgical implants – A case reportâ€. URI: No DOI could be found.
  3. C. Nwaogbe et al. (2017) “Surgeons performing self-surgery: A review from around the worldâ€. DOI: 10.1016/j.tria.2017.11.001. Open access.
  4. N. H. Kalin (1979) “Genital and Abdominal Self-surgeryâ€. DOI: 10.1001/jama.1979.03290460052021.
  5. D. Rennie (1987) “Do it to yourself section. The Kane surgery.â€. DOI: 10.1001/jama.1987.03390060115037.
  6. V. Rogozov, N. Bermel (2009) “Autoappendectomy in the Arcticâ€. DOI: 10.1136/bmj.b4965.
  7. A. Szabó, Ian Brockington (2013) “Auto-Caesarean section: a review of 22 casesâ€. DOI: 10.1007/s00737-013-0398-z.


Biocides (antiseptics and disinfectants) (work in progress)#
First version: 2020-02-09
Last update: 2020-12-27
Persistent link to latest version:
  1. 1 Nomenclature
  2. 2 Targets
    1. 2.1 Prions
    2. 2.2 Bacterial spores
  3. 3 Cleaning
  4. 4 Agents
    1. 4.1 Benzalkonium chloride
    2. 4.2 Benzene-1,2-dicarbaldehyde
    3. 4.3 Chlorhexidine
    4. 4.4 Ethaneperoxoic acid
    5. 4.5 Pentanedial
    6. 4.6 Sodium hypochlorite
  5. 5 Autoclave
  6. 6 Other resources
  7. 7 Notes
  8. 8 References
1 Nomenclature
Biocides are chemical substances that in low concentrations are enough to kill viruses and inactivate bacteria. A vague distinction is made in practice between antiseptics which are biocides suitable for use on living beings and disinfectants which are biocides suitable for use on inanimate objects.

2 Targets
WHO (2016), p. 79 give the resilience of microorganisms to antiseptics as follows, in decreased order of resilience:

  1. Prions
  2. Bacterial spores
  3. Parasites of the taxon Coccidia
  4. Mycobacteria
  5. Small non-enveloped viruses
  6. Vegatative bacteria
  7. Lipid enveloped viruses
An early version of this ranking appeared of McDonnell, Russel (1999) and Russell (1999).

Note that resilience is not an indicator of pathogenicity nor vice-versa. For example: The lowest category, lipid enveloped viruses, includes HIV and the Ebola virus which have caused highly lethal epidemics; bacterial spores include Geobacillus stearothermophilus which is not pathogenic to humans; Coccidia monocellular parasites include Toxoplasma gondii, which can cause infection in humans, usually asymptomatic.

2.1 Prions
Prions are a specific class of abnormally folded proteins that can induce the same misfolding on proteins of the same type. Prions are the causative agent of transmissible spongiform encephalopathie (TSEs) including bobine spongiform encephalopathy (“mad cow diseaseâ€). TSEs are among the few transmissible diseases that can emerge spontaneously in healthy organisms without prior contamination. Prions accumulate especially in the central nervous system of affected organisms and are not common in the outdoor environment, unlike spore-forming bacteria.

2.2 Bacterial spores
Bacterial spores are structures that contain the genetic material of the parent bacterium in a dormant state; when exposed to favorable conditions, they regenerate the vegatative (active) form. Bacterial spores are resilient to extreme conditions including high temperature and most biocides. Only some bacterial species can form spores. Leggett et al. (2001) reviewed the mechanism at the biochemical level known or suspected to be responsible for the resilience of bacterial spores.

Spore-forming bateria are common in outdoor environments. Some species are part of the normal flora of the digestive tract of humans and other animals. A few species cause localized cutaneous infection; examples include Clostridium perfringens (gas gangrene) and Bacillus anthracis (cutaneous anthrax).

Biocides that can inactivate bacterial spores are called sporicides. Sporicides used in practice can be divided in 2 disjoint groups: alkylating agents and oxidizing agents (Maillard (2011) writes: “There is only a limited number of chemical biocides that possess sporicidal activity. These biocides are all highly reactive and theycan be divided into alkylating and oxidising agentsâ€). Oxidizing agents are generally faster to inactivate spores than alkylating agents and can harm metal objects. Alkylating agents are suitable for use with metal objects. Neither class is suitable for use on living tissue. Alkylating agents tend to be mutagenic in in vitro assays; therefore, exposure of operators to their vapors should be minimized as a precautionary measure material disinfected with such agents should be thoroughly rinsed before use.

3 Cleaning
Material should be devoid of macroscopic contamination prior to disinfection. Residues of bodily fluids and solid tissue decrease the effectiveness of biocides through chemical reaction, dilution and hindering penetration of the biocide. This contamination can be removed by manual scrubbing with a brush using clean water and a detergent or an enzymatic cleaner, then rising with water. The water used for cleaning needs not be sterile. Brushes should be discarded or cleaned and disinfected between uses to avoid cross-contamination. Cleaning is not a substitute for disinfection. WHO (2016) contains extensive discussion of recommended practices for cleaning.

4 Agents
4.1 Benzalkonium chloride
Benzalkonium chloride is a quaternary ammonium salt. It is suitable as an antiseptic. It is suitable as a surgical disinfectant provided that contamination with resilient pathogens (especially bacterial spores) can be ruled out. Benzalkonium chloride solutions in water have a slight tendency to foam like soapy water. It is not and oxidant and therefore does not tarnishes stainless steel. It has a mild sweet odor, especially when dry.

Sebben (1983) recommend against benzalkonium chloride because of its narrow spectrum and that it is easily inactivated by ordinary conditions including contact with blood. Acosta-GÃo et al. (2001) found that benzalkonium chloride at a mass concentration[1] of 0.12Â % did not inactivate Bacillus subtilis spores.

Wood, Payne (1998) found that a solution of 2Â g/l of benzalkonium chloride inactivates non-enveloped viruses and coxsackie virus but not poliovirus in 1 minute in an assay made to simulate contamination with bodily fluids.

4.2 Benzene-1,2-dicarbaldehyde
Benzene-1,2-dicarbaldehyde is an alkylating sporicidal. In medical practice it is more commonly known under the archaic name “o-phthalaldehydeâ€. Cabrera-Martinez et al. (2002) examined the sporicidal mechanism of action of benzene-1,2-dicarbaldehyde.

4.3 Chlorhexidine
Chlorhexidine is a broad-spectum biocidal with activity against Gram-positive and Gram-negative bacteria, fungi and viruses but not spores. It has limited activity against spores. Neutral chlorhexidine has low solubility in water. In medical used it is used in the form of chlorhexidine acetate, chloride dichloride or chlorhexidine digluconate in solution with an alcohol (Karpiński, Szkaradkiewicz 2015 for paragraph so far). Chlorhexidine is partially tolerant to autoclaving; it releases small amounts of 4-chloroaniline (Russel 1993 for sentence). Its activity is reduced by blood serum (Russel 1993 for sentence).

4.4 Ethaneperoxoic acid
Ethaneperoxic acid is the linear single-ended peroxic acid with 2 carbon atoms. In medical practice it is more commonly known under the archaic name “peroxyacetic acidâ€. March et al. (2015) found that a solution with a mass fraction[1] of 0.25 % ethaneperoxic acid is effective in inactivating bacterial spores; among the species tested, they found that spores of Bacillus anthracis required the longest time to inactivating (6 decades of reduction) at 4 minutes. A solution of 1.3 % ethaneperoxic acid achieved the same level of inactivation at less than 1 minute.

Black et al. (2017) found that ethaneperoxic acid is suitable for use with steel of alloy AISI 304 but not suitable for use with steel of type AISI 430 because it causes corrosion of the later alloy and is quickly inactivated. Alloy AISI 304 is representative of the stainless steel used for surgical instruments; however surgical instruments almost never state the specific alloy they are made of.

