Best from Ksenia

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#1
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.
 

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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.

reddit.com/r/AskMtFHRT/comments/fhqmcd/question_t_vs_no_t_or_t_vs_e/

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.
 

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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.

 

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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.
 

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#9
male-to-female.org home page#
Use the permalink https://n2t.net/ark:21206/10001 to bookmark and reference this work.

Flag of Alinism-Ksenism. See description.

male-to-female.org 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: trans@muc.snopyta.org 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 https://list.jabber.at/. Alternatively, you can run your own XMPP server. For a client program, I recommend Gajim. For a list of other clients see https://xmpp.org/software/clients.html. If you do not want to install any stand-alone program conversejs.org 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 ksenia@snopyta.org or e-mail through the address ksenia@17beta.top. 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.
 

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#10
Pharmacology of transÂsexualism#
First version: 2018-12-04
Last update: 2020-12-27
Persistent link to latest version: https://n2t.net/ark:21206/10003
Ksenia
ksenia+r8hn1@17beta.top
Contents#
  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.

Code:
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
Code:
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
Code:
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
  1. A. S. Chagin, L. Sävendahl (2007) “Oestrogen receptors and linear bone growthâ€. DOI: 10.1111/j.1651-2227.2007.00415.x.
  2. B. Chávez et al. (2015) “Hamster SRD5A3 lacks steroid 5α-reductase activity in vitroâ€. DOI: 10.1016/j.steroids.2014.11.005.
  3. T. L. Crenshaw et al. (1987) “Pharmacologic modification of psychosexual dysfunctionâ€. DOI: 10.1080/00926238708403896.
  4. S. M. Davis et al. (2017) “Estradiol and progesterone influence on influenza infection and immune response in a mouse modelâ€. DOI: 10.1111/aji.12695.
  5. C. M. Francucci et al. (2005) “Effects of raloxifene on body fat distribution and lipid profile in healthy post-menopausal womenâ€. DOI: 10.1007/BF03347261.
  6. J. Fried (1960) US Patent 2 914 997 “16α,17α-Acetal and ketal derivatives of 16α,17α-dihydroxyprogesteroneâ€.
  7. R. Fung et al. (2017) “Is a lower dose of cyproterone acetate as effective at testosterone suppression in transgender women as higher doses?â€. DOI: 10.1080/15532739.2017.1290566.
  8. J. Garza-Flores (1994) “Pharmacokinetics of once-a-month injectable contraceptivesâ€. DOI: 10.1016/0010-7824(94)90032-9.
  9. E. J. Giltay, L. J. G. Gooren (2000) “Effects of Sex Steroid Deprivation/Administration on Hair Growth and Skin Sebum Production in Transsexual Males and Femalesâ€. DOI: 10.1210/jcem.85.8.6710.
  10. D. E. Golan et al. (2017) “Principles of Pharmacology: The Patophysiologic Basis of Drug Therapyâ€, 4th ed. ISBN: 9781451191004.
  11. D. E. Harrison et al. (2014) “Acarbose, 17α-estradiol, and nordihydroguaiaretic acid extend mouse lifespan preferentially in malesâ€. DOI: 10.1111/acel.12170.
  12. N. I. Idrus, T. D. Hymans (2014) “Balancing benefits and harm: Chemical use and bodily transformation among Indonesia’s transgender wariaâ€. DOI: DOI: 10.1016/j.drugpo.2014.06.012.
  13. Indian Standard IS 160004: Hypodermic Needles for Single Use - Colour Coding for Identification. Available in archive.org under ARK https://n2t.net/ark:13960/t18k96f5j.
  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).
  15. S. Jindarak et al. (2019) “Spermatogenesis Abnormalities following Hormonal Therapy in Transwomenâ€. DOI: 10.1155/2018/7919481. Open access.
  16. E. D. B. Johansson et al. (1986) “Medroxyprogesterone Acetate Pharmacokinetics Following Oral High-Dose Administration in Humans: A Bioavailability Evaluation of a New MPA Tablet Formulationâ€. DOI: 10.1111/j.1600-0773.1986.tb00115.x.
  17. B. Kleine, W. G. Rossmanith (2016) “Hormones and the Endocrine Systemâ€. DOI: 10.1007/978-3-319-15060-4. ISBN: 978-3-319-15059-8, 978-3-319-15060-4.
  18. G. S. Kranz et al. (2014) “High-Dose Testosterone Treatment Increases Serotonin Transporter Binding in Transgender Peopleâ€. DOI: 10.1016/j.biopsych.2014.09.010.
  19. H. Kuhl (2005) “Pharmacology of estrogens and progestogens: influence of different routes of administrationâ€. DOI: 10.1080/13697130500148875.
  20. M. C. Leinung et al. (2018) “Hormonal Treatment of Transgender Women with Oral Estradiolâ€. DOI: 10.1089/trgh.2017.0035. Open access.
  21. L. J. Lerner et al. (1961) “Biological Activities of 16α, 17α Dihydroxyprogesterone Derivativesâ€. DOI: 10.3181/00379727-106-26296. Open access.
  22. J. J. Liang et al. (2018) “Testosterone levels achieved by medically treated transgender women in a United States endocrinology clinicâ€. DOI: 10.4158/EP-2017-0116.
  23. H. Lübbert et al. (1992) “Effects of ethinyl estradiol on semen quality and various hormonal parameters in a eugonadal maleâ€. DOI: 10.1016/s0015-0282(16)55271-6.
  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.
  25. J. R. Newton (1994) “A review of ‘once-a-month’ combinec injectable contraceptivesâ€. DOI: 10.3109/01443619409027641.
  26. M. Oettel (ed.) et al. (1999a) “Estrogens and Antiestrogens I: Physiology and Mechanisms of Action of Estrogens and Antiestrogens†(book). DOI: 10.1007/978-3-642-58616-3. OCLC: 1086475244.
  27. M. Oettel (ed.) et al. (1999b) “Estrogens and Antiestrogens II Pharmacology and Clinical Application of Estrogens and Antiestrogens†(book). DOI: 10.1007/978-3-642-60107-1. OCLC: 851823859.
  28. M. A. Oriowo et al. (2008) “A comparison of the pharmacokinetic properties of three estradiol estersâ€. DOI: 10.1016/s0010-7824(80)80018-7.
  29. R. Recio et al. (1986) “Pharmacodynamic assessment of dihydroxyprogesterone acetophenide plus estradiol enanthate as a monthly injectable contraceptiveâ€. DOI: 10.1016/0010-7824(86)90046-6.
  30. A. E. Schindler et al. (2003) “Classification and pharmacology of progestinsâ€. DOI: 10.1016/j.maturitas.2003.09.014.
  31. F. Schneider et al. (2017) “Andrology of male-to-female transsexuals: influence of cross-sex hormone therapy on testicular functionâ€. DOI: 10.1111/andr.12405.
  32. R. J. Shearer et al. (1973) “Plasma Testosterone: An Accurate Monitor of Hormone Treatment in Prostatic Cancerâ€. DOI: 10.1111/j.1464-410x.1973.tb12238.x
  33. A. L. Stiles, D. W. Russell (2010) “SRD5A3: A Surprising Role in Glycosylationâ€. DOI: 10.1016/j.cell.2010.07.003.
  34. R. Stricker et al. (2006) “Establishment of detailed reference values for luteinizing hormone, follicle stimulating hormone, estradiol, and progesterone during different phases of the menstrual cycle on the Abbott ARCHITECT analyzerâ€. DOI: 10.1515/CCLM.2006.160.
  35. L. J. W. Tack et al. (2017) “Consecutive Cyproterone Acetate and Estradiol Treatment inLate-Pubertal Transgender Female Adolescentsâ€. DOI: 10.1016/j.jsxm.2017.03.251
  36. V. Tangpricha, M. den Heijer (2016) “Oestrogen and anti-androgen therapy for transgender womenâ€. DOI: 10.1016/S2213-8587(16)30319-9. Free authors’ manuscript in PMC.
  37. M. L. Taymor et al. (1964) “Ovulation Inhbition with a Long-Acting Parenteral Progestogen-Estrogen Combinationâ€. DOI: 10.1016/S0015-0282(16)35411-5.
  38. M. Tebbens et al. (2019) “Gender-Affirming Hormone Treatment Induces Facial Feminization in Transwomen and Masculinization in Transmen: Quantification by 3D Scanning and Patient-Reported Outcome Measuresâ€. DOI: 10.1016/j.jsxm.2019.02.011.
  39. A. W. F. T. Toorians et al. (2003) “Venous Thrombosis and Changes of Hemostatic Variables during Cross-Sex Hormone Treatment in Transsexual peopleâ€. DOI: 10.1210/jc.2003-030520.
  40. U. Ulrich et al. (1994) “Rapid Increase in Lumbar Spine Bone Density in Osteopenic Women by High-Dose Intramuscular Estrogen-Progestogen Injectionsâ€. DOI: 10.1055/s-2007-1001723.
  41. H. van Poppel, S. Nilsson (2008) “Testosterone Surge: Rationale for Gonadotropin-Releasing Hormone Blockers?â€. DOI: 10.1016/j.urology.2007.12.070.
  42. L. N. Vandenberg et al. (2006) “The mammary gland response to estradiol: Monotonic at the cellular level, non-monotonic at the tissue-level of organization?â€. DOI: 10.1016/j.jsbmb.2006.06.028.
  43. K. Warkentin et al. (2006) “Restoration of Satisfying Sex for a Castrated Cancer Patient with Complete Impotence: A Case Studyâ€. DOI: 10.1080/00926230600835346.
  44. E. Wibowo, R. Wassersug (2013) “The effect of estrogen on the sexual interest of castrated males: Implications to prostate cancer patients on androgen-deprivation therapyâ€. DOI: 10.1016/j.critrevonc.2013.01.006.
  45. E. Wibowo, R. Wassersug (2016) “Multiple Orgasms in Men—What We Know So Farâ€. DOI: 10.1016/j.sxmr.2015.12.004.
 

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#11
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).
 

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#12
Philosophy
  1. 1 The Alinist-Ksenist Manifesto
  2. 2 The mindset for a smooth and successful transition
1. The Alinist-Ksenist Manifesto
Use the permalink https://n2t.net/ark:/21206/10002 to bookmark and reference this section.

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
Use the permalink https://n2t.net/ark:/21206/10025 to bookmark and reference this section.

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.
 

