Maybe this world is another planet’s hell


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Expert Pharmacologist
Jul 6, 2021
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The epigraph to the article is not chosen by chance. First of all, Aldous Huxley was a great fan of "expanding" his consciousness with the help of various hallucinogenic substances. In fact, the name of the synthetic drug "soma" from Huxley's immortal novel refers to the mysterious but often mentioned in Vedic texts "soma", which had, apparently, pronounced hallucinogenic properties. Second, it was in a letter to Aldous Huxley written in 1956 by psychiatrist Humphrey Osmond that the term "psychedelic" first sounded. The word comes from the ancient Greek words "soul," "mind," "revealing," "manifesting," and is translated as "revealing the mind" or "liberating the soul." Neither Osmond nor Huxley liked the term "hallucinogen" because of its negative connotations, so they decided to come up with something better.

Over time, the term "psychedelic" also seemed too negative to some researchers. So, in 1979, Karl Rook and his colleagues proposed a new definition - "entheogen". This definition is not popular in scientific circles. Only dozens of mentions of the word "entheogen" can be found in PubMed (against more than 27,000 mentions of "psychedelics"), and most of these definitions are from the last decade, a period of renewed interest in psychedelics. Nowadays, entheogens are understood to be anything of plant substances capable of inducing altered states of consciousness and used in various mystical rituals.

To begin with, we need to make some clarity and get acquainted with the main "actors" that will be encountered in the course of the article. In the modern view, psychedelics are not all hallucinogens, but only those that bind in the brain to serotonin subtype 2A receptors (5-HT2A). "Classic" psychedelics belong to three classes of chemicals. The first class are naturally occurring indolamines: N,N-dimethyltryptamine (DMT), 5-methoxy-DMT (5-MeO-DMT), psilocybin, and 4-hydroxy-DMT (psilocin, the active metabolite of psilocybin). The second class includes phenylalkylamines, including mescaline (derived from the peyote cactus) and synthetic "amphetamines" such as 2,5-dimethoxy-4-iodoamphetamine (DOI) and 2,5-dimethoxy-4-bromamphetamine (DOB). The third group are semi-synthetic ergolines, such as the famous LSD.

Today, in most countries, psychedelics are illegal drugs. The "neighborhood" with cocaine and heroin in the restrictive lists greatly damaged the reputation of psychedelics, however, it is no coincidence that they ended up among the "trash". By the mid-1960s, psychedelics were freely circulating in society. Not only young people from the countercultural milieu, but also quite respectable people allowed themselves to rest and relax with the help of hallucinogens (hence the expression "recreational drugs"). Uncontrolled "experimentation" with dosages and combinations of substances predictably led to many reports of serious side effects such as psychosis, prolonged panic attacks, long-term perception disorder, dangerous behavior, sometimes with a tragic outcome. Naturally, this quickly drew public attention. New psychonauts like Timothy Leary also increased public outrage by openly advocating the use of psychedelics. By 1972, psychedelics were listed as one of the "Single Convention on Narcotic Drugs" of the United Nations.


However, if you think that the years of free use of psychedelics gave us nothing but hippie culture, you are wrong. During the 1950s and 1960s, more than 1,000 papers were published examining the effects of psychedelics in psychotherapy, treating mental disorders and addictions in more than 40,000 subjects. Unfortunately, most of these studies were performed, to put it formally, at a low methodological level. Most of the works had no statistical treatment of the results. Conclusions were made on the basis of subjective reports of patients, such as: "Doctor, I think I feel better. There was no unified patient evaluation scale, no scrupulous selection of groups, no precise criteria for disease diagnosis, no analysis of side effects. Nevertheless, in recent years several attempts have been made to extract and analyze data from more or less reliable older studies. One study focused on patients with major depressive disorder. 335 individuals out of 423 (nearly 80%) in 19 studies showed significant improvement after taking psychedelics.