4.5 Pentanedial
Pentanedial is the linear, unsubstituted dialdehyde with 5 carbon atoms. In medical practice it is more commonly known under the archaic name “glutaraldehydeâ€. Acosta-GÃo et al (2001) is found that a solution with (presumed mass) fraction of 2 % pentanedial inactivates Bacillus subtilis spores after 10 h. March et al. (2015) found that a solution of glutaraldehyde at 2.4 % (not specified whether by mass or volume) is effective in inactivating bacterial spores; among the species tested, they found that spores of Bacillus subtilis requied the longest time to inactivate (6 decades of reduction) at 214 minutes.

4.6 Sodium hypochlorite
Sodium hypochlorite is the the active component of household bleach. It is a powerful disinfectant. The United States Center for Disease Control (CDC) includes immerson in sodium hypochlorite among the recommended means of disinfection for instruments contaminated with prions. Brown et al. (2004) examined the effect of concentrated aqueous solution of sodium hypochlorite mass fraction[1] of 5.25Â % to 6Â % on medical instruments. Instruments were immersed in sodium hypochlorite for 1Â h, then washed in water for 30Â min; this was repeated 5 times. They found that some instruments were not harmed at all, some had cosmetic blackening of the surface not affecting the functionality and others had patent corrosion.

Solutions of sodium hypochlorite are degraded with time because chlorine escapes as a gas. To minimize inactivation, solutions of sodium hypochlorite should be kept in a air-tight closed container and diluted only prior to use.

Kampf et al. (2020) found that 0.1Â % sodium hypochlorite[1] inactivates SARS-CoV-2 after 1 minute.

5 Autoclave
Autoclaves are the standard means to disinfect heat-resistant instruments in well-equiped medical facilities. Usual treatment is 30 min of exposure to steam at 121 °C. Validation can be performed by exposing spores of Geobacillus stearothermophilus –a particullarly heat-resistant species– to an autoclave cycle. The exposed sample and an untreated control sample are cultivated. The proccess is deemed valid if there is germination in the control sample and not in the exposed sample. An autoclave proccess cerified in this manner will inactivate most pathogens with the notable exception of prions. The WHO recommend methods for the reprocessing of instruments contaminated with prions, some of which involve combination of autoclave treatment with sodium hypochlorite or sodium hydroxide; see WHO (1999).

Swenson et al. (2018) found that some commercially available pressure cookers are suitable for disinfection up to inactivation of Geobacillus stearothermophilus.

6 Other resources
The WHO published a book on recommended practices for reprocessing of medical devices including biocides for reprocessing surgical instruments (WHO 2016). Rutala, Weber (2004) wrote an introduction to disinfection of medical equipment with chemical products.

7 Notes
  1. Not specified whether mass fraction, volume fraction or amount of substance fraction in source. Assumed to be mass fraction.
  2. of 0.12Â % did not inactivate
8 References
  1. E. Acosta-GÃo et al. (2001) “El cloruro de benzalconio: inaceptable para esterilizar o desinfectar instrumental médico o dental†[in Spanish]. DOI: 10.1590/S0036-36342001000600008. Open access.
  2. E. Black et al. (2017) “Evaluation of AISI Type 304 stainless steel as a suitable surface material for evaluating the efficacy of peracetic acid-based disinfectants against Clostridium difficile sporesâ€. DOI: 10.1371/journal.pone.0187074 . Open access.
  3. S. Brown et al. (2004) “Effects on instruments of the World Health Organization–recommended protocols for decontamination after possible exposure to transmissible spongiform encephalopathy–contaminated tissueâ€. DOI: 10.1002/jbm.b.30125. Open access.
  4. R. M. Cabrera-Martinez et al. (2002) “Studies on the mechanisms of the sporicidal action of ortho-phthalaldehydeâ€. DOI: 10.1046/j.1365-2672.2002.01572.x. Open access.
  5. G. Kampf et al. (2020) “Persistence of coronaviruses on inanimate surfaces and its inactivation with biocidal agents†DOI: 10.1016/j.jhin.2020.01.022.
  6. T. M. KarpiÅ„ski, A.K. Szkaradkiewicz (2015) “Chlorhexidine – pharmaco-biological activity and applicationâ€. No DOI found.
  7. M. J. Leggett et al. (2011) “Bacterial spore structures and their protective role inbiocide resistanceâ€. DOI: 10.1111/j.1365-2672.2012.05336.x. Open access.
  8. J. K. March et al. (2015) “The differential effects of heat-shocking on the viability of spores from Bacillus anthracis, Bacillus subtilis, and Clostridium sporogenes after treatment with peraceticacid- and glutaraldehyde-based disinfectantâ€. DOI: 10.1002/mbo3.277. Open access.
  9. J. Y. Maillard (2011) “Innate resistance to sporicides and potential failure to decontaminateâ€. DOI: 10.1016/j.jhin.2010.06.028.
  10. G. McDonnell, A. D. Russell (1999) “Antiseptics and Disinfectants: Activity, Action, and Resistanceâ€. DOI: 10.1128/cmr.12.1.147 . Open access.
  11. A. D. Russell (1993) “Antibacterial activity of chlorhexidineâ€. DOI: 10.1016/0195-6701(93)90109-d.
  12. Russell, A. D. (1999) “Bacterial resistance to disinfectants: present knowledge and future problemsâ€. DOI: 10.1016/s0195-6701(99)90066-x.
  13. W. A. Rutala, D. A. Weber (2004) “Disinfection and Sterilization in Health Care Facilities: What Clinicians Need to Knowâ€. DOI: 10.1086/423182.
  14. J. E. Sebben (1983) “Surgical antisepticsâ€. DOI: 10.1016/s0190-9622(83)70192-1.
  15. V. A. Swenson et al. (2018) “Assessment and verification of commercially available pressure cookers for laboratory sterilizationâ€. DOI: 10.1371/journal.pone.0208769 .
  16. Cited as “WHO (1999)â€. World Health Organization (1999) “WHO Infection Control Guidelines for Transmissible Spongiform Encephalopathiesâ€. Open access.
  17. Cited as “WHO (2016)â€. World Health Organization (2016) “Decontamination and reprocessing of medical devices for health-care facilities†(version in English). ISBN: 9789241549851. Open access.
  18. A. Wood, D. Payne (1998) “The action of three antiseptics/disinfectants against enveloped and non-enveloped virusesâ€. DOI: 10.1016/s0195-6701(98)90077-9.


Notes about writing and reading treatises about biology#
First version: 2020-03-23
Last update: 2020-11-21
Persistent link to latest version:

  1. 1 Foundational approach
  2. 2 About references
  3. 3 Note-taking
  4. 4 Epistemological soundness
    1. 4.1 Vagueness
    2. 4.2 Illusory differences without empirical distinction
  5. 5 Avoid mixing subjective judgements with scientific content
  6. 6 Units and physical quantities
    1. 6.1 Units
    2. 6.2 Salts
  7. 7 Generalization
    1. 7.1 Inter-individual genetic variation
    2. 7.2 Inter-individual anatomical variation
    3. 7.3 Inter-species variation
  8. 8 Thresholds for the definition of a disease
  9. 9 Fischerian hypothesis testing
  10. 10 Caveats about terminology
    1. 10.1 “alternative medicineâ€
      1. 10.1.1 Plants
    2. 10.2 “associatedâ€
    3. 10.3 “heavy metalsâ€
    4. 10.4 Irreversible inhibitors
    5. 10.5 Mistaking definitions with causal relationship
    6. 10.6 Psychic
    7. 10.7 Race
    8. 10.8 Seropositive, seronegative, seroconversion
    9. 10.9 “There is no evidenceâ€
  11. 11 Footnotes
  12. 12 References
1 Foundational approach
A discipline can be prestened and studied bottom-up or top-down. The bottom-up approach starts by laying the foundational principles, then expresses complex results in terms of simplest constituents. With a pure bottom-up approach, there is a small base of knowledge which is taken for granted (in mathematics, these are the axioms and definitions). Every other concept is introduced in terms of previously presented concepts. This approach is best illustrated by mathematics and to a lesser degree physics. For example: in physics, classical mechanics is the foundation that enable the acceleration of a rocket to be calculated from its mass, flow rate of the propellent and exhaust speed of the propellent.