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#13
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 https://17beta.top/ came online 2018-12-03; the first page was the one about pharmacology. On 2019-08-15 we moved most pages to https://male-to-female.org/. We assign IRIs with care that they will not break and leave dangling links; see https://17beta.top/en/identifiers.

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.
  • amasci.com: 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
 

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#14
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.
 

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#17
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: https://n2t.net/ark:21206/10022

Ksenia

ORCID iD: https://orcid.org/0000-0002-5831-5828

Abstract
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.

Contents#
  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
Thiamidol:
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. http://www.keratin.com/as/as008.shtml 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.

    [etcetera]

    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.
7 References
  1. N. Ai et al. (2014) “Novel Virtual Screening Approach for the Discovery of Human Tyrosinase Inhibitors”. DOI: 10.1371/journal.pone.0112788. Open access.
  2. B. Alharbi et al. (2018) “Dasatinib-Induced Hypopigmentation in Pediatric Patient with Chronic Myeloid Leukemia: A Case Report and Review of the Literature”. DOI: 10.1155/2018/4062431. Open access.
  3. A. S. Alving et al. (1948) “Studies on the chronic toxicity of chloroquine”. DOI: 10.1172/JCI101974. Open access.
  4. H. Ando et al. (2010) “Keratinocytes in culture accumulate phagocytosed melanosomes in the perinuclear area”. DOI: 10.1111/j.1755-148X.2009.00640.x. Open access.
  5. H. Ando et al. (2012) “Melanosomes are transferred from melanocytes to keratinocytes through the processes of packaging, release, uptake, and dispersion”. DOI: 10.1038/jid.2011.413. In ResearchGate.
  6. A. Andrawis, V. Kahn (1986) “Effect of methimazole on the activity of mushroom tyrosinase”. DOI: 10.1042/bj2350091.
  7. N. Arjinpathana, P. Asawanonda (2012) “Glutathione as an oral whitening agent: A randomized, double-blind, placebo-controlled study”. DOI: 10.3109/09546631003801619.
  8. C. Arrowitz et al. (2019) “Effective Tyrosinase Inhibition by Thiamidol Results in Significant Improvement of Mild to Moderate Melasma”. DOI: 10.1016/j.jid.2019.02.013. Open access.
  9. H. Astra, V. Oja (2019) “Vapour pressure data for 2-n-propylresorcinol, 4-ethylresorcinoland 4-hexylresorcinol near their normal boiling points measuredby differential scanning calorimetry”. DOI: 10.1016/j.jct.2019.03.008.
  10. S. Baek, S. Lee (2015) “Proton pump inhibitors decrease melanogenesis in melanocytes”. DOI: 10.3892/br.2015.492.
  11. A. K. Bajaj et al. (1996) “Hair dye depigmentation”. DOI: 10.1111/j.1600-0536.1996.tb02278.x.
  12. A. K. Bajaj et al. (2010) “Chemical leucoderma: Indian scenario, prognosis, and treatment”. DOI: 10.4103/0019-5154.70674. Open access.
  13. S. Bansal et al. (2014) “Concurrent Hand-Foot Skin Reaction and Hair Depigmentation With Sunitinib: Report of a Case and Literature Review of Kinase Inhibitors and Blocking Antibodies”. DOI: 10.4103/0019-5154.143525. Final text in PMC.
  14. A. Basoglu, U. Çelik (2017) “The Effect of SLT Laser Application on Iris to Treat Sectorial Heterochromia: A Promising Technique”. DOI: 10.1097/ICL.0000000000000374.
  15. F. Belleudi et al. (2011) “Expression and signaling of the tyrosine kinase FGFR2b/KGFR regulates phagocytosis and melanosome uptake in human keratinocytes”. DOI: 10.1096/fj.10-162156.
  16. R. E. Boissy, P. Manga (2010) “On the Etiology of Contact/Occupational Vitiligo”. DOI: 10.1111/j.1600-0749.2004.00130.x.
  17. J. G. Bonchak et al. (2014) “Targeting melanocyte and melanoma stem cells by 8-hydroxy-2-dipropylaminotetralin”. DOI: 10.1016/j.abb.2014.07.033. Author’s manuscript in PMC.
  18. M. J. Borad et al. (2014) “Integrated Genomic Characterization Reveals Novel, Therapeutically Relevant Drug Targets in FGFR and EGFR Pathways in Sporadic Intrahepatic Cholangiocarcinoma”. DOI: 10.1371/journal.pgen.1004135. Open access.
  19. N. V. Botchkareva (2001) “SCF/c-kit signaling is required for cyclic regeneration of the hair pigmentation unit” DOI: 10.1096/fj.00-0368com. Open access.
  20. V. Brazzelli et al. (2012) “Hair Depigmentation and Vitiligo-like Lesions in a Leukaemic Paediatric Patient during Chemotherapy with Dasatinib”. DOI: 10.2340/00015555-1289.
  21. S. Briganti et al. (2003) “Chemical and Instrumental Approaches to Treat Hyperpigmentation”. DOI: 10.1034/j.1600-0749.2003.00029.x.
  22. T. Brown et al. (2005) “Vitiligo-like hypopigmentation associated with imiquimod treatment of genital warts”. DOI: 10.1016/j.jaad.2004.10.861.
  23. C. Brzezniak, E. Szabo (2014) “Sunitinib-Associated Hair Depigmentation”. DOI: 10.1056/NEJMicm1309906.
  24. J. G. Bubblin, D. F. Thompson “Drug-induced hair colour changes”. DOI: 10.1111/j.1365-2710.1992.tb01307.x.
  25. J. P. Cain et al. (2006) “Design, synthesis, and biological evaluation of a new class of small molecule peptide mimetics targeting the melanocortin receptors”. DOI: 10.1016/j.bmcl.2006.07.015.
  26. Cairo-André et al. (2006) “Imatinib mesilate inhibits melanogenesis in vitro”. DOI: 10.1111/j.1365-2133.2006.07359.x.
  27. G. Cardinali et al. (2005) “Keratinocyte Growth Factor Promotes Melanosome Transfer to Keratinocytes”. DOI: 10.1111/j.0022-202x.2005.23929.x.
  28. G. Cardinali et al. (2008) “Melanosome Transfer Promoted by Keratinocyte Growth Factor in Light and Dark Skin-Derived Keratinocytes”. DOI: 10.1038/sj.jid.5701063.
  29. C. C. Callander et al. (1989) “Propofol and the colour green”. DOI: 10.1111/j.1365-2044.1989.tb11141.x.
  30. V. D. Callender et al. (2011) “Postinflammatory Hyperpigmentation”. DOI: 10.2165/11536930-000000000-00000.
  31. T. Chang et al. (2007) “Mushroom tyrosinase inhibitory effects of isoflavones isolated from soygerm koji fermented with Aspergillus oryzae BCRC 32288”. DOI: 10.1016/j.foodchem.2007.05.019.
  32. T. Chang (2009a) “An Updated Review of Tyrosinase Inhibitors”. DOI: 10.3390/ijms10062440. Open access.
  33. T. Chang (2009b) “Evaluation of Depigmenting Activity by 8-Hydroxydaidzein in Mouse B16 Melanoma Cells and Human Volunteers”. DOI: 10.3390/ijms10104257. Open access.
  34. T. Chang et al. (2010) “Identifying 8-hydroxynaringenin as a suicide substrate of mushroom tyrosinase”. DOI: 10.1111/j.1468-2494.2010.00619_1.x. Open access.
  35. T. Chang (2012) “Natural Melanogenesis Inhibitors Acting Through the Down-Regulation of Tyrosinase Activity”. https://doi.org/10.3390/ma5091661.
  36. T. Chang (2014) “Isolation, Bioactivity, and Production of ortho-Hydroxydaidzein and ortho-Hydroxygenistein”. DOI: 10.3390/ijms15045699. Open access.
  37. S. P. Chang et al. (2018) “Nilotinib induction of melanogenesis via reactive oxygen species-dependent JNK activation in B16F0 mouse melanoma cells”. DOI: 10.1111/exd.13797.
  38. R. Chaudhuri (2015) “Hexylresorcinol: Providing Skin Benefits by Modulating Multiple Molecular Targets” chapter of book “Cosmeceuticals and Active Cosmetics”, 3rd edition, pages 71-82. DOI: 10.1201/b18895-8. In ResearchGate.
  39. N. Chen et al. (2009) “The role of keratinocyte growth factor in melanogenesis: a possible mechanism for the initiation of solar lentigines”. DOI: 10.1111/j.1600-0625.2009.00957.x.
  40. H. Chen et al. (2014a) “UV Signaling Pathways within the Skin”. DOI: 10.1038/jid.2014.161.
  41. Z. Chen et al. (2014b) “Design, synthesis and biological evaluation of hydroxy- or methoxy-substituted 5-benzylidene(thio) barbiturates as novel tyrosinase inhibitors”. DOI: 10.1016/j.bmc.2014.04.060. In ResearchGate.
  42. B. Chen et al. (2015) “Inhibitory effects of α-Na8SiW11CoO40 on tyrosinase and its application in controlling browning of fresh-cut apples”. DOI: 10.1016/j.foodchem.2015.05.003.
  43. M. Y. Choi et al. (2008) “Whitening Activity of Luteolin Related to the Inhibition of cAMP Pathway in α-MSH-stimulated B16 Melanoma Cells”. DOI: 10.1007/s12272-001-1284-4.
