Psychedelic Use in Psychiatry

Introduction.

Psychedelics have been used since before recorded history for both religious and medicinal purposes.  However, their “discovery” by western medicine was relatively recent.   A substantial body of evidence supports a variety of different psychedelic drugs having psychiatric value including glutamate psychedelics (eg. ketamine), serotonin-like psychedelics (including psilocybin, LSD and ayahuasca), and catecholamine psychedelics (eg. MDMA, aka Ecstasy). However,  only ketamine is currently approved by the FDA/DEA for clinical use.  Since ketamine is approved by the FDA as an anesthetic, sub-anesthetic doses can be used “off label” to treat psychiatric issues such as depression and suicidal ideation.  The other psychedelics are DEA schedule-1 drugs (the same category as heroin) supposedly making them unavailable for any purpose.  However both psilocybin and MDMA were recently granted breakthrough status by the FDA for the purpose of allowing research to determine whether they are appropriate for therapeutic purposes.    It seems likely to me that the FDA will, at some point, approve them for this purpose.  This approval will also require the DEA to reschedule them.

Psychedelic Use in Psychiatry.

One of the earliest therapeutic uses of a psychedelic was a synthetic form of mescaline (a catecholamine-like psychedelic) as an adjunct to psychotherapy in the late 1930’s.  However the first use of a serotonin-like psychedelic was likely that of LSD in the early 1940’s.  LSD does not occur in nature and was first synthesized in the late 1930’s by Albert Hofmann, a Sandoz pharmacologist.  However, its psychedelic properties weren’t discovered until 1943, when Hofmann accidentally dosed himself and had the first LSD “trip.”  The potential implications for psychiatry quickly became apparent and shortly thereafter, Sandoz began making LSD available to psychiatrists and scientists under the brand name Delysid.

Over 2000 papers were published between 1960 and 1966 on the therapeutic uses of LSD!   LSD was seen both as a model for understanding schizophrenia and as a treatment for a wide range of disorders, including depression, anxiety, schizophrenia, alcohol abuse, migraines, gambling and homosexuality.  Therapeutically, it was used mainly for patients that did not respond to conventional treatments.  Three different approaches were used:  1) Psycholytic therapy where LSD was used in conjunction with traditional Freudian psychoanalytic therapy; 2) Psychedelic Chemotherapy employing a more limited psychotherapeutic approach and 3) Psychedelic/Peak Therapy that attempted to induce a “mystical-like” experience.    Evidence supported all three approaches having value for some disorders and all were considered safe in controlled medical settings.  While LSD dominated this early phase of psychedelic research and therapy, other psychedelics such as mescaline and psilocybin were also used.  Unfortunately this early work was performed before medical research began using  modern research methods, leaving this work open to alternative explanations.

However, before modern research methods could be applied,  these psychedelics were declared illegal.    One factor leading to their illegality was the increasing recreational use of LSD in the 1960’s  by “hippies,” whose counterculture perspectives many found threatening.  “Turn on, tune in, and drop out” was a famous expression of the hippie movement popularized by Timothy Leary, a Harvard Professor and a leading proponent of recreational psychedelic use.  As recreational use was not as controlled for dosage, mindset, and setting as medical use, the incidence of “bad trips” became more common.  The resulting increase in emergency room visits and suicides following recreational use certainly contributed to the negative public opinion.  In the 1960’s, there were also disturbing reports that the military had been trying to “weaponize” LSD as both a truth serum and as an incapacitating agent.  There were also reports of the bad physiological effects of LSD, including chromosomal breakage, which were later proven incorrect.

By the mid 1960’s the damage to LSD’s reputation had been done and, in 1966 the Drug Abuse Control Amendments  severely limited LSD sales and use.   In response, Sandoz stopped making LSD, and LSD’s use in medical treatment and research was largely brought to a halt.  And in 1970, the Comprehensive Drug Abuse Prevention and Control Act took it a step further and prohibited the therapeutic use of LSD and psilocybin altogether.

Public antipathy toward traditional psychedelics continued through the 1970s and 80s.  This perspective was reinforced by Nixon’s “war on drugs.”   Research proposing a link between LSD use and schizophrenia was also published at this time.  At the same time, underground recreational and therapeutic use continued in the US and western Europe, with more open therapeutic use in Eastern Europe.

However, psychedelic therapy began making a comeback in the 1980’s, but with MDMA (commonly known as Ecstasy or Molly) rather than LSD.  MDMA is a synthetic catecholamine-like psychedelic first synthesized in 1912 but not widely used as a psychotherapeutic drug until late 1970’s and early 1980s.