In biology the foundational approach is of limited application because for many systems of interest it is not fully known how their behavior arises from its parts or from its interaction with other systems. For example: It is known that most of the effects of estrogens are mediated by the nuclear receptors ERα and ERβ. It is known that estradiol (the main endogenous estrogen) binds to ERα and ERβ and that this modifies genetic expression. It is not know with full detail which genes are affected nor how the altered genetic expression gives rise to all the perceptible effects of endogenous or exogenous estrogens. Thus it is not possible to give an exposition of the physiology of sex hormones in a fully foundational bottom-up approach. It is often the case that medication enters widespread use before all its pharmacological targets are known. In our example of estrogens: Exogenous estrogens including naturaly occurring (estradiol, estrone, estriol) and with human-made structures (diethylstilbestrol, ethynylestradiol) were already in widespread use as anticonceptives when the ERβ receptor was discovered [1].

2 About references
The purposes of providing references in a treatise are:

  • To enable the reader to verify the claims, ideally following the sequence of referenced works until the primary source.
  • To direct the reader for further information about the topic.
Unless it is very clear otherwise, explicitly mention the relation of a reference to the topic in prose instead of parenthetically. Present the reference in a conscise way that answers the following questions:

  • Does it provide support for a claim made in the present article or further reading?
  • If it supports a claim, which claim?
  • If it is for further reading, what is it about?
To merely specify the reference parenthetically often leaves unclear what is the relevance of the reference; thus the reader has to waste time checking whether it is of any relevance in his/her case.

For claims which do not depend on subjective judgement, cite the primary source. Example: Suppose one wants to state the biological half-life for a compound. If one finds it in a review and this review cites a primary source which evaluated the pharmacokinetic parameters of the compound, then cite the primary source, not the review. The primary source contains a detailed description of the experiment and the results with the least distortion; therefore it is more relevant in relation to the half-life. If the review is useful, then cite it separately (e.g.: “[primary source] found the half-life of [compound] is [...]. [reference] reviewed the pharmacology of [compound]â€).

When available, include quantitative data. E.g.: “[reference] found that norfluoxetine has a half-life of 14 daysâ€, not “[reference] found that norfluoxetine has a very long half-lifeâ€. The former is a stronger statement from which the latter follows.

3 Note-taking
When researching a topic within biology that is not thoroughly understood and the scientific knowledge is scattered in many scientific articles, take notes of the relevant articles and their main findings in a coherent document. Consider publishing this document so that it may be useful to other interested parties. Taking notes is not neccessary for topics for which there are comprehensive treatises.

Example 1: The anatomy and histology of the liver is thoroughly known and described in books like Tortora, Derrickson (2017).

Example 2: Knowledge about treatments that reduce pigmentation of skin, hair and eyes is scattered among hundreds of papers. We took notes and published them as a review that provides a complete or almost complete outline of these treatments and their mechanisms of actions.

4 Epistemological soundness
The goal of science is to make predictions about objectively observable properties of the real world.

4.1 Vagueness
Vague concepts can be useful as heuristical tools to help interested parties in arriving at scientific conclusions and in thier application; they are not scientific knowledge and must not be presented as such.

For example, “irritable bowel syndrome†is a vague non-scientic concept. It is useful as a heading under which related articles are grouped and can be found more easily. Any experiment done on irritable bowel syndrome should define a concrete criterion to be used in its stead. This is also called operationalization. The term “operationalization†is misleading because it suggest the error that “irratable bowel syndrome†is the primary entity of scientific study and the concrete definitions are secondary [2].

4.2 Illusory differences without empirical distinction
Assertions that appear to speak about the real world and do not make any objectively verifiable prediction are not scientific hypothesis. Example: In physics, special relativity and aether theory with Lorentz transform make exactly the same predictions about the outcome of measurements in any experiment. It is outside of science to argue “which one is trueâ€. Note that the Lorentz transform used in relativity was originally derived in the context of aether theory.

5 Avoid mixing subjective judgements with scientific content
Avoid mixing subjective judgments of the authors with the scientific content. Do not start an article with a non-technical justification of the importance of the treatise. There are 2 main reasons for this:

  • The reader is looking for information on a given topic (as opposed to opening books or articles at random). The reader already has his/her own justification to be interested in this topic.
  • For justification that depends on subjective values, values are not science and have only a marginal place in scientific treatises. They are tolerated, rather than required. Note that this applies to the common values in the discipline at the time of writing the article as much as it applies to the values particular to the authors of the treatise.
For example, articles about volitional use of cross-sex hormones often start by justifying the intervention in terms of treating a supposed mental disorder. This conflates the science and technique of endocrinology with the pseudoscience of psychiatry. Unfortunately, the malpractice of conflating subjective judgement with scientifically established facts is pervasive in medicine. This can make the problem not apparent to workers limited to this area. By contrast, consider an hypothetical article that presents a more efficient system for transmission of electric power that starts by giving a justification in terms of addressing class struggle. To the electrical engineer it is obvious that the talk of class struggle in this hypothetical paper is a digression and out of place. Yet today’s medic fails to see that in the same way the talk of supposed mental disorders and self-identities is likewise out of place.

6 Units and physical quantities

6.1 Units
The International System of Units (SI for its acronym in French) is the humanity-wide standard rational system of units suitable for practical scientific purposes. Treatises must use SI units or units allowed for use within the SI. The choice for SI units as opposed to British imperial or US customary units is not arbitrary. Among them, only the SI has the property that all units within the system that are of the same dimension differ by a factor that is a power of 10; therefore, they can be converted by shifting the decimal point or simple addition to the exponent in scientific notation.

Blood pressure. Expressing blood pressure only in millimetres of mercury is unacceptable. Express blood pressure using the pascal or its multiples.

Heart rate. The minute is an unit accepted for use within the SI; therefore, it is acceptable to express heart frequency in units of inverse minutes (symbol: 1/min or min−1).

Nutritional energy. Expressing nutritional energy in calories is unacceptable. There are several units called “calorie†that differ by over a factor of 1 000. Use the joule (symbol: J) or its multiples.

The symbol for microgram is “μgâ€. Both letters are upright, not italic nor cursive. Any other symbol or abbreviation is incorrect and inacceptable. It is widespread mistake to refer to the unit microgram as “mcg†or “microgâ€.

6.2 Salts

When writing the amount of a pharmaceutical that can form salts, write which salt. If it is the free pharmaceutical (not a salt), write that. Otherwise there is uncertainty of the dose because an unknown fraction of the mass is the counterion. For example: caffeine is used as free and as caffeine citrate.

Caffeine formMolecular massRelative potencyCaffeine (free/anhydrous)194.19Â g/mol1 (by definition)Caffeine citrate386.31Â g/mol0.503

It is standard to assume that the counterion is itself biologically inert except in studies that examine the difference in effect among different counterions for the same free pharmaceutical.