  44. H. Choi et al. (2014) “Melanosome uptake is associated with the proliferation and differentiation of keratinocytes”. DOI: 10.1007/s00403-013-1422-x. In ResearchGate.
  45. J. Choi, J. Jee (2015) “Repositioning of Thiourea-Containing Drugs as Tyrosinase Inhibitors”. DOI: 10.3390/ijms161226114. Open access.
  46. J. Choi et al. (2016) “Ensemble-Based Virtual Screening Led to the Discovery of New Classes of Potent Tyrosinase Inhibitors”. DOI: 10.1021/acs.jcim.5b00484.
  47. J. Dai et al. (2017) “Pigmentary changes in patients treated with targeted anticancer agents: a systematic review and meta-analysis”. DOI: 10.1016/j.jaad.2017.06.044. Authors’ manuscript.
  48. M. I. Davis et al. (2011) “Comprehensive analysis of kinase inhibitor selectivity”. DOI: 10.1038/nbt.1990.
  49. D’Orazio et al. (2013) “UV Radiation and the Skin”. DOI: 10.3390/ijms140612222.
  50. C. J. Denman et al. (2008) “HSP70i Accelerates Depigmentation in a Mouse Model of Autoimmune Vitiligo”. DOI: 10.1038/jid.2008.45. Open access.
  51. C. R. Denton et al. (1962) “Inhibition of Melanin Formation by Chemical Agents”. DOI: 10.1038/jid.1952.16.
  52. E. Doyle, C. Liu (1999) “A case of acquired iris depigmentation as a possible complication of levobunolol eye drops ”. DOI: 10.1136/bjo.83.12.1403c. Open access.
  53. J. P. Ebanks et al. “Mechanisms Regulating Skin Pigmentation: The Rise and Fall of Complexion Coloration”. DOI: 10.3390/ijms10094066.
  54. J. C. Espín, H. J. Wichers (2001) “Effect of captopril on mushroom tyrosinase activity in vitro”. DOI: 10.1016/S0167-4838(00)00230-2.
  55. S. Falvre et al. (2006) “Safety, Pharmacokinetic, and Antitumor Activity of SU11248, a Novel Oral Multitarget Tyrosine Kinase Inhibitor, in Patients With Cancer”. DOI: 10.1200/JCO.2005.02.2194.
  56. A. Fujimi et al. (2015) “Reversible skin and hair depigmentation during chemotherapy with dasatinib for chronic myeloid leukemia”. DOI: 10.1111/1346-8138.13150. Open access.
  57. A. Galanis, M. Levis (2015) “Inhibition of c-Kit by tyrosine kinase inhibitors”. DOI: 10.3324/haematol.2014.117028.
  58. A. Garcia-Jimenez et al. (2016) “4-n-butylresorcinol, a depigmenting agent used in cosmetics, reacts with tyrosinase”. DOI: 10.1002/iub.1528. Open access.
  59. F. García-Molina et al. (2010) “Melanogenesis Inhibition Due to NADH”. DOI: 10.1271/bbb.90965. Open access.
  60. F. García-Molina et al. (2011) “Tetrahydrofolic Acid is a potent suicide substrate of mushroom tyrosinase”. DOI: 10.1021/jf1035433.
  61. S. Ghosh (2010) “Chemical leukoderma: What's new on etiopathological and clinical aspects?”. DOI: 10.4103/0019-5154.70680. Open access.
  62. J. M. Grichnik et al. (2006) “Kit and Melanocyte Migration”. DOI: 10.1038/sj.jid.5700164. Open access.
  63. P. E. Grimes, R. Nashawati (2017) “Depigmentation Therapies for Vitiligo”. DOI: 10.1016/j.det.2016.11.010.
  64. J. V. Gruber, R. Holtz (2013) “Examining the Impact of Skin Lighteners In Vitro”. DOI: 10.1155/2013/702120. Open access.
  65. D. Gupta et al. (2012) “Depigmentation therapies in vitiligo”. DOI: 10.4103/0378-6323.90946. Open access.
  66. V. Hariharan et al. (2010) “Monobenzyl Ether of Hydroquinone and 4-Tertiary Butyl Phenol Activate Markedly Different Physiological Responses in Melanocytes: Relevance to Skin Depigmentation”. DOI: 10.1038/jid.2009.214. Open access.
  67. V. Hariharan et al. (2011) “Topical application of bleaching phenols; in vivo studies and mechanism of action relevant to melanoma treatment”. DOI: 10.1097/CMR.0b013e328343f542. Authors’ manuscript in PMC.
  68. J. T. Hartmann, L. Kanz (2008) “Sunitinib and Periodic Hair Depigmentation Due to Temporary c-KIT Inhibition”. DOI: 10.1001/archderm.144.11.1525.
  69. J. E. Harris (2017) “Chemical-Induced Vitiligo”. DOI: 10.1016/j.det.2016.11.006. Author’s manuscript in PMC.
  70. Hideki et al. (2015) “UVB Stimulates the Expression of Endothelin B Receptor in Human Melanocytes via a Sequential Activation of the p38/MSK1/CREB/MITF Pathway Which Can Be Interrupted by a French Maritime Pine Bark Extract through a Direct Inactivation of MSK1”. DOI: 10.1371/journal.pone.0128678. Open access.
  71. Y. Higa et al. (2000) “Studies on thyroid function in rats subjected to repeated oral administration with kojic acid”. DOI: 10.2131/jts.25.3_167. Open access.
  72. L. Ho-Sung et al (2015) “A systems-biological study on the identification of safe and effective molecular targets for the reduction of ultraviolet B-induced skin pigmentation”. DOI: 10.1038/srep10305. Open access.
  73. H. Hurwitz et al. (2006) “ Safety, tolerability and pharmacokinetics of oral administration of GW786034 in pts with solid tumors”. DOI: 10.1200/jco.2005.23.16_suppl.3012.
  74. H. I. Hurwitz et al. (2009) “Phase I Trial of Pazopanib in Patients with Advanced Cancer”. DOI: 10.1158/1078-0432.ccr-08-2740.
  75. G. Imokawa, K. Ishida (2014) “Inhibitors of Intracellular Signaling Pathways that Lead to Stimulated Epidermal Pigmentation: Perspective of Anti-Pigmenting Agents”. DOI: 10.3390/ijms15058293.
  76. S. Ito, K. Wakamatsu (2018) “Biochemical Mechanism of Rhododendrol-Induced Leukoderma”. DOI: 10.3390/ijms19020552. Open access.
  77. S. E. Jacob, M. Blyumin (2008) “Vitiligo-like Hypopigmentation with Poliosis following Treatment of Superficial Basal Cell Carcinoma with Imiquimod”. DOI: 10.1097/00042728-200806000-00026.
  78. K. Jimbow et al. (1974) “Mechanism of depigmentation by hydroquinone”. DOI: 10.1111/1523-1747.ep12701679. Open access.
  79. K. Jin et al. (2014) “Betulinic acid isolated from Vitis amurensis root inhibits 3-isobutyl-1-methylxanthine induced melanogenesis via the regulation of MEK/ERK and PI3K/Akt pathways in B16F10 cells”. DOI: 10.1016/j.fct.2014.03.001.
  80. E. Jung et al. (2013) “Madecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation”. DOI: 10.3390/molecules181215724. Open access.
  81. G. Kahn (1970) “Depigmentation Caused by Phenolic Detergent Germicides”. DOI: 10.1001/archderm.1970.04000080049010.
  82. M. W. Karaman et al. (2008) “A quantitative analysis of kinase inhibitor selectivity”. DOI: 10.1038/nbt1358.
  83. L. Karlsson et al. (1999) “Roles for PDGF-A and sonic hedgehog in development of mesenchymal components of the hair follicle”. https://dev.biologists.org/content/126/12/2611. Open access.
  84. S. J. Kang et al (2015) “Inhibitory Effect of Dried Pomegranate Concentration Powder on Melanogenesis in B16F10 Melanoma Cells; Involvement of p38 and PKA Signaling Pathways”. DOI: 10.3390/ijms161024219. Open access.
  85. B. Kasraee et al. (2006) “Retinoic acid synergistically enhances themelanocytotoxic and depigmenting effectsof monobenzylether of hydroquinone in black guinea pig skin”. DOI: 10.1111/j.1600-0625.2006.00441.x.
  86. M. G. Kassem et al. (2012) Chapter “Sunitinib Malate” in “Profiles of Drug Substances, Excipients, and Related Methodology, Volume 37”. DOI: 10.1016/B978-0-12-397220-0.00009-X.
  87. D. Kim et al. (2005) “Inhibitory Effects of 4-n-Butylresorcinol on Tyrosinase Activity andMelanin Synthesis”. DOI: 10.1248/bpb.28.2216. Open access.
  88. C. Kim et al. (2010) “Imiquimod induces apoptosis of human melanocytes”. DOI: 10.1007/s00403-009-1012-0.
  89. H. Kim et al. (2012) “The effects of Caffeoylserotonin on inhibition of melanogenesis through the downregulation of MITF via the reduction of intracellular cAMP and acceleration of ERK activation in B16 murine melanoma cells”. DOI: 10.5483/BMBRep.2012.45.12.039. Open access.
  90. J. Y. Kim et al. (2016) “PAR-2 is involved in melanogenesis by mediating stem cell factor production in keratinocytes”. DOI: 10.1111/exd.12982.
  91. K. Kim et al. (2018) “Induction of pigmentation by a small molecule tyrosine kinase inhibitor nilotinib”. DOI: 10.1016/j.bbrc.2018.06.148.
  92. E. Kobayashi et al. (2014) “Reversible hair depigmentation in a Japanese female treated with pazopanib”. DOI: 10.1111/1346-8138.12654.
  93. L. Kolbe et al. (2012) “4-n-butylresorcinol, a highly effective tyrosinase inhibitor for the topical treatment of hyperpigmentation”. DOI: 10.1111/jdv.12051.
  94. T. Kondo, V. J. Hearing (2014) “Update on the regulation of mammalian melanocyte function and skin pigmentation”. DOI: 10.1586/edm.10.70.
  95. T. M. Kroll et al. (2005) “4-Tertiary Butyl Phenol Exposure Sensitizes Human Melanocytes to Dendritic Cell-Mediated Killing: Relevance to Vitiligo”. DOI: 10.1111/j.0022-202X.2005.23653.x. Open access.