[As an aside, when MDMA began being used therapeutically in the 1980’s, it fell into a category that nowadays would be called  “designer drug.”  Until the DEA puts a new drug into one of its 5 schedules, there are no legal restrictions on its recreational or therapeutic use.  However, a new drug cannot be scheduled until the DEA becomes aware of it and is able to study its effects.  Unfortunately, this delay provides a window of opportunity for unscrupulous parties to develop and legally sell newly synthesized “designer drugs” before the DEA can schedule them.

While designer drugs sometimes work as advertised, they typically come with  little or no toxicology or pharmacology. In some cases, particularly with designer opioids, the outcome has been disastrous.  Despite the DEA making changes to attempt to close this “loophole”, the problem has only gotten worse.  The most common designer drugs today are in the opioid, anabolic steroid, and psychedelic categories although there are also designer stimulants, sedatives, and viagra analogs as well as synthetic cannabinoids, synthetic cathinones and αMSH analogs (for tanning).]

By the late 1970’s, some psychiatrists were finding MDMA to be a more than adequate replacement for LSD.  MDMA is not a classical serotonin-like psychedelic, but rather falls into the catecholamine-like category because its molecular structure closely resembles the catecholamines, norepinephrine and dopamine.   The structure and effects of MDMA are similar to amphetamine, a drug that pharmacologists sometimes also place in the catecholamine-like psychedelic category.  Amphetamine and MDMA both cause sympathetic arousal (i.e. “fight or flight” physiology) by increasing norepinephrine levels, are rewarding by increasing dopamine levels, and are psychedelic by binding serotonin 5-HT2A receptors.  The differences between MDMA and amphetamine are largely a matter of degree.  While amphetamine is more potent in stimulating sympathetic arousal, MDMA is more potent in stimulating psychedelic responses.

Psychotherapists found MDMA to have several desirable properties when compared to LSD.   MDMA is shorter acting and produces a gentler, more rewarding, and more manageable psychedelic effect than LSD.  Through promoting empathy and bonding, it appears to help patients work through emotional trauma and depression and appears particularly useful for treating Post Traumatic Stress Disorder (PTSD).

Although psychotherapists had hoped to confine MDMA to therapeutic use only, by the mid 1980’s it too was “discovered” by recreational users, most notably for its use at “rave” dance parties.  While MDMA was considered safe in controlled medical settings, the same could not be said for its recreational use.  The main problem was, when coupled with strenuous dancing, MDMA could cause hyperthermia and salt imbalance which could result in kidney and liver damage, and even death.  Further adding to public disaffection was a published primate study showing that “recreational dosages” of MDMA caused brain damage.  However, the paper was later shown to be incorrect and had to be retracted. In contrast, evidence from therapeutic settings did not provide evidence of long-term harm.  Although there are risks associated with MDMA use, they are considered less serious than for some legally available drugs such as alcohol and tobacco.  In 1985, the DEA nonetheless overruled input from medical professionals and placed MDMA in an emergency 1-year Schedule-1 category that prohibited both recreational and medical use.  The scheduling was later made permanent.

In the 1990’s other psychedelics began to be explored for therapeutic potential, such as dimethyltriptamine (DMT), the active ingredient in ayahuasca, a psychedelic drug coming from plants mainly in S. America.  There was also research using some of the newly synthesized catecholamine-like “designer” psychedelics before they could be scheduled by the DEA.   However, underground therapy in the US and legal research elsewhere continued to be performed.

Ketamine was originally approved by the FDA in 1962 as an anesthetic.  However around 2000, sub-anesthetic, psychedelic doses of ketamine were serendipitously found to possess significant antidepressant properties.  It soon became apparent that ketamine was a major breakthrough for treating depressed patients who don’t respond to traditional antidepressants.  Although approved by the FDA as an anesthetic, ketamine began being used“off label”as a treatment mainly for “treatment-resistant” depression.

In the early 2000’s the situation for the illegal psychedelics also began to turn around with the development of psychedelic research centers  at prestigious universities, such as Johns Hopkins, and Harvard here in the U.S. and Imperial College London and Bristol University in the U.K. as well as funding by a number of organizations supporting psychedelic research.   Some of the early research at these centers debunked many of the earlier negative findings.  For example, when the concurrent use of other recreational drugs was accounted for, there was much less evidence for the serotonin-like psychedelics having severe negative effects.  Although there are risks associated with MDMA use, they are considered less serious than for some legally available drugs such as alcohol and tobacco.