Assuming that the counterion is biologically inert, to compute the relative potency among different salts or the free form, use the formula:

  • Potency of B relative to A = Molecular mass of A / Molecular mass of B

  • Potency of caffeine citrate relative to free caffeine
    = (194.19Â g/mol) / (386.31Â g/mol)
    = 0.503
The conversion then proceeds as if it were converison of units. Example:

  • Give the equivalent of 200Â mg of caffeine citrate as free caffeine.
    Answer: 200 mg of caffeine citrate are equivalent to 200 mg · 0.503 = 101 mg of caffeine citrate.
  • Give the equivalent of 400Â mg of free caffeine as caffeine citrate.
    Answer: 400Â mg of caffeine citrate are equivalent to 400Â mg / 0.503 = 795Â mg of caffeine citrate.
7 Generalization
Biology studies very complex systems whose behavior depends on conditions that can not be fully fixed yet do not vary with a well-characterized random distribution in the relevant scenario. Much of the behavior of biological systems that humanity is interested in can not be characterized with a measurement. For example: severity of an illness; only in a few cases there exists an objective marker (e.g.: blood concentration creatinine for kidney dysfunction, blood concentration of clotting factors for hemophilia).

In practice one has to use knowledge gained under specific experimental conditions to make choices under different conditions. One has to generalize, that is, one assumes that the system in question will behave in a similar way under similar conditions conditions without having experimentally confirmed that this is the case. Typically generalization works. The importance of being aware that one is depending on generalizations to be able to identify when things does not work because the generalization one used does not work.

7.1 Inter-individual genetic variation
Genetic variation contributes uncertainty that is rarely accounted for in the literature. For example: Garza-Flores (2014) compared the pharmacokinetics of esters of estradiol administered as depot injections; this study used 2 medical centers, one in Latin America and another in Asia. This study found different pharmacokinetic parameters between the 2 study centers. It is very likely this is in part caused by genetic variation between the populations.

An especially salient example of genetic variation breaking generalization is the taste of phenylthiourea: some people experience it as bitter and others as tasteless. In a review, Risso et al. (2016) found that this variation is mostly attributable to a single gene: TAS2R38.

The notion that women have 46,XX genotype and men have 46,XY genotype is an oversimplification. Counterexamples include:

  • Male phenotype with natural 46,XX genotype. E.g.: Ryan et al (2013).
  • Female phenotype with 46,XY genotype beacuse of a loss of function allele in the nuclear androgen receptor.
  • Genotypes other than 46,XY and 46,XX.
  • Transsexuals change their phenotype to the other sex with the use of cross-sex hormones and/or surgery.
7.2 Inter-individual anatomical variation
There exists anatomical variations that cause no functional difference and therefore go unnoticed for most individuals. These differences become relevant when performing surgery. For example, the fact that some people have no frontal sinus is relevant to facial feminization surgery for MTF transsexuals. Deschamps-Braly (2018) states that in people without frontal sinus, forehead reduction can be accomplished by burring whereas people with frontal sinus usually require forehead reconstruction.

7.3 Inter-species variation
For many reasons, species other than humans are used to research the effect of treatments intended to be used in humans. An example of where this fails follows: Tyrosinase is the main enzyme involved in the generation of the pigmentation of skin, hair and eyes. Tyrosinase from mushrooms has been used to screen compounds for inhibitors of tyrosinase. Mann et al. (2018) found that the molecular structure required to strongly inhibit mushroom tyrosinase is different from that required to strongly inhibit human tyrosinase. They found that in humans thiamidol is a much stronger inhibitor of tyrosinase that kojic acid; in mushrooms it is the opposite.

8 Thresholds for the definition of a disease
The boundary between healthy and pathological is ultimately subjective. When there are objective markers for a pathological biological condition there is subjective judgement involved in chosing a threshold for the definition of the disease. For some pathological conditions there are no “in-between†cases in practice; all cases are clearly healthy or clearly pathological. For example: bone fractures. In practice a bone is either intact or broken all or most of the way (greenstick fractures). Some other conditions have in-between cases in practice. For example: hyperthyroidism. The threshold between pathological hyperthyroidism and sub-clinical hyperthyroidism is a matter of subjective judgement.

9 Fischerian hypothesis testing
p-values are not the probability that the hypothesis is false given the observation; popular media often make this mistake in presenting scientific findings. p-values are the probability that the observation is false given the hypothesis is also false. As-is, this does not tell what is the probability that the hypothesis is true.

Why is the probability that the hypothesis is true not routinely given in scientific papers? Becuase computing it requires the use of Bayesian statistics. Bayesian statistics require as input a detailed model of prior beliefs about the possible outcomes of the experiment. In simple cases there exists a model which is obviously neutral. In most cases found in practice, chosing a model among several plausible ones is a matter of judgement. In these cases, chosing among prior probabilities is a matter of judgement. Thus we do not give a recommendation to avoid fischerian hypothesis testing, only to be aware of its counterintuitive meaning.

10 Caveats about terminology

10.1 “alternative medicineâ€
The term “alternative medicine†is ill-defined. In common usage it referes to a class of techniques which purport to treat disease which have in common that they are based on magical thinking or contradict basic laws of physics. This includes homeopathy, crystal healing, use of static magnetic fields. The term is unfortunate because it focuses on the fact that these purported treatments are an alternative from mainstream medicine, which is irrelevant by itself. The relevant property that they have in common is that they can be immediately inferred to not to work because they are incompatible with elementary principles of the laws of the natural world.

10.1.1 Plants
Use of plants with the intention to treat disease is often included under the category of alternative medicine; this carries the erroneous implication that consumption of plants has no pharmacological effect. Some plants contain pharmacologically active ingredients in meaningful amounts. A well-known example is caffeine in tea and coffee which has a stimulating effect.

Plants have been used with the intention to treat disease since before the advent of modern medicine. Effectiveness can not be confirmed nor ruled out in the general case. The effectiveness of a plant species to elicit an effect should be evaluated on a case per case basis with the same scientific methods expected to evaluate the effectiveness novel synthetic pharmaceuticals.

10.2 “associatedâ€
Instead of “X is associated with Y†or “X has been implicated in Y†write “X and Y are correlatedâ€, “X causes Yâ€, “Y causes X†or “X and Y have a common cause†as it corresponds.

The term “associated†is very common in the biology literature. For example: “[X lifestyle choice] is associated with [Y disease]â€. The term “implicated†is equivalent. This usage is misleading because it invites a conflation between a correlation and a causal relationship. Statements like this are commonly used to express a correlation found through observational studies which are insufficient to show a causal relationship.

We suspect that the reason for the poplularity of this phrasing is intellectual cheating: It gives the impression of presenting strong knowledge (a causal relationship) while paying the burden of proving a much weaker statement (a correlation).

10.3 “heavy metalsâ€
Instead of “heavy metals†write the concrete elements and the numerical amount if known. Example: Write “We found that FooBar brand bread contains a mass fraction 2.4×10−5 of leadâ€, not “We found that FooBar brand bread contains heavy metalsâ€.

Exactly which metals are “heavy metals� There is no standard definition. The term is nearly meaningless. Is iron a heavy metal? The term does not say. It is used to elicit an emotional reaction of being toxic. It has no place in a scientific context.

10.4 Irreversible inhibitors
Irreversible inhibitors do not have a permanent effect. The “irreversible†refers to the mechanism of action as molecular level. Irreversible inhibitors create a covalent bound with the active site of the enzyme, effectively clogging it. At an organism level the effect is reversible because the body renews enzymes in the span of weeks.

10.5 Mistaking definitions with causal relationship
Avoid writing that an observation is caused by a condition that is defined to entail the observation.

Example: A local anesthetic is defined as a substance that suppresses pain sensation where it is applied. The sentence “topical lidocaine relieves pain because it is a local anesthetic†is equivalent to “lidocaine relieves pain where it is applied because it relieves pain where it is applied†which is a tautology and therefore conveys no information about the real world. Instead write the real cause: “Lidocaine relieves pain because it blocks voltage-gated sodium channels and therefore suppresses the propagation of action potentials that signal painâ€.