  96. T. F. M. Kuijpers et al. (2013) “The antibrowning agent sulfite inactivates Agaricus bisporus tyrosinase through covalent modification of the copper-B site”. DOI: 10.1111/febs.12539.
  97. Y. Kuroda et al. (2014) “Depigmentation of the skin induced by 4-(4-hydroxyphenyl)-2-butanol is spontaneously re-pigmented in brown and black guinea pigs”. DOI: 10.2131/jts.39.615. Open access.
  98. A. F. B. Lajis, A. B. Ariff (2019) “Discovery of new depigmenting compounds and their efficacy to treat hyperpigmentation: Evidence from in vitro study”. DOI: 10.1111/jocd.12900.
  99. I. C. Le Poole et al. (1993) “Phagocytosis by Normal Human Melanocytes in Vitro”. DOI: 10.1006/excr.1993.1102.
  100. H. J. Lee et al. (2011) “Serotonin induces melanogenesis via serotonin receptor 2A”. DOI: 10.1111/j.1365-2133.2011.10490.x.
  101. A. Lee, M. Noh (2013) “The regulation of epidermal melanogenesis via cAMP and/or PKC signaling pathways: insights for the development of hypopigmenting agents”. DOI: 10.1007/s12272-013-0130-6.
  102. S. J. Lee et al. (2014) “Inhibition of c-Kit signaling by diosmetin isolated from Chrysanthemum morifolium”. DOI: 10.1007/s12272-013-0158-7. Open access.
  103. W. J. Lee et al. (2015) “The natural yeast extract isolated by ethanol precipitation inhibits melanin synthesis by modulating tyrosinase activity and downregulating melanosome transfer”. DOI: 10.1080/09168451.2015.1032880. Open access.
  104. S. J. Lee et al. (2016a) “4-n-butylresorcinol enhances proteolytic degradation of tyrosinase in B16F10 melanoma cells”. DOI: 10.1111/ics.12368.
  105. H. J. Lee et al. (2016b) “Hesperidin, A Popular Antioxidant Inhibits Melanogenesis via Erk1/2 Mediated MITF Degradation”. DOI: 10.3390/ijms160818384.
  106. J. Leyden, W. Wallo (2011) “The mechanism of action and clinical benefits of soy for the treatment of hyperpigmentation”. DOI: 10.1111/j.1365-4632.2010.04765.x.
  107. J. Liu et al. (2011) “Evaluation of dihydropyrimidin-(2H)-one analogues and rhodanine derivatives as tyrosinase inhibitors”. DOI: 10.1016/j.bmcl.2011.02.076.
  108. J. Liu et al. (2012) “Biological evaluation of coumarin derivatives as mushroom tyrosinase inhibitors”. DOI: 10.1016/j.foodchem.2012.07.055.
  109. J. Liu et al. (2013) “Microwave-assisted synthesis and tyrosinase inhibitory activity of chalcone derivatives”. DOI: 10.1111/cbdd.12126.
  110. J. Liu et al. (2015) “Design and synthesis of aloe-emodin derivatives as potent anti-tyrosinase, antibacterial and anti-inflammatory agents”. DOI: 10.1016/j.bmcl.2015.10.004.
  111. M. McEwan, P. G. Parsons (1987) “Inhibition of melanization in human melanoma cells by a serotonin uptake inhibitor”. DOI: 10.1111/1523-1747.ep12580425. http://www.sciencedirect.com/science/article/pii/S0022202X87900194/pdf?md5=3de25ec9fbadfa4aa11b3274a3bc145d&pid=1-s2.0-S0022202X87900194-main.pdf. Open access.
  112. J. B. Macdonald et al. (2015) “Cutaneous adverse effects of targeted therapies”. DOI: 10.1016/j.jaad.2014.07.032.
  113. P. Manga et al. (2006) “A Role for Tyrosinase-Related Protein 1 in 4-tert-Butylphenol-Induced Toxicity in Melanocytes”. DOI: 10.2353/ajpath.2006.050769. Open access.
  114. T. Mann et al. (2018a) “Inhibition of Human Tyrosinase Requires Molecular Motifs Distinctively Different from Mushroom Tyrosinase”. DOI: 10.1016/j.jid.2018.01.019. Open access.
  115. T. Mann et al. (2018b) “Structure-Activity Relationships of Thiazolyl Resorcinols, Potent and Selective Inhibitors of Human Tyrosinase”. DOI: 10.3390/ijms19030690. Open access.
  116. C. Makino-Okamura et al. (2014) “Heparin inhibits melanosome uptake and inflammatory response coupled with phagocytosis through blocking PI3k/Akt and MEK/ERK signaling pathways in human epidermal keratinocytes”. DOI: 10.1111/pcmr.12287.
  117. A. Martinez-Anton et al. (2018) “KIT as a therapeutic target for non-oncological diseases”. DOI: 10.1016/j.pharmthera.2018.12.008.
  118. J. M. Menter et al. (1993) “In vivo depigmentation by hydroxybenzene derivatives”. DOI: 10.1097/00008390-199311000-00007.
  119. T. Miki et al. (1992) “Determination of ligand-binding specificity by alternative splicing: two distinct growth factor receptors encoded by a single gene”. DOI: 10.1073/pnas.89.1.246.
  120. K. G. Moss et al. (2003). “Hair Depigmentation Is a Biological Readout for Pharmacological Inhibition of KIT in Mice and Humans”. DOI: 10.1124/jpet.103.052530. Authors’ manuscript.
  121. J. L. Muñoz-Muñoz et al. (2010) “Suicide inactivation of tyrosinase in its action on tetrahydropterines”. DOI: 10.3109/14756366.2010.548811.
  122. J. L. Muñoz-Muñoz et al. (2012) “Kinetic characterisation of o-aminophenols and aromatic o-diamines as suicide substrates of tyrosinase”. DOI: 10.1016/j.bbapap.2012.02.001.
  123. J. Na et al. (2019) “Resveratrol as a Multifunctional Topical Hypopigmenting Agent”. DOI: 10.3390/ijms20040956. Open access.
  124. K. Nagasaki et al. (2008) “Purification, characterization, and gene cloning of Ceriporiopsis sp. strain MD-1 peroxidases that decolorize human hair melanin”. DOI: 10.1128/AEM.00253-08. Open access.
  125. M. D. Njoo et al. (2000) “Depigmentation therapy in vitiligo universalis with topical 4-methoxyphenol and the Q-switched ruby laser”. DOI: 10.1067/mjd.2000.103813.
  126. S. Nie et al. (2010) “Kinetic Evaluation of Aminoethylisothiourea on Mushroom Tyrosinase Activity”. DOI: 10.1007/s12010-009-8760-3.
  127. Oh et al. (2016) “Activation of 5-HT2B receptors with BW-723C86 inhibits melanogenesis”. DOI: 10.3390/ijms17040546. Open access.
  128. E. A. Oliver et al. (1939) “Occupational leukoderma”. DOI: 10.1001/jama.1939.72800350003010a.
  129. L. Pala et al. (2020) “Extensive vitiligo associated to response to c-kit inhibitor in metastatic mucosal melanoma”. DOI: 10.1097/CAD.0000000000000906 . In ResearchGate.
  130. K. Pezdirc et al. (2015) “Fruit, Vegetable and Dietary Carotenoid Intakes Explain Variation in Skin-Color in Young Caucasian Women: a Cross-Sectional Study”. DOI: 10.3390/nu7075251. Open access.
  131. T. Pillaiyar et al. (2015) “Inhibitors of melanogenesis: a patent review (2009-2014)”. DOI: 10.1517/13543776.2015.1039985. In ResearchGate.
  132. T. Pillaiyar et al. (2017) “Downregulation of melanogenesis: drug discovery and therapeutic options”. DOI: 10.1016/j.drudis.2016.09.016.
  133. P. M. Plonka et al. (2006) “Oral zinc sulphate causes murine hair hypopigmentation and is a potent inhibitor of eumelanogenesis in vivo”. DOI: 10.1111/j.1365-2133.2006.07376.x.
  134. B. P. Pulos et al. (2019) “Propofol-associated Green Hair Discoloration”. DOI: 10.1097/ALN.0000000000002544.
  135. K. Qing et al. (2015) “Synthesis and Biological Evaluation of Resveratrol Derivatives as Melanogenesis Inhibitors”. DOI: 10.3390/molecules200916933. Open access.
  136. L. Qiu et al. (2005) “Irreversibly inhibitory kinetics of 3,5-dihydroxyphenyl decanoate on mushroom (Agaricus bisporus) tyrosinase”. DOI: 10.1016/j.bmc.2005.06.034.
  137. M. Radmanesh (2004) “Temporary Hair Color Change from Black to Blond afterIntense Pulsed Light Hair Removal Therapy”. DOI: 10.1111/j.1524-4725.2004.30566.x.
  138. F. Ricci et al. (2016) “Drug-induced hair colour changes”. DOI: 10.1684/ejd.2016.2844.
  139. F. Ricci et al. (2017) “Propofol-induced irreversible hair depigmentation: a case report”. DOI: 10.1111/ijd.13594.
  140. P. A. Riley (1969a) “Hydroxyanisole depigmentation: In-vitro studies”. DOI: /10.1002/path.1710970203.
  141. P. A. Riley (1969b) “Hydroxyanisole depigmentation: In-vitro studies”. DOI: 10.1002/path.1710970203.
  142. P. A. Riley (1970) “Mechanism of pigment-cell toxicity produced by hydroxyanisole”. DOI: 10.1002/path.1711010211.
  143. C. Robert et al. (2012) “Advances in the Management ofCutaneous Toxicities of Targeted Therapies”. DOI: 10.1053/j.seminoncol.2012.01.009.
  144. C. I. Rodríguez, V. Setaluri (2014) “Cyclic AMP (cAMP) signaling in melanocytes and melanoma”. DOI: 10.1016/j.abb.2014.07.003.
  145. G. M. Rooman, B. Forslind (1980) “Copper in Green Hair: A Quantitative Investigation by Electron Probe X-Ray Microanalysis”. DOI: 10.3109/01913128009141433. Open access.