And finally in 2018, as a step towards possibly legalizing therapeutic use, the FDA granted “breakthrough status” to psilocybin and MDMA.  This status allowed  medical professionals to treat depression and PTSD on an experimental basis.  Unlike earlier treatments, these FDA-approved treatments are required to meet the exacting standards of FDA Phase II and III drug trials and are designed to examine therapeutic effectiveness under highly controlled conditions, determine the best treatment protocols, and also characterize any issues that might arise. Ultimately, this research could be used to determine whether FDA would approve these drugs for more widespread therapeutic use.  So far the results look promising.

However, current views on the therapeutic use of psilocybin and MDMA by different organizations encompass the full range of possibilities.  For example, the “official” position of the DEA, is that serotonin-like psychedelics (such as psilocybin) and catecholamine-like psychedelics (such as MDMA) are “hard drugs” whose extreme dangers outweigh any benefits (much like heroin, another schedule 1 drug) .  On the other hand, many psychiatric experts (e.g. Reiff et al, 2020), as well as the FDA,  believe these drugs have medical value but that more research is necessary before formal approval can be granted. At the other end of the spectrum, the state of Oregon recently “jumped the gun” and legalized psilocybin for therapeutic use by state-licensed professionals.

Some of these “illegal” psychedelic drugs will almost certainly receive federal approval for therapeutic use in the near future.   Clearly, there are obvious parallels to the disjointed process by which cannabis (another DEA Schedule 1 drug) is being legalized here in the U.S.

References.

Reiff, C. M., Richman, E. E., Nemeroff, C. B., Carpenter, L. L., Widge, A. S., Rodriguez, C. I., . . . McDonald, W. M. (2020). Psychedelics and psychedelic-assisted psychotherapy. Ajp, 177(5), 391-410. doi:10.1176/appi.ajp.2019.19010035

Sessa, B. (2016). The history of psychedelics in medicine. In von Heyuden, M. et al (Ed.), Handbuch psychoaktive substanzen (pp. 1-26). Heidelberg: Springer -Verlag. doi:10.1007/978-3-642-55214-4_96-1

Tullis, P. (2021). The rise of psychedelic psychiatry. Nature, 589, 506-509.

 

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Depression VII: Background for Antidepressant Effects of Traditional Psychedelics

Introduction.

In the 1940’s and 50’s, traditional serotonin-like psychedelics, such as LSD and psilocybin, were sometimes used to treat depression (and other disorders).   In fact, some consider this early use to be a significant contribution to the beginnings of modern biological psychiatry.  However, this use was derailed in the 1960’s when these drugs became illegal for any purpose (more about this in the next post).  Currently, ketamine, a glutamate-related psychedelic, is the only psychedelic drug available for treating depression without special FDA permission.

Some psychiatric professionals strongly opposed the banning of psilocybin and LSD for therapeutic use, and, once banned, began advocating for overturning this restriction.  Finally, in 2018 the FDA granted psilocybin “breakthrough status”, which permitted approved medical professionals to use it, on an experimental basis, for depression and other psychiatric disorders.  This status was granted to expedite the evaluation of what the FDA now viewed as a “promising” therapy.  Although psilocybin is currently the only traditional serotonin-like psychedelic with this status, other serotonin-like psychedelics, such as LSD and ayahuasca, would appear to possess similar antidepressant properties.  In fact there is evidence that traditional psychedelics may be even more effective than ketamine.

In this post, background information is presented to put these drugs into a broader context and also lay some groundwork for future posts.

Different Classes of Psychedelics.

There are actually five different categories of psychedelic drugs defined either by their structural similarity to certain neurotransmitters, or, if they don’t physically resemble a neurotransmitter, by the type of neurotransmitter receptor(s) with which they interact.  Traditional psychedelics, such as psilocybin, LSD, and ayahuasca, are all in the serotonin-like category because their molecular structure is similar to that of serotonin. Their psychedelic effects are also mediated through binding serotonin receptors.   Ketamine, a glutamate-related psychedelic (also called a dissociative psychedelic), whose structure is different from glutamate, nonetheless works by binding a glutamate receptor.

