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.

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

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.

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-HT_2A 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-HT_2A 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-HT_2A  receptor.  One confusing relationship is that serotonin itself does not possess psychedelic properties despite binding the 5-HT_2A 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.