  146. S. E. Rosenbaum et al. (2008) “Dermatological reactions to the multitargeted tyrosine kinaseinhibitor sunitinib”. DOI: 10.1007/s00520-008-0409-1.
  147. S. Routhouska et al. (2006) “Hair Depigmentation During Chemotherapy With a Class III/V Receptor Tyrosine Kinase Inhibitor”. DOI: 10.1001/archderm.142.11.1477. Open access.
  148. S. Samimi et al. (2013) “Dasatinib-Induced Leukotrichia in a Patient With Chronic Myelogenous Leukemia”. DOI: 10.1001/jamadermatol.2013.75.
  149. M. Sasaki et al. (2014) “Rhododendrol, a depigmentation-inducing phenolic compound, exerts melanocyte cytotoxicity via a tyrosinase-dependent mechanism”. DOI: 10.1111/pcmr.12269. Open access.
  150. H. Satooka, I. Kubo (2012) “Resveratrol as a kcat type inhibitor for tyrosinase: Potentiated melanogenesis inhibitor”. DOI: 10.1016/j.bmc.2011.11.030.
  151. R. Schoental (1971) “Irreversible Depigmentation of Hair by N-Methyl-N-Nitrosourethane”. DOI: 10.1007/BF02147596.
  152. R. Schoental et al. (1978) “Irreversible depigmentation of dark mouse hair by T-2 toxin (a metabolite of Fusarium sporotrichioides) and by calcium pantothenate”. DOI: 10.1007/bf01947311.
  153. C. E. Searle, P. A. Riley (1990) “Chemically Induced Depigmentation of Skin and Hair”. DOI: 10.1007/978-3-642-74612-3_38.
  154. Y. K. Seo et al. (2010) “Effects of p-coumaric acid on erythema and pigmentation of human skin exposed to ultraviolet radiation”. DOI: 10.1111/j.1365-2230.2010.03983.x.
  155. J. O. Seo et al. (2018) “Finasteride inhibits melanogenesis through regulation of the adenylate cyclase in melanocytes and melanoma cells”. DOI: 10.1007/s12272-018-1002-x. Open access.
  156. R. Šeparović et al. (2018) “Rapid hair depigmentation in patient treated with pazopanib”. 10.1136/bcr-2018-224209. Open access.
  157. D. R. Shimshek et al (2016) “Pharmacological BACE1 and BACE2 inhibition induces hair depigmentation by inhibiting PMEL17 processing in mice”. DOI: 10.1038/srep21917. Open access.
  158. S. H. Shin, Y. M. Lee (2013) “Glyceollins, a novel class of soybean phytoalexins, inhibit SCF-induced melanogenesis through attenuation of SCF/c-kit downstream signaling pathways”. DOI: 10.1038/emm.2013.20.
  159. H. Shin et al. (2015) “A novel adamantyl benzylbenzamide derivative, AP736, inhibits melanogenesis in B16F10 mouse melanoma cells via glycogen synthase kinase 3β phosphorylation”. DOI: 10.3892/ijmm.2015.2348.
  160. A. Slominski et al. (2004) “Melanin Pigmentation in Mammalian Skin and its Hormonal Regulation”. DOI: 10.1152/physrev.00044.2003.
  161. N. Smit et al. (2009) “The Hunt for Natural Skin Whitening Agents”. DOI: 10.3390/ijms10125326. Open access.
  162. S. Sonthalia et al. (2016) “Glutathione as a skin whitening agent: Facts, myths, evidence and controversies”. DOI: 10.4103/0378-6323.179088.
  163. S. Sonthalia et al. (2018) “Glutathione for skin lightening: a regnant myth or evidence-based verity?”. DOI: 10.5826/dpc.0801a04.
  164. J. D. Spillane (1963) “Brunette to Blonde”. DOI: 10.1136/bmj.1.5336.997.
  165. M. Stradford et al. (2013) “Mechanistic studies of the inactivation of tyrosinase by resorcinol”. DOI: 10.1016/j.bmc.2012.12.031.
  166. S. T. Suchi et al. (2008) “Contact allergic dermatitis and periocular depigmentation after using olapatidine eye drops”. DOI: 10.4103/0301-4738.42431. Open access.
  167. U. Sultan et al. (2016) “Tyrosinase inhibitors: a patent review (2011-2015)”. DOI: 10.1517/13543776.2016.1146253. In ResearchGate.
  168. S. S. Tai et al. (2009) “Evaluation of Depigmenting Activity by 8-Hydroxydaidzein in Mouse B16 Melanoma Cells and Human Volunteers”. DOI: 10.3390/ijms10104257. Open access.
  169. M. Tess et al. (2011) “A randomized and placebo-controlled study to compare the skin-lightening efficacy and safety of lignin peroxidase cream vs. 2% hydroquinone cream”. DOI: 10.1111/j.1473-2165.2011.00581.x.
  170. S. Toosi et al. (2012) “Vitiligo-Inducing Phenols Activate the Unfolded Protein Response in Melanocytes Resulting in Upregulation of IL6 and IL8”. DOI: 10.1038/jid.2012.181. Open access.
  171. G. S. Turner (1983) “Brunette to Blonde”. DOI: 10.1136/bmj.1.5339.1231-a.
  172. J. G. Van den Broon et al. (2010) “Effective Melanoma Immunotherapy in Mice by the Skin-Depigmenting Agent Monobenzone and the Adjuvants Imiquimod and CpG”. DOI: 10.1371/journal.pone.0010626 . Open access.
  173. J. G. Van den Broon et al. (2011) “Monobenzone-induced depigmentation: from enzymatic blockade to autoimmunity”. DOI: 10.1111/j.1755-148x.2011.00878.x.
  174. R. B. Verheijen et al. (2017) “Clinical Pharmacokinetics and Pharmacodynamics of Pazopanib: Towards Optimized Dosing”. DOI: 10.1007/s40262-017-0510-z.
  175. C. D. Villarama, H. I. Maibach “Glutathione as a depigmenting agent: an overview”. DOI: 10.1111/j.1467-2494.2005.00235.x.
  176. Y. Wang et al. (2014) “Inhibitory effects of imatinib mesylate on human epidermal melanocytes”. DOI: 10.1111/ced.12261.
  177. K. C. Webb et al. (2014) “Enhanced bleaching treatment: opportunities for immune-assisted melanocyte suicide in vitiligo”. DOI: 10.1111/exd.12449. Open access.
  178. R. Whitehead et al. (2012) “You Are What You Eat: Within-Subject Increases in Fruit and Vegetable Consumption Confer Beneficial Skin-Color Changes”. DOI: 10.1371/journal.pone.0032988. Open access.
  179. Y. Yamaguchi, V. J. Heanring (2009) “Physiological factors that regulate skin pigmentation”. DOI: 10.1002/biof.29.
  180. Y. Yamazaki et al. (2009) “N-[(Dihydroxyphenyl)acyl]serotonins as potent inhibitors of tyrosinase from mouse and human melanoma cells”. DOI: 10.1016/j.bmcl.2009.05.115.
  181. Y. Yamazaki, Y. Kawano (2010) “N-(3,5-dihydroxybenzoyl)-6-hydroxytryptamine as a novel human tyrosinase inhibitor that inactivates the enzyme in cooperation with L-3,4-dihydroxyphenylalanine”. DOI: 10.1007/s12010-009-8760-3. Open access.
  182. Q. Yan et al (2009a) “Inhibitory effects of 5-benzylidene barbiturate derivatives on mushroom tyrosinase and their antibacterial activities”. DOI: 10.1016/j.ejmech.2009.05.023. In ResearchGate.
  183. Q. Yan et al. (2009b) “Synthesis and evaluation of 5-benzylidene(thio)barbiturate-β-D-glycosides as mushroom tyrosinase inhibitors”. DOI: 10.1016/j.bmcl.2009.06.018. In ResearchGate.
  184. F. Yang et al. (2000) “The Cytotoxicity and Apoptosis Induced by 4-Tertiary Butylphenol in Human Melanocytes are Independent of Tyrosinase Activity”. DOI: 10.1046/j.1523-1747.2000.00836.x. Open access.
  185. F. Yang, R. E. Boissy (2009) “Effects of 4-Tertiary Butylphenol on the Tyrosinase Activity in Human Melanocytes”. DOI: 10.1111/j.1600-0749.1999.tb00756.x.
  186. F. Yang, R. E. Boissy (2006) “Effects of 4‐Tertiary Butylphenol on the Tyrosinase Activity in Human Melanocytes”. DOI: 10.1111/j.1600-0749.1999.tb00756.x.
  187. Y. Yildirim et al. (2016) “Evaluation of Color-Changing Effect and Complications After Nd: YAG Laser Application On Iris Surface”. DOI: 10.12659/MSM.895086. Open access.
  188. S. Yokoyama et al. (2008) “Pharmacologic suppression of MITF expression via HDAC inhibitors in the melanocyte lineage”. DOI: 10.1111/j.1755-148X.2008.00480.x. Authors’ manuscript in PMC.
  189. J. Yongfu et al. (2013) “Synthesis and Biological Evaluation of Unsymmetrical Curcumin Analogues as Tyrosinase Inhibitors”. DOI: 10.3390/molecules18043948. Open access.
  190. J. Yu-Long et al. (2016) “Anti-tyrosinase kinetics and antibacterial process of caffeic acid N-nonyl ester in Chinese Olive (Canarium album) postharvest”. DOI: 10.1016/j.ijbiomac.2016.05.
  191. X. Zhang et al. (2012) PDE5 inhibitor promotes melanin synthesis through the PKG pathway in B16 melanoma cells. DOI: 10.1002/jcb.24147.
  192. S. Zhong et al. (2015) “Reduction of facial pigmentation of melasma by topical lignin peroxidase: A novel fast-acting skin-lightening agent”. DOI: 10.3892/etm.2014.2118.
  193. J. Zhou et al. (2016) “Cross-talk between 5-hydroxytryptamine and substance P in the melanogensis and apoptosis of B16F10 melanoma cells”. DOI: 10.1016/j.ejphar.2016.02.026.
  194. J. Zhuang et al. (2010) “Irreversible Competitive Inhibitory Kinetics of Cardol Triene on Mushroom Tyrosinase”. DOI: 10.1021/jf103723k.
  195. R. C. Zuo et al (2019) “Cutaneous Adverse Effects Associated With the Tyrosine-Kinase Inhibitor Cabozantinib”. DOI: 10.1001/jamadermatol.2014.2734. Open access.
 

