Notes about psychopharmacology#

First version: 2019-11-06
Last update: 2021-01-09
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This article contains assorted notes about psychopharmacology. These notes are not comprehensive about any subtopic. Currently, SSRIs are covered with the most detail. These notes are written from a scientific viewpoint as much as possible; this implies objectivity and value-neutrality. An important question about any psychoactive compound is how it feels like. E.g: Does a psychopharmaceutical considered “antidepressant” cause the depressed person to feel relieved of depression? Since current techniques do not allow this to be answered objectively, we allow ourselves a departure from a purely scientific approach in answering it subjectively in the form of anecdotal reports and results of questionnaires filled by human subjects. In addition to psychopharmaceuticals, some activities with relatively well-characterized psychological effects are included.

1 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 Brain”.

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 like”.

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 disorder”. 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 “antidepressants”; 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 “antipsychotics”.

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 mushrooms”).
  • 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 “opioids”. 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.”. 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, Ågesen 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 30 mg and linear pharmacokinetics at an higher dose; this review gives the time to peak blood concentration after oral administration as approximately 2 h and half life as 3.9 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 5 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, 7.1 %]: 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 50 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 1.5 h. They found that pharmacokinetics followed a 2-compartment model with terminal half-life of 18.4 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 2 mg and 5 mg.

5.3.1 Pharmacokinetics

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

5.3.2 Psychological effects

Pomara et al. (2010) found that an acute dose of 2 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 50 mg of diphenhydramine in healthy volunteers. They found that the time to peak concentration is between 1.5 h and 2.5 h and the half-life is 4.8 h (computed from elimination rate constant of 0.144 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 100 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 50 mg for an hypnotic effect and 300 mg-700 mg for an hallucinogenic effect. Sicari, Zabbo (2019) give the dose as 25 mg-50 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 50 mg to 3000 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 10 min to 30 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 50 mg-100 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 ~200 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 ~250 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 away””.

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 11.6 h in men and 14.1 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 2 h or 1.8 h (depending on formulation) and the mean half-life was 8.9 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 0.5 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 0.5 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 cortex”.

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 33 % (range: 10 %-56 %) and a half-life of 47 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 20 h and 40 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]
Citalopram3.4 mg/d20 mg/d-40 mg/d
Fluoxetine2.7 mg/d20 mg/d-80 mg/d
Paroxetine5.0 mg/d20 mg/d-50 mg/d
Sertraline9.1 mg/d50 mg/d-200 mg/d
Venlafaxine (extended release)5.8 mg/d75 mg/d-225 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 20 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 20 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 10 mg per day of citalpram for 2 days followed by 20 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 20 mg per day of fluoxetine increases the critical flicker fusion frequency threshold in humans through 2 weeks of chronic use from 25.5 Hz to 27 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 10 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 10 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 10 mg daily for 7 days, then 20 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.”.

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 40 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 30 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 psychopath”:

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 means”:

[...] 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 sociopath”:

[...] 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 empathy”:

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 “feeling”, 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 600 mg of amantadine given as 3 doses of 200 mg every day. Of the 5 users to which amantadine was given, 2 reported mild side effects (one rash, which is not clearly attributable to amantadine and the other slight nausea), 2 reported no side effect and 1 was lost to follow-up. Zahiroddin et al. (2017) examined separately amantadine and bupropion to restore sexual functioning in subjects receiving various SSRIs; they found that bupropion increased self-reported sexual functioning; amantadine increased it too to a lesser extent. Costa et al. (2006) reviewed the literature for treatments of antipsychotic-induced sexual dysfunction; this can be applicable to SSRI-induced sexual dysfunction too.

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

14.6.1 Reduced genital sensitivity

Reduced general sensitivity is an uncommon effect of SSRIs. In some extreme cases this is referred to as “genital anesthesia”. 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 20 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.””. 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.”. 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 ejaculation”. 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 31 % 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.”. 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 2 d to 3 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 7 d-15 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 50 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 66 h and time to peak concentration of 7 h-11 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 10 mg/d-20 mg/d of vortioxetine compared to 20 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

19 Acknowledgements

Thanks to A. and E. for bringing several of the studies cited herein to my attention.

20 Notes

  1. Meyer et al. (2002) give the ED50 for receptor occupacy of SSRIs and venlafaxine (also a SERT inhibitor) in humans
  2. Stahl (2017)

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