10.6 Psychic
In the context of study of humans, “psychic†is synonymous with “psychologicalâ€. The term “psychic†was more common in the first 3 quarters of the 20th century for this usage. It should not be confused with the everyday meaning of “psychic†as purported supernatural powers.

10.7 Race

Do not hesitate to explicitly refer to race in a scientific context when it is relevant to the discussion.

Because of an undue influence of political correctness, workers are sometimes reluctant to use the word “race†and often misuse “ethnicity†instead. Race is genetic; ethnicity is a combination of genetics and culture. An attempt at a rational explaination for this avoidance is the claim that races have no scientific basis. This is a deception. It is well established that many traits that are part of the classical conception of race (facial proportions, stature, pigmentation of skin, hair and eyes) are genetically determined and cluster by broad geographic region after accounting for recent migrations. The precise number and boundaries of races are subjective. That is not a reason to discard the concept. In biology many concepts have subjective boundaries including many well-accepted diseases and syndromes. E.g: hyperthyroidism, irritable bowel syndrome. The singling of race among them is hypocritical and purely because of political reasons that have no place in science.

10.8 Seropositive, seronegative, seroconversion
“seropositive†is a person that has antibodies for an antigen mentioned in the context. “seronegative†is somebody that does not have antibodies for that antigen. “seroconversion†is the event where the immune system starts to produce those antibodies.

Laypeople often erroneously believe that “seropositive†means “infected with HIVâ€. The term “seropositive†is not specific to HIV. It is possible to develop antibodies for a pathogen without being infected with it. The principle of vaccines is to cause the immune system to generate antibodies to counter a disease without causing the disease. It is possible to have an infection without having antibodies against the pathogen. Many pathogens produce an infection before the immune system produces antibodies against them. When an infection is cured it is usually the case that the antibodies against the pathogen that causes it persist for years or life-long. Antibodies are not always against a pathogen. In autoimmune diseases the antigen is a normal part of the body.

10.9 “There is no evidenceâ€
Avoid writing “there is no evidence that Xâ€.

If what is meant is that X is false, then write that and provide a reasoning. Example: Instead of “There is no evidence that crystal healing has any effect other than placebo.â€. write “From basic physics it follows that crystal healing has no effect other than placebo.â€.

If a search was made for evidence and none was found then write that. Example: Instead of “There is no evidence that drinking tea daily reduces risk of autoimmune diseases.†write â€We searched PubMed using the query “tea autoimmune†and we did not find any experiment that confirms this nor any proposed biological mechanismâ€.

11 Footnotes
  1. The discovery of ERβ was presented in Kuiper et al. (1996). See Koehler et al. (2005) for a review that mentions the previous paper
  2. A similar consideration applies to capturing intuitive concepts in mathematical definitions. The thesis that the mathematical definition captures the intuitive concept is not strictly speaking mathematics becuase it concerns a mathematical entity and an intuitive non-mathematical entity. Instead that thesis is pre-mathematical. See Szabó (2018) for an account of the comments of Kalmár László regarding the mathematical definition of effectively computable functions which include this consideration.
12 References
  1. J. C. Deschamps-Braly (2018) “Facial Gender Confirmation Surgery Facial Feminization Surgery and Facial Masculinization Surgeryâ€. DOI: 10.1016/j.cps.2018.03.005.
  2. J. Garza-Flores (1994) “Pharmacokinetics of once-a-month injectable contraceptivesâ€. DOI: 10.1016/0010-7824(94)90032-9.
  3. K. F. Koehler et al. (2005) “Reflections on the Discovery and Significance of Estrogen Receptor βâ€. DOI: 10.1210/er.2004-0027.
  4. G. G. J. M. Kuiper et al. (1996) “Cloning of a novel estrogen receptor expressed in rat prostate and ovaryâ€. DOI: 10.1073/pnas.93.12.5925.
  5. T. Mann et al. (2018) “Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinaseâ€. DOI: 10.1016/j.jid.2018.01.019. Open access.
  6. D. S. Risso et al. “Global diversity in the TAS2R38 bitter taste receptor: revisiting a classic evolutionary PROPosalâ€. DOI: 10.1038/srep25506. Open access.
  7. N. A. Ryan et al. (2013) “A case report of an incidental finding of a 46,XX, SRY-negative male with masculine phenotype during standard fertility workup with review of the literature and proposed immediate and long-term management guidanceâ€. DOI: 10.1016/j.fertnstert.2012.11.040.
  8. M. Szabó (2018) “Kalmár’s Argument Against the Plausibility of Church’s Thesisâ€. DOI: 10.1080/01445340.2017.1396520. Full text in ResearchGate.
  9. G. J. Tortora, B. Derrickson (2017) “Principles of anatomy & phisiologyâ€. ISBN (electronic version): 978-1-119-32064-7.


Notes about rhinoplasty (work in progress)#
First version: 2020-03-20
Last update: 2020-12-27
Persistent link to latest version:

  1. 1 Overview
    1. 1.1 Overview of procedure
  2. 2 Instruments
  3. 3 Opening the nose
    1. 3.1 Columellar incision
    2. 3.2 Dissection
  4. 4 Removal of a dorsal hump
    1. 4.1 Lateral osteotomy
  5. 5 Reduction of alar flares
  6. 6 Closing the nose
  7. 7 Comparison of open with closed techniques
  8. 8 Other sources of information
    1. 8.1 Videos
  9. 9 Footnotes
  10. 10 References
1 Overview
Rhinoplasty is any surgery performed on the nose. Several specific procedures are part of rhinoplasty. They can be performed for purely cosmetic purposes or to fix an anatomical defect that causes difficulty in breathing.

When performed for cosmetic purposes the goals can include any of the following:

  • Removal of a dorsal hump (the characteristic of so-called Greek/Roman/Jewish nose)
  • Increased projection of the tip
  • Rotating the tip so that it is higher or lower
  • Narrowing a boxy tip
  • Narrowing the base of the nose
  • Correction of deviation of the nose to one side
  • Correction of asymmetric nostrils
  • Adding material to the dorsum, especially to correct an overly aggressive previous rhinoplasty
  • Reduction of alar flare
For an overview of the surgical techniques used in rhinoplasty see Rohrich et al. (2014), Tasman (2008). Adamson, Gantous (2019) describe the historical development of rhinoplasty.

In current practice use of unpowered tools is the norm more common. Powered tools can be used instead to perform the osteotomies. See section Videos for an example of a rhinoplasty with powered tools.

Current trend is to avoid removal of tissue as much as possible in favor of remodelling existing tissue. The maxim “resect and regret†embodies this philosophy. For a short paper arguing in favor of this philosophy see Daniel (2018).

1.1 Overview of procedure
Rhinoplasty is not an invariant sequence of steps. The techniques used vary depending on the goal and personal choice. Rhinoplasty involves work in at least one of the following: Lower alar cartilages, upper alar cartilages, nasal bone, frontal protrusion of the maxillary bone, septum and nasal turbinates.

Most rhinoplasties involve access to the nose from the lower alar cartilages to the nasal bone. There are 2 main ways to achieve this:

  • Open rhinoplasty. Access is through an incision made through or below the columella and continued by the interior of the nose through the nostrils.
  • Closed rhinoplasty. Access is through one incision in the interior of each nostril. The skin of the columella is unperturbed.
When rhinoplasty is limited to work in and around the lower alar cartilages, a closed approach is usual. There is a choice between:

  • Delivery approach. The lower alar cartilages are partially removed from their anatomical position and pulled through the nostrils.
  • Non-delivery approach. The lower alar cartilages are worked in situ.
Conceptually, the location and orientation of the tip of the nose is given by a tripod. 2 legs of the tripod are the lateral crura of the lower alar cartilages and the other leg is the central crura of both alar cartilages.