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#18
Notes about psychopharmacology#
First version: 2019-11-06
Last update: 2021-01-09
Persistent link to latest version: https://n2t.net/ark:21206/10023
Ksenia
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Abstract
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.

Contents#
  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 https://pssdforum.org/ 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.
  • https://examine.com/supplements/cognitive-function/: Reviews of products commercialized as “supplements†with a claimed psychological effect.
  • https://rxisk.org/: 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)
21 References
  1. A. Agorastos et al. (2015) “Blunted autonomic reactivity to pharmacological panic challenge under long-term escitalopram treatment in healthy menâ€. DOI: 10.1093/ijnp/pyu053. Open access.
  2. F. N. Ã…gesen et al. (2019) “Pharmacokinetic variability of betaâ€adrenergic blocking agents used in cardiologyâ€. DOI: 10.1002/prp2.496. Open access.
  3. A. A. Al-Majed (2017) “Propranololâ€. DOI: 10.1016/bs.podrm.2017.02.006.
  4. B. S. Alexander, M. D. Wood (1987) “Stereoselective blockade of central [3H]5-hydroxytryptamine binding to multiple sites (5-HT1A, 5-HT1B and 5-HT1C) by mianserin and propranolol.
  5. C. Andrade (2019) “Anticholinergic Drug Exposure and the Risk of Dementia: There Is Modest Evidence for an Association but Not for Causalityâ€. DOI: 10.4088/JCP.19f13000. Open access.
  6. S. A. K. Anttila, E. V. J. Leinonen (2001) “A Review of the Pharmacologicaland Clinical Profile of Mirtazapinâ€. DOI: 10.1111/j.1527-3458.2001.tb00198.x. Open access.
  7. M. Atmaca (2019) “Selective Serotonin Reuptake Inhibitor-Induced Sexual Dysfunction: Current Management Perspectivesâ€. DOI: 10.2147/NDT.S185757. Open access.
  8. M. Aucoin, S. Bhardwaj (2016) “Generalized Anxiety Disorder and Hypoglycemia Symptoms Improved with Diet Modificationâ€. DOI: 10.1155/2016/7165425.
  9. G. Bagdy et al. (2001) “Anxiety-like effects induced by acute fluoxetine, sertraline or m-CPP treatment are reversed by pretreatment with the 5-HT2C receptor antagonist SB-242084 but not the 5-HT1A receptor antagonist WAY-100635â€. DOI: 10.1017/S1461145701002632. Open access.
  10. A. Bala et al. (2018) “Post-SSRI Sexual Dysfunction: A Literature Reviewâ€. DOI: 10.1016/j.sxmr.2017.07.002.
  11. M. D. Banov (1999) “Improved Outcome in Fluvoxamine-Treated Patients With SSRI-Induced Sexual Dysfunctionâ€. DOI: 10.4088/jcp.v60n1214. Open access.
  12. B. Basu (2014) et al. “A Case of Akathisia induced by Escitalopram: Case Report & Review of Literatureâ€. DOI: 10.2174/157488630901140224104651.
  13. G. Bellucci et al (2020). “Effects of a dopamine agonist on trusting behaviors in femalesâ€. DOI: 10.1007/s00213-020-05488-x.
  14. J. P. Bennett, M. F. Piercey (1999) “Pramipexole — a new dopamine agonist for the treatment of Parkinson’s diseaseâ€. DOI: 10.1016/s0022-510x(98)00307-4.
  15. M. E. Berman et al. (2009) “Serotonin Augmentation Reduces Response to Attack in Aggressive Individualsâ€. DOI: 10.1111/j.1467-9280.2009.02355.x.
  16. A. Bertani et al. (1997) “Pharmacologic Effect of Imipramine, Paroxetine, and Sertraline on 35% Carbon Dioxide Hypersensitivity in Panic Patientsâ€. DOI: 10.1097/00004714-199704000-00006.
  17. A. Bertani et al. (2001) “The 35% CO2 Hyperreactivity and Clinical Symptomatology in Patients With Panic Disorder After 1 Week of Treatment With Citalopram: An Open Studyâ€. DOI: 10.1097/00004714-200106000-00003.
  18. J. M. Bolton et al. (2006) “Genital Anaesthesia Persisting Six Years after Sertraline Discontinuationâ€. DOI: 10.1080/00926230600666410.
  19. J. M. Bostwick et al. (2009) “Frequency of New-Onset Pathologic Compulsive Gambling or Hypersexuality After Drug Treatment of Idiopathic Parkinson Diseaseâ€. DOI: 10.1016/S0025-6196(11)60538-7. Open access.
  20. M. Browning et al. (2006) “A single dose of citalopram increases fear recognition in healthy subjectsâ€. DOI: 10.1177/0269881106074062.
  21. R. E. Burke, S. Fahn (1985) “Pharmacokinetics of trihexyphenidyl after short-term and long-term administration to dystonic patientsâ€. DOI: 10.1002/ana.410180107.
  22. F. P. Bymaster et al. (2002) “Fluoxetine, but not other selective serotonin uptake inhibitors, increases norepinephrine and dopamine extracellular levels in prefrontal cortexâ€. DOI: 10.1007/s00213-001-0986-x.
  23. S. G. Carruthers et al. (1976) “Intrinsic heart rate on exercise and the measurement of β-adrenoceptor blockade.†Full article in PMC.
  24. E. P. Calandre, et al. (2016) “Alpha2delta ligands, gabapentin, pregabalin and mirogabalin: a review of their clinical pharmacology and therapeutic use.†DOI: 10.1080/14737175.2016.1202764.
  25. L. P. Capitão et al. (2015) “Acute fluoxetine modulates emotional processing inyoung adult volunteersâ€. DOI: 10.1017/S0033291715000240.
  26. J. L. Carrasco et al. (2005) “Clinical effects of pharmacological variations in selective serotonin reuptake inhibitors: an overviewâ€. DOI: 10.1111/j.1368-5031.2005.00681.x.
  27. M. L. Catterson, S. H. Preskorn (1996) “Pharmacokinetics of Selective Serotonin Reuptake Inhibitors: Clinical Relevanceâ€. DOI: 10.1111/j.1600-0773.1996.tb00206.x.
  28. G. Chen et al. “Vortioxetine: Clinical Pharmacokinetics and Drug Interactionsâ€. DOI: 10.1007/s40262-017-0612-7.
  29. P. Chidiac et al. (1993) “Inverse Agonist Activity of β-Adrenergic Agonistsâ€. In ResearchGate. No DOI found.
  30. T. Colton (1968) “The tolerance of coffee drinkers to caffeineâ€. DOI: 10.1002/cpt19689131.
  31. A. M. N. Costa et al. (2006) “A systematic review on clinical management of antipsychotic-induced sexual dysfunction in schizophreniaâ€. DOI: 10.1590/S1516-31802006000500012. Open access.
  32. M. J. Crockett et al. (2010) “Serotonin selectively influences moral judgment and behavior through effects on harm aversionâ€. DOI: 10.1073/pnas.1009396107. Open access.
  33. M. J. Crockett et al. (2015) “Dissociable Effects of Serotonin and Dopamine on the Valuation of Harm in Moral Decision Makingâ€. DOI: 10.1016/j.cub.2015.05.021. Open access.
  34. M. Davis et al. (1979) “Noradrenergic agonists and antagonists: Effects on conditioned fear as measured by the potentiated startle paradigmâ€. DOI: 10.1007/bf00433036.
  35. C. S. Degoute (2007) “Controlled Hypotensionâ€. DOI: 10.2165/00003495-200767070-00007.
  36. C. De Montigny (1989) “Cholecystokinin Tetrapeptide Induces Panic-like Attacks in Healthy Volunteersâ€. DOI: 10.1001/archpsyc.1989.018100600310.
  37. E. A. Deisenhammer, R. Trawöger (1999) “Penile Anesthesia Associated With Sertraline Useâ€. DOI: 10.4088/jcp.v60n1218.
  38. W. Di et al. (1997) “Variable Bioavailability of Oral Melatoninâ€. DOI: 10.1056/nejm199704033361418.
  39. M. Di Mascio et al. (1998) “Selective serotonin reuptake inhibitors reduce thespontaneous activity of dopaminergic neuronsin the ventral tegmental areaâ€. DOI: 10.1016/S0361-9230(98)00054-9.
  40. I. E. Dick et al. (2007) “Sodium Channel Blockade May Contribute to the Analgesic Efficacy of Antidepressantsâ€. DOI: 10.1016/j.jpain.2006.10.001.
  41. K. Dorph-Petersen et al. (2005) “The Influence of Chronic Exposure to Antipsychotic Medications on Brain Size before and after Tissue Fixation: A Comparison of Haloperidol and Olanzapine in Macaque Monkeysâ€. DOI: 10.1038/sj.npp.1300710. Open access.
  42. J. S. Dowben et al. (2013) “Hydroxyzine for Anxiety: Another Look at an Old Drugâ€. DOI: 10.1111/ppc.12012.
  43. W. C. Drevets et al. (2013) “Antidepressant Effects of the Muscarinic Cholinergic Receptor Antagonist Scopolamine: A Reviewâ€. DOI: 10.1016/j.biopsych.2012.09.031.
  44. B. W. Dunlop et al. (2011) “The Effects of Sertraline on Psychopathic Traitsâ€. DOI: 10.1097/YIC.0b013e32834b80df. Free author’s manuscript in PMC.
  45. J. M. Ellison, P. DeLuca (1998) “Fluoxetine-Induced Genital Anesthesia Relieved by Ginkgo biloba Extractâ€. DOI: 10.4088/jcp.v59n0409f. Open access.
  46. M. Ernst et al. (2017) “The effects of methylphenidate and propranolol on the interplay between induced-anxiety and working memoryâ€. DOI: 10.1007/s00213-016-4390-y.
  47. J. R. Fanning et al. (2014) “Serotonin (5-HT) augmentation reduces provoked aggression associated with primary psychopathy traitsâ€. DOI: 10.1521/pedi_2012_26_065.
  48. Mesenteric vasoconstrictor response to 5-hydroxytryptamine in the in situ blood autoperfused rat mesentery: involvement of 5-HT2B and/or 5-HT2A receptor activation.
  49. W. W. Fleischhacker et al. (1987) “Mood-altering effects of biperiden in healthy volunteersâ€. DOI: 10.1016/0165-0327(87)90008-5.
  50. W. W. Fleischhacker (1991) “Propanolol for Fluoxetine-lnduced Akathisiaâ€. DOI: 10.1016/0006-3223(91)90323-e.