But that’s not all folks!  There are also catecholamine-like psychedelics (also referred to as empathogens or entactogens) whose structures resemble the catecholamines, norepinephrine and dopamine.  While these psychedelics molecularly resemble catecholamine neurotransmitters, their psychedelic effect is actually caused by  binding the same receptor(s) as the serotonin-related psychedelics.  The final 2 classes are sometimes referred to as atypical psychedelics and include the acetylcholine-related psychedelics that work through binding an acetylcholine receptor, and an opioid-related psychedelic that works through binding an opiate receptor.  There is evidence that catecholamine-like psychedelics such as MDMA, (also known as ecstasy) and the opioid-related psychedelic (salvinorin A) also have antidepressant properties.

I mention in passing that MDMA  (also normally illegal for any purpose) also recently received FDA breakthrough status for treating post traumatic stress disorder (PTSD).  Psilocybin also has efficacy in PTSD treatment, however, this and the next post will focus on the use of psilocybin and other serotonin-like psychedelics in the treatment of depression.

Serotonin-like Psychedelics.

The serotonin-like psychedelics are defined by their structural similarity to serotonin.  As seen in Figure 1, they all contain the serotonin “carbon backbone” and, with the exception of LSD, differ differ mainly in possessing methyl (-CH3) functional groups.  In fact most are essentially methylated versions of serotonin. Since serotonin itself is not psychedelic, the methyl groups have been proposed to confer the psychedelic and hallucinatory properties.

Figure 1: Serotonin and some serotonin-like psychedelics.   The serotonin-like psychedelics are structurally similar to serotonin.

These psychedelics induce symptoms that bear some resemblance to the hallucinations and altered mental states seen in schizophrenia.  In fact, the striking structural similarity of the serotonin-like and catecholamine-like psychedelics to neurotransmitters led to the “endogenous psychotogen hypothesis” of schizophrenia.   According to this idea, schizophrenic symptoms are caused by abnormalities during neurotransmitter synthesis (such as methylation) resulting in defective neurotransmitters.  While there are differences in the relative amounts of certain neurotransmitters in the brains of schizophrenics, there is no evidence that the neurotransmitter structures are abnormal.  Consequently this hypothesis has not received much support.

At the same time, there is evidence that DMT (the psychedelic ingredient in ayahuasca) may be produced in small amounts by the pineal gland.  However, there is not convincing evidence that endogenous DMT contributes to schizophrenic symptomology. And even if there were, most experts view schizophrenia as a complex disorder that likely has multiple causes.

It is worth noting that the serotonin-like psychedelics are not the only drugs that produce temporary schizophrenia-like symptoms.  Glutamate-related psychedelics such as ketamine and phencyclidine can also produce such symptoms.  In addition, chronic abuse of amphetamine, methamphetamine, or cocaine can also result in a temporary psychotic state that resembles schizophrenia.  However, as yet, these “models” of schizophrenia have not provided definitive breakthroughs in our understanding of this complicated disorder.

And finally, in a small percentage of users, the serotonin-like psychedelics can precipitate a psychiatric disorder called Hallucinogen Persisting Perception Disorder (HPPD).  In HPPD, hallucinations and other psychiatric symptoms continue to recur long after the drug has been cleared from the body.  However, current thinking is that psychedelic drug use doesn’t so much cause this disorder as “reveal” it in predisposed individuals.  For this reason, individuals with a history of psychosis, or evidence of a psychotic predisposition, are normally excluded from psychedelic therapies.

The Brain’s Serotonin System

Figure 2: The Serotonin System.  The cell bodies of serotonin-releasing neurons are in the Raphe nucleus while their axons project throughout the brain and spinal cord.

Since serotonin-like psychedelics work through their interactions with serotonin receptors, a brief review of the brain’s serotonin system is in order.   Serotonin is a neurotransmitter secreted by a small population of neurons whose cell bodies are in the Raphe Nuclei in the brainstem (see figure 2).  However their unmyelinated axons project to virtually all areas of the brain and spinal cord.  Upon reaching their destination, the terminals release serotonin both synaptically and extra-synaptically.  These two modes of release complement each other.  Synaptic transmission produces quick, punctate effects, while extra-synaptic volume transmission results in slower, more lasting, hormone-like effects.

Once released, serotonin can bind to, and activate, 15 different serotonin receptors that fall into 4 different gene families.  These receptors are found in neuron membranes both inside and outside of synapses, and are also differentially expressed in different parts of the brain.  Given this complexity, serotonin undoubtedly plays a variety of roles in different parts of the brain and spinal cord.

Fig 3. A schematic of serotonin secretion during wakefulness and sleep. The amount of serotonin secretion correlates with the amount of body movement.   Secretion ceases altogether during REM sleep when the body is paralyzed.  A brief burst of serotonin release at the beginning of a non-REM period is thought to delay the occurrence of the next REM period and contribute to the approximately 90-min periodicity of a REM + Non-REM bout.