To increase pointyness of the tip a columellar strut can be used. This consists of a long and narrow piece of grafted cartilage.

2 Instruments
Rhinoplasty usually employs the following special instruments. Instruments used in virtually any surgery (scalpel, needle holder, etc.) are not listed.

  • Hook with 2 prongs
  • Chisel-type osteotome
  • Guarded osteotome
  • Bone rasp
  • Mallet
  • Tenotomy scissors
  • Aufricht elevator
  • Cottle elevator
  • Joseph elevator
  • Takahashi forceps
  • Vacuum aspirator
For percutaneous lateral osteotomy, the osteotome must necessarily be non-guarded; good practice is to have the width of the tip be 2Â mm.

3 Opening the nose
The “open†in “open rhinoplasty†referes to opening the nose itself with an incision in the columella and dissection that exposes the nasal cartilages and nasal bones.

3.1 Columellar incision
Open rhinoplasty starts with an incision in the columella. There are 2 options:

  • Incision at the middle of the columella. Also called “Réthi incision†by Abbou et al. (2014). This is the most common option. An incision is made in the middle of the columella ending at the nostrils. A simple line is avoided because of inferior cosmetic results after healing. Usual shapes for the columellar incision include stair-step and inverted-V. Ivhan et al. (2017) compared an inverted-W shape with an inverted-V shape and found them to be similar; subjectively-rated results did not reach statistical significance.
  • Columellar-transalar incision. An incision is made at the lowest of the columella where it joins the nasolabial skin.
Abbou et al. (2014) found that open rhinoplasty with the mid-columella incision resulted in a difference average increase the nasolabial angle of 4.2° and columellar-transalar incision resuled in a average decrease of 6.4°. Aksu et al (2008) found that a straight line columellar incision results in more scar formation than an inverted-V columellar incision; strangely, they did not publish the difference in ratings, only p-values.

Rohrich et al. (1995) examined the arrangement of the blood vessels of the nasal tip and around it and concluded that the columellar incision in rhinoplasty is not a risk to the blood supply of the nose.

After the columellar incision, an incision is performed inside each nostril below the inferior alar cartilages. The intra-nostril incisions meets the transcolumellar incision to make a single opening. This opening is the main access to the nose during the surgery. See Rohrich et al. (2014) p. 1429-1430 for a description of the opening of the nose.

3.2 Dissection
After the columellar incision, the cartilages and nasal bone are mostly inaccessible. Only the lower part of the lower alar cartilage and the septum is exposed. The nose has to be dissected (separated) between the perichondium and the cartilages and between the periostium and the nasal bone, thus making a tunnel that allows access to the nasal cartilages, septum and nasal bone. This dissection is usually performed by inserting closed scissors and opening them to separate the tissue and by using a scalpel wih blade type 15 to directly cut the tissue that joins the perichondium and periostium with the cartilages and bone.

Rohrich et al. (2014) p. 199-201 describes briefly the dissection between the perichondium and cartilage. Toriumi et al. (1996) describe dissection along the areolar tissue with more detail; they used Converse scissors, opening them to dissect.

4 Removal of a dorsal hump
Structurally, a dorsal hump consists of an excess of the projection of the nasal bone, septum and upper alar cartilages towards the front.

Removal of a dorsal hump to transform a Greek nose into a straight or concave nose is usually accomplished with the open method. It consists of the following basic steps.

  1. Removal of the excess projection of the septum. The lower nasal cartilages are separated from the septum with a scalpel. The septum is reduced by cutting vertically with scissors or a scalpel.
  2. Removal of a central section of both lateral cartilages.
  3. Reduction of the frontal bone that underlies the top of the nose. At this point there exists a gap along the middle of the nose, called “open roofâ€.
  4. Lateral osteotomy to allow movement of the nasal bone and the part of the frontal bone that underlies the nose.
  5. Moving the upper cartilages close together to close the open roof.
  6. External fixation to allow the bones and soft tissue to heal in the desired position in the span of days to weeks after the surgery.
4.1 Lateral osteotomy
Interrupted (a.k.a. perforating) lateral osteotomy. In practice this method is always performed percutaneous. It is performed with a non-guarded 2Â mm wide osteotome.[1] For each side a small incision is made in the skin covering the malar, near the nose. The osteotome is introduced through this hole. A series of holes are made in the piriform protrusion and nasal bone, leaving intact roughly 2Â mm of bone between them. A single incision is used to introduce the osteotome; the tip is moved under the skin. Care should be taken to not to damage the maxillary nerve. After both sides are perforated the bones of the nose are fractured in one step by crushing the nose between the index and thumb fingers with one hand.

Continuous osteotomy. This method is nearly always performed intranasally. There is more margin for different types of osteotomes. Intranasal osteotomy consists of a continuous cut on each side of the piriform protrusion and nasal bone. It can be performed with a 4Â mm wide guarded osteotome.[1]

5 Reduction of alar flares
A small slice of skin of the nasal alae is excised in each side just frontal to where it joins the skin above the maxilla, then it is sutured. See Rohrich et al. (2014). This procedure is rarely required and rarely performed (author’s observation).

6 Closing the nose
The final surgical step in open rhinoplasty is suturing the columellar incision. Berghaus (2016) writes: “This incision is closed accurately with five stitches utilizing 6-0 monofilament suture material.â€.

7 Comparison of open with closed techniques
For a prose comparison of open with closed rhinoplasty see Berghaus (2016).

8 Other sources of information
Hwang (2019) describes a good way to hold the osteotome.

8.1 Videos
9 Footnotes
  1. Chen et al. (2017) write “Perforating percutaneous nosteotomies were performed with 2-mm straight osteotomes; continuous intranasal osteotomies were performed with 4-mm curved guarded osteotomes.â€.
  2. For each side a small incision is made in the skin covering the malar, near the nose. The osteotome is introduced through this hole. A series of holes are made in the piriform protrusion and nasal bone, leaving intact roughly 2Â mm of bone between them. A single incision is used to introduce the osteotome; the tip is moved under the skin. Care should be taken to not to damage the maxillary nerve. After both sides are perforated the bones of the nose are fractured in one step by crushing the nose between the index and thumb fingers with one hand.
10 References
  1. R. Abbou (2014) “Open Rhinoplasty: Influence of Incisions, Alar Resection, and Columellar Strut on Final Appearance of the Tipâ€. DOI: 10.1007/s00266-014-0395-2.
  2. P. A. Adamson, A. Gantous (2019) “Once Upon a Rhinoplasty: The History of the “Queen†of Facial Plastic Surgeryâ€. DOI: 10.1055/s-0039-1693443.
  3. A. Berghaus (2016) “Modern Rhinoplasty: Is There a Place for the Closed Approach?â€. DOI: 10.1055/s-0036-1585422.
  4. J. X. Chen et al. (2017) “Educational Cadaveric Module for Teaching Percutaneous and Intranasal Osteotomies in Rhinoplastyâ€. DOI: 10.1177/0194599817706328.
  5. I. Aksu et al. (2008) “Comparative Columellar Scar Analysis Between Transverse and Inverted-V Incision in Open Rhinoplastyâ€. DOI: 10.1007/s00266-008-9170-6.
  6. R. K. Daniel (2018) “The Preservation Rhinoplasty: A New Rhinoplasty Revolutionâ€. DOI: 10.1093/asj/sjx258.
  7. K. Hwang (2019) “How to Hold an Osteotome? Michelangelo Gripâ€. DOI: 10.1097/SCS.0000000000005247.
  8. O. Ivhan et al. (2017) “Comparative Columellar Scar Analysis Between W Incisions and Inverted-V Incision in Open Technique Nasal Surgeryâ€. DOI: 10.1007/s12070-017-1096-3.
  9. R. J. Rohrich et al. (1995) “Nasal Tip Blood Supply: An Anatomic Study Validating the Safety of the Transcolumellar Incision in Rhinoplastyâ€. DOI: 10.1097/00006534-199504001-00004.
  10. R. J. Rohrich et al. (editor) (2014) “Dallas Rhinoplastyâ€, 3rd ed.
  11. A. Tasman (2008) “Rhinoplasty – indications and techniquesâ€. No DOI found. Full text in PMC.
  12. D. M. Toriumi et al. (1996) “Vascular Anatomy of the Nose and the External Rhinoplasty Approachâ€. DOI: 10.1001/archotol.1996.01890130020003.
Cosmetic self-surgery in the arm
Mario Xerxes Castelán Castro «Ksenia»
14 February 2020
Last revised 24 February 2020