  51. M. L. Furey, W. C. Drevets (2006) “Antidepressant Efficacy of the Antimuscarinic Drug Scopolamineâ€. DOI: 10.1001/archpsyc.63.10.1121.
  52. H. Gallant et al. (2016) “Pramipexole Impairs Stimulus-Response Learning in Healthy Young Adultsâ€. DOI: 10.3389/fnins.2016.00374.
  53. F. Gengo et al. (1989) “The pharmacodynamics of diphenhydramine-induced drowsiness and changes in mental performanceâ€. DOI: 10.1038/clpt.1989.3.
  54. R. L. Goldsmith et al. (2000) “Exercise and autonomic functionâ€. DOI: 10.1097/00019501-200003000-00007.
  55. C. Grillon et al. (2008) “Two-Week Treatment With the Selective Serotonin Reuptake Inhibitor Citalopram Reduces Contextual Anxiety but Not Cued Fear in Healthy Volunteers: A Fear-Potentiated Startle Studyâ€. DOI: 10.1038/npp.2008.141. Open access.
  56. G. Guaiana et al. (2010) “Hydroxyzine for generalised anxiety disorderâ€. DOI: 10.1002/14651858.cd006815.pub2.
  57. E. M. Haberfellner, H. Rittmannsberger “Spontaneous Remission of SSRI-induced Orgasm Delayâ€. DOI: 10.1055/s-2004-818991.
  58. S. Hajsadeghi et al. (2016) “Effects of energy drinks on blood pressure, heart rate, and electrocardiographic parameters: An experimental study on healthy young adultsâ€. DOI: 10.5152/akd.2015.5930.
  59. E. D. Hall et al. (1996) “Neuroprotective effects of the dopamine D2/D3 agonist pramipexole against postischemic or methamphetamine-induced degeneration of nigrostriatal neuronsâ€. DOI: 10.1016/s0006-8993(96)00968-7.
  60. C. H. Hansen et al. (2017) “The six most widely used selective serotonin reuptake inhibitors decrease androgens and increase estrogens in the H295R cell lineâ€. DOI: 10.1016/j.tiv.2017.02.001.
  61. C. J. Harmer et al. (2004) “Increased Positive Versus Negative Affective Perception and Memory in Healthy Volunteers Following Selective Serotonin and Norepinephrine Reuptake Inhibitionâ€. DOI: 10.1176/appi.ajp.161.7.1256.
  62. H. He et al. (1995) “Development and Application of a Specific and Sensitive Radioimmunoassay for Trihexyphenidyl to a Pharmacokinetic Study in Humansâ€. DOI: 10.1002/jps.2600840509.
  63. C. Hiemke, S. Härtter et al. (2000) “Pharmacokinetics of selective serotonin reuptake inhibitorsâ€. DOI: 10.1016/S0163-7258(99)00048-0.
  64. R. Hoehn-Saric et al. (1990) “Apathy and Indifference in Patients on Fluvoxamineâ€. DOI: 10.1097/00004714-199010000-00007.
  65. A. B. Hollander et al. (2016) “Cabergoline in the Treatment of Male Orgasmic Disorder—A Retrospective Pilot Analysisâ€. DOI: 10.1016/j.esxm.2015.09.001. Open access.
  66. M. Hollmann, et al. (1984) “Biperiden effects and plasma levels in volunteersâ€. DOI: 10.1007/bf00556903.
  67. C. Huang et al. (2016) “Characterization of voltage-gated sodium-channelblockers by electrical stimulation and fluorescencedetection of membrane potentialâ€. DOI: 10.1038/nbt1194.
  68. J. C. Huffman, T. A. Stern (2007) “Neuropsychiatric consequences of cardiovascular medicationsâ€. Full text in PMC.
  69. N. J. Jacobsen (2015a) “Effects of selective serotonin reuptake inhibitors on three sex steroids in two versions of the aromatase enzyme inhibition assay and in the H295R cell assayâ€. DOI: 10.1016/j.tiv.2015.07.005.
  70. P. L. Jacobsen et al. (2015b) “Effect of Vortioxetine vs. Escitalopram on Sexual Functioning in Adults with Well-Treated Major Depressive Disorder Experiencing SSRI-Induced Sexual Dysfunctionâ€. DOI: 10.1111/jsm.12980.
  71. T. Kaila, R. Marttila “Receptor occupancy in lumbar CSF as ameasure of the antagonist activity of atenolol, metoprolol and propranolol in the CNSâ€. Full text in PMC.
  72. S. Kang et al. (2017) “Association between resting heart rate, metabolic syndrome and cardiorespiratory fitness in Korean male adultsâ€. 10.1016/j.jesf.2017.06.001. Open access.
  73. G. Kay (1997). “Initial and Steady-State Effects of Diphenhydramine and Loratadine on Sedation, Cognition, Mood, and Psychomotor Performanceâ€. DOI: 10.1001/archinte.1997.00440410082009.
  74. M. Kellner et al. (2009) “The selective serotonin re-uptake inhibitor escitalopram modulates the panic response to cholecystokinin tetrapeptide in healthy men depending on 5-HTTLPR genotypeâ€. DOI: 10.1016/j.jpsychires.2008.09.001.
  75. A. H. Kemp (2010) “Impact of Depression and Antidepressant Treatmenton Heart Rate Variability: A Review and Meta-Analysisâ€. DOI: 10.1016/j.biopsych.2009.12.012.
  76. J. S. Kerr et al. (1993) “Effects of fluoxetine on psychomotor performance, cognitive function and sleep in depressed patientsâ€. DOI: 10.1097/00004850-199300840-00025.
  77. S. Keller, W. H. Frishman (2003) “Neuropsychiatric Effects of Cardiovascular Drug Therapyâ€. DOI: 10.1097/01.CRD.0000053453.89776.2D.
  78. Y. Kimura et al. (1999) “Amnesic effects of the anticholinergic drugs, trihexyphenidyl and biperiden: differences in binding properties to the brain muscarinic receptorâ€. DOI: 10.1016/s0006-8993(99)01526-7.
  79. B. Knutson et al. (1998) “Selective Alteration of Personality and Social Behavior by Serotonergic Interventionâ€. Full paper in ResearchGate. DOI: 10.1176/ajp.155.3.373.
  80. E. Kokotos et al. (1996) “MDMA (Ecstasy) Inhibition of MAO Type A and Type B: Comparisons with Fenfluramine and Fluoxetine (Prozac)â€. DOI: 10.1038/npp.1994.26. Open access.
  81. T. H. C. Krüger et al. (2003) “Effects of acute prolactin manipulation on sexual drive and function in malesâ€. DOI: 10.1677/joe.0.1790357. In ResearchGate.
  82. T. H. C. Krüger et al. (2005) “Prolactinergic and dopaminergic mechanisms underlying sexual arousal and orgasm in humans. DOI: 10.1007/s00345-004-0496-7.
  83. R. Krysiak et al. (2018) “The effect of bromocriptine treatment on sexual functioning and depressive symptoms in women with mild hyperprolactinemiaâ€. DOI: 10.1016/j.pharep.2017.10.008.
  84. B. Lara et al. (2019) “Time course of tolerance to the performance benefits of caffeineâ€. DOI: 10.1371/journal.pone.0210275. Open access.
  85. J. Le Mellédo et al. (1998) “The Role of theb-Noradrenergic System in Cholecystokinin-Tetrapeptide-Induced Panic Symptomsâ€. DOI: 10.1016/s0006-3223(97)00536-2.
  86. W. Llewelyn (2011) “William Llewelyn’s Anabolicsâ€, 10th edition.
  87. E. B. London (2020) “The Safety and Effectiveness of High-Dose Propranolol as a Treatment for Challenging Behaviors in Individuals With Autism Spectrum Disordersâ€. DOI: 10.1097/jcp.0000000000001175.
  88. H. S. Lustig et al. (1992) “Antiparkinsonian drugs and in vitro excitotoxicityâ€. DOI: 10.1016/0006-8993(92)91517-i.
  89. R. B. Mailman, V. Murthy (2010) “Third generation antipsychotic drugs: partial agonism or receptor functional selectivity?â€. Full text in PMC.
  90. F. E. Martinez et al. (2012) “Biperiden Dependence: Case Report and Literature Reviewâ€. DOI: 10.1155/2012/949256. Open access.
  91. P. S. Massand (1994) “SSRI-induced sexual dysfunction successfully treated with amantadineâ€. DOI: 10.1002/depr.3050020608.
  92. J. H. Meyer et al. (2002) “Serotonin Transporter Occupancy of Five Selective Serotonin Reuptake Inhibitors at Different Doses: An [11C]DASB Positron Emission Tomography Studyâ€. DOI: 10.1176/appi.ajp.161.5.826.
  93. A. Michael, S. Andrews (2002) “Paroxetine-Induced Vaginal Anaesthesiaâ€. DOI: 10.1055/s-2002-33196.
  94. J. Micallef et al. (2009) “Antiparkinsonian drug-induced sleepiness: a doubleâ€blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjectsâ€. DOI: 10.1111/j.1365-2125.2008.03310.x.
  95. G. Mistraletti, G. Iapichino (2016) “Hydroxyzine and QTc interval: drugs without sin cast the first stone!â€. https://www.ncbi.nlm.nih.gov/pubmed/26375793. No DOI found.
  96. T. J. Moore et al. (2010) “Prescription Drugs Associated with Reports of Violence Towards Othersâ€. DOI: 10.1371/journal.pone.0015337 . Open access.
  97. C. H. Munkboel (2018) “Sertraline Suppresses Testis and Adrenal Steroid Production and Steroidogenic Gene Expression While Increasing LH in Plasma of Male Rats Resulting in Compensatory Hypogonadismâ€. DOI: 10.1093/toxsci/kfy059.
  98. A. N. Nafzinger et al. (1999) “Reply to Letter to the Editor “Improved Outcome in Fluvoxamine-Treated Patients With SSRI-Induced Sexual Dysfunctionâ€â€. DOI: 10.4088/jcp.v60n1215. Open acess.
  99. S. A. Nappo et al. (2005) “Trihexyphenidyl (Artane®): A Brazilian Study of Its Abuse. Substance Use & Misuseâ€. DOI: 10.1081/ja-200052423.
  100. A. Naguy (2016) “Clonidine Use in Psychiatry: Panacea or Panacheâ€. DOI: 10.1159/000446441.
  101. M. J. E. Neil (2011) “Clonidine: Clinical Pharmacology and Therapeutic Use in Pain Managementâ€. DOI: 10.2174/157488411798375886.
  102. E. J. Nestler et al. (2015) “Molecular Neuropharmacology: A Foundation for Clinical Neuroscienceâ€, 3rd edition. OCLC No.: 918965624.
  103. W. J. Newman, B. E. McDermott (2011) “Beta Blockers for Violence Prophylaxisâ€. DOI: 10.1097/JCP.0b013e318234eeaa.