Because serotonin secretion intensifies during physical exertion, one of its roles is thought to aid the brain and spinal cord in preparing for, and executing, motor movements.   As would be expected, serotonin secretion shows a pronounced circadian rhythm, being highest when awake and physically active (See Figure 3).  Daytime secretion declines as activity levels drop.  Secretion declines even further after falling asleep and ceases altogether during Rapid Eye Movement (REM) Sleep when you are dreaming and your body is paralyzed.

As described in earlier posts, a chronic deficit in brain serotonin typically accompanies depression, while various treatments that boost brain serotonin are often effective in relieving depression.  However, these serotonin-boosting treatments do not work for all patients indicating that brain serotonin concentration is only part of a more complicated story.

Mechanism of action of the serotonin-like psychedelics.

While the serotonin-like psychedelics also work through serotonin neurophysiology they do so quite differently from traditional antidepressants (such as SSRI’s).  Whereas SSRI’s block serotonin reuptake transporters, serotonin-like psychedelics work as agonists for serotonin receptors.

However, these psychedelics do not bind all serotonin receptors, and  typically bind with less effectiveness than serotonin (i.e. are partial agonists).  One strategy for trying to understand which serotonin receptor(s) underly their psychedelic effect is to look for commonalities in the binding profiles of the different serotonin-like psychedelics.  It turns out that all serotonin-like psychedelics show a high affinity for the serotonin 5-HT2A receptor (the chemical name for serotonin is 5-hydroxytryptophan, abbreviated 5-HT).  The importance of this receptor is also supported by finding that the administration of  a 5-HT2A receptor blocker (that blocks the ability of the psychedelic drug to bind) attenuates the psychedelic response.   However there is also overlap in the  binding of several other serotonin receptors, raising the possibility that other receptors may play a lesser role as well.  Catecholamine-like psychedelics, such as MDMA (i.e. Ecstasy) also produce their psychedelic effect by binding  the 5-HT2A  receptor.  One confusing relationship is that serotonin itself does not possess psychedelic properties despite binding the 5-HT2A receptor.  So exactly how this receptor would confer psychedelic properties is unclear.

Psychedelic drugs often bind non-serotonin receptors as well.  Although this binding may not contribute to psychedelic effects, it could possibly contribute to antidepressant properties (more about that when examining specific psychedelics) as well other side effects.

A Psychedelic “Trip”

Because taking a psychedelic drug is often perceived as going to a strangely different world, it is sometimes referred to as taking a trip.  Certain aspects of this “trip” also appear central to the antidepressant effect.  Since psychedelic experiences have been described in detail by others, I only briefly touch on them here, paying more attention to effects that might contribute to the treatment of depression.

These drugs are particularly well known for their perceptual distortions.  Shortly after taking the drug, colors become brighter and geometric patterns can often be seen when closing the eyes (similar to “phosphenes” when rubbing your eyes).  As the trip continues, these patterns intensify and can sometimes even be seen with eyes open, superimposed on the visual background.  At this time, stationary objects may also seem to move or ripple or change texture and sometimes one object can morph into another.  Auditory input is also altered and many report enhanced pleasure in listening to music. Taste and smell are also intensified and are also often experienced as more pleasurable.  Sometimes the user may experience synesthesia, where sensory input seems cross circuited. For example, colors can be heard and sounds seen.   Depending upon intensity, the sensory alterations can be classified as true hallucinations.   Time also becomes distorted. Initially it appears to slow down but as the experience intensifies, time can appear to change speed, stop, or even go backwards.

Regular recreational users take psychedelics because they enjoy these bizarre effects, the intensity of which depend upon dosage and individual susceptibility.  The time course of a trip typically varies from between 6 to 12 hours also depending upon dosage and susceptibility.

However, more relevant to its antidepressant effect, users can also have a “mystical” or “spiritual” experience.   In this regard, these drugs are sometimes referred to as “entheogens” which means they release the divine within us.  In such an experience, the normal boundaries that separate the individual from the the outside world appear to dissolve, resulting in  a lessening of individual identity. This state is thought to permit the individual to look more realistically both “outward” and “inward”.  When looking outward, they become more empathetic to, and understanding of, others.  When introspectively looking inward, they are able to perceive themselves as other see them and in a more realistic fashion.  In this state, the person is sometimes able to gain new perspectives on themselves and on their relationship to the world about them.