A kind of reassessment of the legacy of psychedelic therapy is an important part of the new renaissance and rethinking of the role of psychedelics in modern psychopharmacology. On the one hand, technology and methods have come a long way in half a century and allow for research at a level unavailable in the 1960s, and if the work of those years, for all its imperfections, does report something interesting. On the other hand, clinicians are facing the problem of resistance to antidepressant treatment. Only 30% of patients respond to such treatment, which, with the concomitant increase in the incidence of depressive disorders, is worrisome. Desperate times, as we know, call for desperate measures. Thus began a resurgence of interest in psychedelics.

In 1960, Sidney Cohen became concerned about side effects and sent out a special questionnaire to 62 researchers who had used LSD and mescaline. Forty-four of them responded and gave information on 5,000 patients. It turned out that very few patients had attempted suicide (0.12 percent), successfully committed suicide (0.04 percent) or fell into psychosis (0.18 percent), and certainly none had become addicted to LSD or mescaline after taking the drugs. The responding physicians, however, relied on data from clinical studies, but on their subjective recollections. I think you'll agree that testimonials like "I think this guy was fine" don't weigh any more than "Doctor, I think I'm feeling better.

Psychedelics in the Second Renaissance
In late 2018, the influential FDA (Food and Drug Administration) called psilocybin a "breakthrough therapy" for the treatment of therapeutically resistant depression. Well, let's see what research this organization's opinion is based on. In Robin Carhart-Harris's pioneering study, 12 patients who could not be treated with conventional antidepressants were given two doses of psilocybin (10 and 25 mg) one week apart. Symptoms of depression in patients decreased significantly after one week and remained at the same level even after 3 months. The same researchers increased the sample to 20 patients and looked at what would happen six months after taking psilocybin. Again, there was a steady improvement. When psilocybin administration was accompanied by psychotherapy, patients became more open (in psychological terms, extraversion increased), their anhedonia (unwillingness and inability to enjoy) disappeared, which coincided with better facial recognition of emotions. In a similar study, patients were even evaluated for their sense of oneness with nature and political views (liberal/authoritarian). In addition to improving depressive symptoms, those who took psilocybin had a stronger love of nature and a more liberal political outlook.

By the way, the era of modern clinical trials of psychedelics also began with psilocybin. In 2006, Francisco Moreno published the results of a study in which nine patients with obsessive-compulsive disorder were given psilocybin in different doses (25, 100, 200 and 300 µg/kg). In total, each patient received 29 doses, one week apart. Regardless of the dosage, there was a marked improvement in the symptoms of the disease.

Psilocybin has also been used in several placebo-controlled studies. Their purpose was to evaluate the qualities of this psychedelic in reducing signs of anxiety and depression in terminally ill cancer patients. One study used niacin - nicotinic acid - as a placebo, which at a high dose (250 mg) caused some physiological effects similar to those of psychedelics, while psilocybin was given at a low dose (0.2 mg/kg). The treatment was accompanied by psychological support for the patients (and there were 12 in all), and was blinding.

For ethical reasons, the patients were the control for themselves (the pre-treatment condition was considered as a reference point). No statistically significant improvement was found in this study. On the other hand, another placebo-controlled study involving 51 patients with severe cancer showed a significant improvement five weeks after taking psilocybin. A low dose of psilocybin (1 or 3 mg) was used as a placebo and compared to a high dose (22 or 30 mg). Interestingly, after five weeks, the patients were switched from a low dose to a high dose, and vice versa (in clinical trials, this is called a crossover design). The positive effect of the high dose did not disappear. The effect of the low dose was much weaker and did not last long, even if the subjects were switched to the high dose.

About the mechanism of psychedelics
Let us consider the established viewpoint on the mechanisms of action of psychedelics. We already know that true psychedelics bind to 5-HT2A receptors. They act as complete or partial agonists. This means that the compound mimics the receptor's "native" ligand (in our case, serotonin) in its structure and effects. But let's be honest: psychedelics also have an affinity to other serotonin receptors. The only difference is the degree of affinity - higher for some receptors and lower for others.