Self-surgery was performed to remove a small cosmetic defect in the left
arm, superior to the cubital fossa. Local anaesthesia was used. The
surgery was performed mostly with the right hand because the location of
the defect made impossible to use the left hand. Uncommon techniques
had to be used. Extensive practical details are given as a chronology
including preoperative preparations.
This article is Copyright © 2020 Mario Xerxes Castelán Castro «Ksenia». This
work can be used, copied, modified and sold under the terms of the license Cre-
ative Commons Attribution-ShareAlike 4.0 International. This work is provided
as-is, without any warranty. The reader is solely responsible for the use made
of this information.
Persistent link to latest version: To
this version:
1 Overview 2
2 Materials 2
3 Preparation 3
3.1 Sterilization with sodium hypochlorite . . . . . . . . . . . . . . . 3
3.2 Disinfection of surgical instruments . . . . . . . . . . . . . . . . . 4
3.3 Disinfection of site to be operated . . . . . . . . . . . . . . . . . 4
3.4 Donning of gloves . . . . . . . . . . . . . . . . . . . . . . . . . . . 4
4 Surgery 5
4.1 Incision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6
4.2 Suture . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7
4.3 Wound dressing and cleaning . . . . . . . . . . . . . . . . . . . . 8
5 Removal of stitches 8
6 References 8

1 Overview
The defect to be removed was approximately 6 mm in the longest direction.
It was located in the left arm above the cubital fossa and near the radial side
(distal in anatomical position). There was no pain during nor after the surgery.
A living room served as the operating room for this procedure. It was deemed
unnecessary to sterilize it given that this was a superficial procedure. Windows
were closed to reduce contamination by dust. We note that it is usual practice
to perform minor cosmetic surgery in surgeon offices.
A reliable person close to the author took the photographs reproduced
therein. This person did not participate in the surgery.
We have previously reviewed case reports of self-surgery in the literature[2].
2 Materials
The following surgical instruments were prepared for this surgery. All of them
are of stainless steel (alloy not specified anywhere) and had not been used for
any previous surgery:
• Scalpel handle type 3
• Scalpel handle type 4 (disinfected but not used)
• Scalpel blade type 10
• Scalpel blade type 15
• Metzenbaum scissors, straight
• Needle holders, 14 cm long
• Dissection forceps
• Adson dressing forceps
• Adson tissue forceps, 1 teeth on one side, 2 teeth on other side
In addition the following material was used during or prior to surgery:
• Sachet of suture thread with needle, atraumatic, monofilament Nylon, 5-0,
needle of 3/8 of a circle
• Ampoule with solution of lidocaine, 50 ml, concentration 20 mg/ml
• 2 syringes with built-in needle, capacity 1 ml, needle outer diameter 0.3 mm
• Surgical mask
• Big food-safe pan with lid, blue
• Small food-safe pan with lid, transparent
• Dish sponge
• Toothbrush

• Measuring vessel, capacity 12.5 ml, marked in 2.5 ml increments.
• Bottle of 500 ml of surgical biocide with 120 g/l of benzalkonium chloride
(BAC), brand name Krit
• Bottle of household bleach brand name Cloralex
When procuring the instruments a surgical cap was ordered; the vendor dropped
it from the order by mistake.
Toothbrush and dish sponge were only used to scrub material. They had
not been used for washing teeth nor dishes.
3 Preparation
The author’s long hair was tied up with a ribbon and twisted into a bun. The
bun was self-holding; for safety 3 hair pins were used to further secure the bun.
A small table with glass top was sterilized with household bleach. The label
stated the active ingredient was sodium hypochlorite; the concentration was not
stated; it was assumed to be 52.5 g/l. The table was cleaned of macroscopic con-
tamination with a non-sterile cloth. During the subsequent handling of sodium
hypochlorite solution the author used gloves.
Sodium hypochlorite solution was poured from the bottle over 2 cotton
swabs. The top surface of the table, the edges, corners and a part of the bottom
of the glass top were first wiped with one cotton swab. Then the top surface,
edges and corners (bottom of the glass top not wiped again) were wiped with
the other cotton swab.
Surgical instruments were cleaned with sponge and toothbrush using dish
detergent. Both scalpel handles had some loose stainless steel shavings from
factory in the slots for the scalpel blade; they were removed by scrubbing with
the toothbrush.
3.1 Sterilization with sodium hypochlorite
Both pans were new and were sealed from factory in distinct plastic envelopes.
The plastic envelopes were removed. The pans were scrubbed with sponge and
toothbrush using dish detergent and thoroughly washed with running tap water.
The blue pan was almost filled with solution of sodium hypochlorite (Na(ClO))
at a concentration of 5.25 g/l, prepared by diluting 1 part in volume of bleach
with 9 parts of bottled water. This Na(ClO) solution was used to sterilize some
material described next.
The transparent pan (without lid) and measuring vessel were sterilized by
immersion in the blue pan for 30 min, then rinsed with bottled water and placed
in the glass-top table. The transparent lid was immersed in the blue pan for
30 min, reusing the Na(ClO) solution, then rinsed with bottled water and placed
with inner side up in the table.
The bottle of Hartmann solution and vial of lidocaine were new. Their
protective lids were removed, then they were sterilized by immerson in Na(ClO)
for 20 minutes. The bottle of the Hartmann solution floated, leaving a small
fraction of one side outside the solution. Likewise, the vial of lidocaine was wide
enough that one side was left outside the solution. Therefore, both were rotated

180 degrees halfway through the sterilization procedure to ensure all the extenal
surface had been in contact with the sterilizant.
A decision was made to not to sterilize the surgical instruments with sodium
hypochlorite because they were new and sodium hypochlorite can damage them
3.2 Disinfection of surgical instruments
The author donned the surgical mask to avoid contaminting the disinfectant
solution with saliva; this surgical mask was only removed after the surgery. The
author handled all material during the subsequent disinfection with BAC with
sterile latex examination gloves.
The transparent pan was used to disinfect the surgical instruments. It was
filled halfway with biocide solution prepared from bottle water and BAC-based
surgical biocide dissolved to 5 g/l. The BAC solution was noted to be blue and
slightly foam-forming.
All the surgical instruments, the unopened sachet of suture and the needles
were immersed. The plunger of the syringes was pulled all the way to fill them
with biocidal solution, then pushed again. This ensured that the dead space was
filled with biocidal solution rather than air. The syringes came each with an
orange plastic protector for the tip and another protector for the handle of the
plunge; these were also disinfected in the aforementioned solution, detached from
the syringes. The scalpel blades in their individual wraps were also immersed in
the disinfectant solution. The wraps had previously been cleaned on the outside
with a toothbrush, dish soap and running tap water. A cotton swab was cut in
half with scissors and both parts soaked in the benzalknoium chloride solution.
One half was put over the rubber of the Hartmann solution and another half
over the rubber of the lidocaine solution.
3.3 Disinfection of site to be operated
The author cleaned an area around to be operated with a cotton swab soaked
with aqueous solution of ethanol. Using sterile examination gloves the author
soaked a different cotton swab into the pan with biocide solution, disinfected the
area to be operated with this cotton swab and placed it over the arm, secured
with tape. The pan with biocide solution was covered with its corresponding
lid and left unperturbed for 30 min.
3.4 Donning of gloves
As mentioned, the author was already wearing the surgical mask at this point.
The author consumed coffee and 5 mg of methylphenidate, both oral, to increase
attentiveness and endurance to tiredness and pain, then removed the cotton
swab secured to the arm.
The surgical gloves came packaged in 2 bags. The outer bag was cleaned with
a wet cloth, then discarded. The author washed hands with household soap,
then dried them with ambient air. The inner bag of the gloves was opened,
placed on a clean surface, and then the gloves were donned with care of not
touching the outer surface except in the cuffs. Care was taken to not to touch
any non-disinfected surface with the gloves until the surgery was finished. Care