  104. A. Nolen, T. Dai (2019) “Diphenhydramine Use Disorder and Complicated Withdrawal in a Palliative Care Patientâ€. DOI: 10.1089/jpm.2019.0308.
  105. H. Obata (2017) “Analgesic Mechanisms of Antidepressants for Neuropathic Painâ€. DOI: 10.3390/ijms18112483. Open access.
  106. A. Opbroek et al. (2002) “Emotional blunting associated with SSRI-inducedsexual dysfunction. Do SSRIs inhibit emotional responses?â€. DOI: 10.1017/S1461145702002870. Open access.
  107. A. Patacchini, F. Cosci (2019) “A Paradigmatic Case of Postselective Serotonin Reuptake Inhibitors Sexual Dysfunction or Withdrawal After Discontinuation of Selective Serotonin Reuptake Inhibitors?â€. DOI: 10.1097/jcp.0000000000001154.
  108. K. W. Perry, R. W. Fuller (1992) “Effect of fluoxetine on serotonin and dopamine concentration in microdialysis fluid from rat striatumâ€. DOI: 10.1016/0024-3205(92)90423-m.
  109. H. Pols et al. (1996) “Fluvoxamine attenuates 35% CO2 challenge-induced panicâ€. DOI: 10.4088/jcp.v57n1107.
  110. N. Pomara, et al. (2010) “Retrograde facilitation of verbal memory by trihexyphenidyl in healthy elderly with and without the APOE ε4 alleleâ€. DOI: 10.1016/j.euroneuro.2010.03.004.
  111. J. Price et al. (2009) “Emotional side-effects of selective serotonin reuptake inhibitors: qualitative studyâ€. DOI: 10.1192/bjp.bp.108.051110. Full text.
  112. R. S. I. Putri et al. (2016) “A Comparative Pharmacokinetics Study of the Anti-Parkinsonian Drug Pramipexoleâ€. DOI: 10.3390/scipharm84040715. Open access.
  113. D. Radovanovic et al. (2000) “Dose-dependent toxicity of diphenhydramine overdoseâ€. DOI: 10.1191/096032700671040438.
  114. A. K. Reimers et al. (2018) “Effects of Exercise on the Resting Heart Rate: A Systematic Review and Meta-Analysis of Interventional Studiesâ€. DOI: 10.3390/jcm7120503. Open access.
  115. S. Reiss et al. (1986) “Anxiety sensitivity, anxiety frequency and the prediction of fearfulnessâ€. DOI: 10. 1016/0005-7967(86)90143-9.
  116. D. Robertson et al. (1981) “Tolerance to the humoral and hemodynamic effects of caffeine in manâ€. DOI: 10.1172/jci110124. Open access.
  117. P. Romano et al. (2004) “Anxiety sensitivity and modulation of the serotonergic system in patients with PDâ€. DOI: 10.1016/s0887-6185(02)00295-5.
  118. P. A. Routledge, D. G. Shand (1979) “Clinical Pharmacokinetics of Propranololâ€. DOI: 10.2165/00003088-197904020-00001.
  119. M. Rütgen et al (2019) “Antidepressant treatment, not depression, leads to reductions in behavioral and neural responses to pain empathyâ€. DOI: 10.1038/s41398-019-0496-4 Open access.
  120. J. A. Schmitt et al. (2002) “Modulation of the Critical Flicker Fusion effects of serotonin reuptake inhibitors by concomitant pupillary changesâ€. DOI: 10.1007/s00213-001-0993-y.
  121. C. Sanchez et al. (2014) “A comparative review of escitalopram, paroxetine, and sertraline: are they all alike?â€. DOI: 10.1097/YIC.0000000000000023. In PMC.
  122. R. A. Sansone, L. A. Sansone (2010) “SSRI-Induced Indifferenceâ€. No DOI found. Authors’ manuscript in PMC.
  123. I. Sagar-Ouriaghli et al. (2018) “Propranolol for treating emotional, behavioural, autonomic dysregulation in children and adolescents with autism spectrum disordersâ€. DOI: 10.1177/0269881118756245.
  124. E. Samochowiec-Donocik et al. (2004) “Influence of beta-adrenergic antagonists on tear secretion in childrenâ€. https://pubmed.ncbi.nlm.nih.gov/15662104/. No DOI found. Full text.
  125. E. R. Samuels et al. (2007) “Comparison of pramipexole with and without domperidone co-administration on alertness, autonomic, and endocrine functions in healthy volunteersâ€. DOI: 10.1111/j.1365-2125.2007.02938.x. Open access.
  126. K. M. Shannon et al. (1997) “Efficacy of pramipexole, a novel dopamine agonist, as monotherapy in mild to moderate Parkinson’s diseaseâ€. DOI: 10.1212/wnl.49.3.724.
  127. V. Sicari, C. P. Zabbo (2019) “Diphenhydramineâ€. https://www.ncbi.nlm.nih.gov/books/NBK526010/.
  128. J. M. A. Sitsen, M. Zivkov (1995) “Mirtazapine: Clinical profileâ€. DOI: 10.2165/00023210-199500041-00007.
  129. J. M. Silver et al (1999) “Propranolol Treatment of Chronically Hospitalized Aggressive Patients. The Journal of Neuropsychiatry and Clinical Neurosciences†DOI: 10.1176/jnp.11.3.328.
  130. L. Singer et al. (1984) “Influence of systemic administrated beta-blockers on tear secretionâ€. https://pubmed.ncbi.nlm.nih.gov/6149719/.
  131. Sowa-Kućma et al. (2017) “Vortioxetine: A review of the pharmacology and clinical profile of the novel antidepressantâ€. DOI: 10.1016/j.pharep.2017.01.030.
  132. A. V. Srinivasan (2019) “Propranolol: A 50-Year Historical Perspectiveâ€. DOI: 10.4103/aian.AIAN_201_18. Open access.
  133. S. M. Stahl (2017) “Stahl’s Essential Pharmacology Prescriber Guideâ€, 6th ed. OCLC No.: 1014207429.
  134. S. A. Steen (2015) “Propranolol for the treatment of anxiety disorders: Systematic review and meta-analysisâ€. DOI: 10.1177/0269881115612236. Open access.
  135. J. J. G. Steffensmeier et al. (2006) “Do Randomized Controlled Trials Always Trump Case Reports? A Second Look at Propranolol and Depressionâ€. DOI: 10.1592/phco.26.2.162.
  136. T. Szasz (1974) “The Myth of Mental Illnessâ€, 2nd ed. ISBN: 0060911514.
  137. T. Szasz (2011) “The Therapeutic State: The Tyranny of Pharmacracyâ€. https://www.independent.org/pdf/tir/tir_05_4_szasz.pdf. Open access.
  138. A. T. Taneku et al. (2018) “Effect of propranolol on heart rate variability in hyperthyroidismâ€. DOI: 10.1186/s13104-018-3224-x. Open access.
  139. A. Thomas et al. (2008) “Diphenhydramine abuse and detoxification: a brief review and case reportâ€. DOI: 10.1177/0269881107083809.
  140. C. J. Timmer et al. (2000) “Clinical Pharmacokinetics of Mirtazapineâ€. DOI: 10.2165/00003088-200038060-00001.
  141. S. Tordjman et al. (2017) “Melatonin: Pharmacology, Functions and Therapeutic Benefitsâ€. DOI: 10.2174/1570159X14666161228122115. Open access.
  142. S. J. Traub, M. D. Levine (2017) “Acute neurotoxicology of drugs of abuseâ€. DOI: 10.1016/b978-0-444-63599-0.00027-2.
  143. H. Tsuchihashi et al. (1990) “Characteristics of 125I-iodocyanopindolol Binding to β-Adrenergic and Serotonin-1B Receptors of Rat Brain: Selectivity of 1β-Adrenergic Agentsâ€. DOI: 10.1254/jjp.52.195. Open access.
  144. P. Turner et al. (1965) “Effect of adrenergic receptor blockade on the tachycardia of thyrotoxicosis and anxiety state†DOI: 10.1016/S0140-6736(65)92340-8.
  145. G. M. Peterson, M. Naunton (2005) “Valproate: a simple chemical with so much to offerâ€. DOI: 10.1111/j.1365-2710.2005.00671.x.
  146. H. J. G. M. van Megen et al. (1997) “Effect of the selective serotonin reuptake inhibitor fluvoxamine on CCK-4 induced panic attacksâ€. DOI: 10.1007/s002130050201.
  147. A. N. Voineskos et al. (2020) “Effects of Antipsychotic Medication on Brain Structure in Patients With Major Depressive Disorder and Psychotic Features Neuroimaging Findings in the Context of a Randomized Placebo-Controlled Clinical Trialâ€. DOI: 10.1001/jamapsychiatry.2020.0036.
  148. M. D. Waldinger et al. (2015) “Penile anesthesia in Post SSRI Sexual Dysfunction (PSSD) respondsto low-power laser irradiation: A case study and hypothesis aboutthe role of transient receptor potential (TRP) ion channelsâ€. DOI: 10.1016/j.ejphar.2014.11.031.
  149. J. W. Watkins (2014) “The Use of Physostigmine by Toxicologists in Anticholinergic Toxicityâ€. DOI: 10.1007/s13181-014-0452-x. In PMC.
  150. J. M. Witkin et al. (2019). “Rapid-acting antidepressantsâ€. DOI: 10.1016/bs.apha.2019.03.002.
  151. D. T. Wong et al. (1974) “A selective inhibitor of serotonin uptake: Lilly 110140, 3-(p-trifluoromethylphenoxy)-N-methyl-3-phenylpropylamineâ€. DOI: 10.1016/0024-3205(74)90345-2.
  152. D. T. Wong et al. (1995) “Prozac (fluoxetine, Lilly 110140), the first selective serotonin uptake inhibitor and an antidepressant drug: twenty years since its first publicationâ€. DOI: 10.1016/0024-3205(95)00209-o.
  153. P. B. Woods, M. L. Robinson (1981) “An investigation of the comparative liposolubilities of β-adrenoceptor blocking agentsâ€. DOI: 10.1111/j.2042-7158.1981.tb13743.x.
  154. C. E. Wright et al. (1997) “Steady-State Pharmacokinetic Properties of Pramipexole in Healthy Volunteersâ€. DOI: 10.1002/j.1552-4604.1997.tb04330.x.
  155. A. Zahiroddin et al. (2017) “Comparing the Efficacy of Bupropion and Amantadine on Sexual Dysfunction Induced by a Selective Serotonin Reuptake Inhibitorâ€. DOI: 10.5812/ircmj.24998. Open access.
  156. P. Zwanzger et al. (2002) “Effects of Alprazolam on Cholecystokinin-Tetrapeptide-Induced Panic and Hypothalamic–Pituitary–Adrenal-Axis Activity: A Placebo-Controlled Studyâ€. DOI: 10.1038/sj.npp.1300131. Open access.
 
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