Some clinicians characterize this “ego-dissolving” mystical effect as a “peak experience” which, in turn, can lead to a restructuring of personality.  In depressed individuals, this experience is hypothesized to reorganize brain processing in such a way that the patient no longer ruminates upon the negative mental processes underlying depression.  A number of investigators provide evidence that such a psychedelic experience can have a lasting effect in relieving depression (several months and perhaps even permanently in some individuals).  In this regard, several investigations have also noted a correlation between the intensity of the “mystical” experience and the magnitude of the antidepressant effect.

The downside  is that not all users have positive experiences under the influence of these drugs.  In fact, for some individuals, the experience can be terrifying and, in rare cases, even precipitate a psychotic episode.  It has not been unusual for a recreational user experiencing high levels of anxiety and confusion to end up in a hospital emergency room seeking treatment.  Obviously not an experience that you would want a depressed individual to undergo.

Whether an individual has a positive or negative experience is influenced by at least 3 variables.  1) The first is the mindset prior to taking the psychedelic.  If the individual is convinced, in advance, that the experience will be positive, it usually is.  2) The setting in which the drug is taken is also important.  A positive experience is optimized by taking the drug in a safe and comfortable environment where the user is free to experience the drug’s effects without outside interruptions or disturbances.  It is also helpful to have an experienced person available who can provide guidance and reassurance if needed.   3) Negative and even psychotic reactions are most likely in individuals with a past history of psychosis or in individuals possessing such a predisposition (such as a person with a schizoid personality).  Individuals known to possess such traits are generally excluded from psychedelic therapies.  Since some hallucinogens can also cause a rise in blood pressure, individuals with severe cardiac disorders are also contraindicated.  However, when appropriate measures are taken in controlled medical settings, few serious problems are normally observed.

Other related issues.

Drugs such as opiates, alcohol, nicotine, methamphetamine, cocaine, etc. are taken mainly because they activate the brain’s reward circuitry.  They make you feel really good.  Activation of the reward circuitry is central to understanding a drug’s abuse potential and addictive qualities.  On the other hand, the serotonin-like psychedelics are generally poor activators of the brain’s reward circuitry.  These psychedelics are taken mainly because users enjoy experiencing the perceptual distortions and altered states of consciousness.  While the catecholamine-like psychedelics (such as ecstasy and other amphetamine-like drugs) are rewarding, they too are taken more for their perceptual and consciousness-altering properties than for their rewarding effects.  Thus you typically do not see the level of abuse and addiction to psychedelics seen for other recreational drugs.  At the same time, psychedelics do have their downsides.  For example, the activation of the sympathetic nervous system by ecstasy (and other catecholaminergic psychedelics) can be fatal in rare cases, and all psychedelics can produce lingering psychiatric effects in a small percentage of users.

An issue I find particularly interesting, is why plants and fungi (and animals, in the case of toads) make psychedelics in the first place.  It turns out that most psychedelic molecules possess one or more nitrogen atoms which classifies them as “alkaloids.”  Alkaloids have 2 common properties: 1) they taste bitter and 2) they are often poisonous.  In this way, organisms that make alkaloids protect themselves from being eaten.  In many cases the bitter taste is sufficient.  However, if that “warning” doesn’t work, many alkaloids also disrupt the functioning of the central nervous system.  In some cases this disruption can be deadly (e.g.  atropine, nicotine), but even if it isn’t deadly, negative consequences are likely.  Insects, which are usually the greatest danger to plants, are generally more susceptible than humans and other vertebrates.

A related issue is that bitter taste perception in animals appears to have undergone parallel evolution to alkaloid evolution.  The other 4 taste modalities (sweet, sour, salty and umami (savory)) have not changed much over evolutionary time and each can be accounted for by only one or a few genes.   In contrast, there are 25 different bitter receptors in humans, each coded for by a different gene.  In mice there are 35.  The apparent reason is that, unlike other taste qualities, bitter tastants possess so many different chemical structures that more different receptors are required to detect them all.  The number of bitter receptors in a given species appears related to the alkaloids regularly encountered by that species over evolutionary time.  Clearly, bitter receptors have been a critically important animal adaptation to the evolution of plant (and toad) alkaloids.

And finally, I find it remarkable that we humans have exploited these “poisons” by turning them into drugs (e.g. nicotine, caffeine, heroin, morphine, cocaine, LSD, psilocybin, etc) that provide both recreational pleasure (at least sometimes) and medical therapy.

Concluding Remarks.

The next post will provide background on the history of the therapeutic use of traditional psychedelics.

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