was taken to not to touch the table because of any possible leftover of sodium

4 Surgery

Figure 1: The material as laid during the surgery.

From left to rigth: Bluepan with instruments, transparent pan with biocide, lid with cotton swabs with biocide, vial of lidocaine, bottle of Hartmann solution. The surgery was performed by the author sit with crossed legs on a bed near the edge. In front of the bed was the glass-top table with instruments and material (figure 1). The author sit in the bed and only got up after the surgery was finished. The author moved the surgical instruments from the biocide solution to the dry pan. The author filled a syringe with half Hartmann solution and half lidocaine. Before the first incision 5 injections were made, one just below the defect to be removed and 4 around it in an quincux pattern. There was loss of tactile sensitivity in a matter of seconds.

The author massaged the site while waiting for further loss of sensation, occasionally proving for thermal sensitivity with the closed tip of the needle holders. More anaesthesia was applied during the course of the surgery as needed; individual occasions are not listed. At some point near the start of suturing the author switched from 10 mg/ml of lidocaine (diluted with Hartmann solution) to 20 mg/ml lidocaine (undiluted from vial). Motor control of the left limb and sensitivity far from the area operated on were preserved at all times. Attenuated tactile sensitivity was present around 30 % of the time during the surgery; some incisions and sutures were felt; however there was no pain. Complete loss of tactile sensitivity was
deemed unneccessary. Blade type 15 was placed in the scalpel handle. In all occasions where scalpel blades were placed on the handle or removed from it this was done with the needle holder to avoid accidental cuts. 5


Figure 2: The technique used to remove the portion of skin to be excised and the leftover of subcutaneous tissue.

4.1 Incision
The author performed an incision with a rhombus shape that encompassed the cosmetic defect; inner angles were approximately 30° and 120°; the longest diagonal was in longitudinal direction along the arm. The rhombus of skin remained attached through subcutaneous tissue. The author attempted to cut with the scalpel the subcutaneous tissue that held the rhombus of skin. Given the position of the incision, the left hand was unavailable to hold the rhombus of skin to excise it. The attempt to cut it directly with the scalpel failed because the rhombus of skin slipped. The author then held the rhombus of skin with the tip of the needle holder, locked, and put the needle holder over the arm, held by its own weight and static friction. The author then cut the skin to be excised slipping a scalpel between the needle holder and the arm (figure 2). In this manner the rhombus of skin was excised with one hand. Shortly after starting to excise the rhombus of skin the author changed from blade type 15
to blade type 10. The blade type 15 was placed in the blue pan in case it was neccessary again.

Some subcutaneous tissue remained near the proximal end of the rhombus. Most of this subcutaneous tissue was excised in portions with the aforementioned procedure using the needle holder. When very little subcutaneous tissue remained it could no longer be held with the needle holder. The needles of the syringe (attached to the syringe) were used to hold it in a similar manner as the needle holder for excision. Some excess skin remained near the distal end of the rhombus. This was also excised aided with the tip of a syringe as done with subcutaneous tissue.

During the orginal incision and the subsequent removal of subcutaneous tissue there was enough bleeding to impair visibility. The right hand pressed
the wound as needed for hemostasis. The pieces of cotton swab previously used to disinfect the bottle of Hartmann solution and the vial of lidocaine were used to clean the blood in the wound and the area around the wound. The pan with BAC biocide was used to rinse the blood from the swabs. The solution in 6


Figure 3: The wound after excising the cosmetic defect.

the pan changed color from blue to green because of the blood. The blood on the author’s arm and gloves also became green because of the biocide solution (figure 6).

4.2 Suture
Before suturing local anaesthesia was applied again. Suturing was by simple interrupted suture; this type of suture was chosen for its good capacity for
eversion and control of tension of individual knots. 3 stitches were given starting with the middle one, then proximal, then distal.

Suturing was performed with the right hand. With the left hand the author held the non-needle end of the thread in order to prevent it from hanging and
touching non-sterile surfaces; the thread was grabbed slightly after the needle rather than grabbing the needle itself, to avoid the risk of the thread becoming detached from the needle.

Passing the needle through the skin was done using the needle holder the usual way. After the thread went through both sides of skin, the thread was
pulled leaving most of it on the side of the needle end. The right hand held the needle holder to tie the first step of the knot (first 2 throws of surgeon’s knot). To tighten the knot with one hand, the needle holder was used to hold the short end of the knot (non-needle end of the thread). The needle holder was in turn held between fingers 3-5 and the arm; fingers 1-2 were used to pull the long end of the knot (needle end of the thread); see figure 4. On each stitch was tied a surgeon knot followed by half a square knot. As is usual practice, each step was tied in direction opposite to the last one, so as to make a square knot and not a slip knot. The ends were clipped with the Metzenbaum scissors. For the last iteration the thread was short enough that it could no longer be grabbed with the left hand and it did not hang low enough to touch any non-disinfected surface; therefore the needle end was left to hang. 7


Figure 4: The technique used to tighten the knots with one hand.

4.3 Wound dressing and cleaning
The sutured wound was covered with sterile gauze held in place with tape. Instruments were cleaned of blood and detritus by rubbing them with the cotton swabs using during surgery, still soaked in disinfectant solution. The cotton swab was held with the dissection forceps when cleaning the scalpel blades to avoid accidental cuts. The blades were removed with the needle holder and placed in a sharps-resistant container along with the leftover suture. The exterior surface of the gloves –still in the author’s hands– were washed with hand soap. The surgical instruments were scrubbed with the toothbrush under running tap water and left to dry on top of a towel, then saved in a plastic bag. The gloves were removed. To reduce wastage they can be re-used for some non-sterile procedure. At this point a slight aroma similar to pineapple but sweeter was noticed in the OR, attributable to the BAC solution. This aroma was not noticed during the surgery.

5 Removal of stitches
Stitches were removed 5 days after the surgery with one hand using a similar
procedure than for suture. The needle holder was held between fingers 4-5 and
one arm with the other fingers used to cut the thread with a scalpel with type
15 blade.

6 References
[1] S. Brown et al. (2004) “Effects on instruments of the World Health Organization–recommended protocols for decontamination after possible exposure to transmissible spongiform encephalopathy–contaminated tissue”. DOI: Open access. 8


Figure 5: The sutured wound just after the surgery. Wound dressing was lifted to take the photography and is visible to the right of the wound.

[2] M. X. Castelán Castro (living document, no year) “Case reports of selfsurgery”. ARK: Open access. 9

Figure 6: The author holding a needle holder after the surgery. The glove has dry blood, most of it turned green by benzalkonium