However, 5-HT2A receptors were not randomly chosen as the main "targets". The activation of these receptors in the cerebral cortex and subcortical structures is believed to be a mechanism common to animals and humans through which psychedelics alter behavior and psychology. In rodents, which are most commonly used in various pharmacological experiments, the analogue of the psychedelic effect in humans is head twitch response. From the observer's point of view, a few minutes after a psychedelic injection, the mouse begins to make sharp head twitches as if it is being overpowered by an annoying insect. The point of view of the mouse is unknown to us. It is unclear whether the mouse sees any hallucinations as we humans understand them, but various studies suggest that animals have impaired visual perception, which is necessary for spatial learning. The fact that it is the 5-HT2A receptors that are involved in the effects of psychedelics became known due to their blockade by the selective antagonist ketanserin, after which any psychedelic could no longer cause head shaking.

I think you won't be surprised to learn that in humans, too, ketanserin almost completely eliminates any subjective effects of psychedelics, such as LSD. Using positron emission tomography, researchers from Copenhagen were able to show that the binding of 5-HT2A receptors to the ligand in the subjects' prefrontal cortex correlated positively with the dose and effect of psilocybin. They also showed that taking as little as 3 mg of psilocybin, 43% of the receptors bind in the cortex.

Where does all the variety of effects come from? - Let's look into it. 5-HT2A receptors are interesting because they are widespread in the brain. One of the most "saturated" areas of the brain with these receptors is the cortex (especially the prefrontal part), or, more precisely, the fifth layer of the cortex filled with pyramidal neurons (they have excitatory activity). Nerve pathways (afferents) from the thalamus to the cortex also have 5-HT2A receptors at their ends. The thalamus receives a great deal of sensory and cognitive information from the environment and sends it to the cortex. The pyramidal neurons in this case play the role of a liaison that connects information flows from the underlying neuronal loops from the thalamus to the overlying loops in the cortex. Inhibitory (GABA) neurons in the cortex and subcortical structures are also richly "spaced" by 5-HT2A receptors.

There is a widespread view that the introduction of psychedelics disrupts the corticothalamic communication. The thalamus, where filtration of sensory information is disturbed, "overloads" this information to the cortex, where redistribution of neuronal activity is also disturbed. This leads to changes in perception, sense of split "I", hallucinations. Curiously enough, similar perturbations in the cortico-thalamic connection can also be found in schizophrenic patients. There is also a different view of what happens to neural connections under the influence of psychedelics. This view is related to the notion of brain entropy - that is, the number of neuronal states that the brain is capable of achieving. Taking psychedelics increases entropy. This is expressed as a significant decrease in alpha oscillations on magneto- and electroencephalography in patients. This should lead to weakening of predictive functions of the cortex, which leads to a decrease of "top-down" information flow and an increase of "bottom-up" flow. Because of this, in particular, under the influence of psychedelics the reaction to unexpected stimuli slows down. According to this hypothesis, psychedelics do not disrupt cortico-thalamic connections, but modify them. However, some studies support entropic effects, while others do not. The question obviously requires further investigation.

Taking psychedelics is accompanied by a number of psychological changes that can be regarded as positive, especially in the context of depression or anxiety. In many studies on healthy volunteers and in clinical trials, emotional excitement, heightened sensitivity, and liberation are noted, while sensitivity to negative emotional stimuli is reduced. In healthy subjects, LSD and psilocybin improve the recognition of positive emotions on faces, and conversely, make it difficult to recognize negative ones. Normally, this complex fixes information about negative experiences and is always ready to reproduce it if necessary. It is essentially a defense mechanism that is now known to get out of control in depression and post-traumatic stress disorder. Then the negative memories are replayed over and over again, like a broken record, and the perception and processing of negative emotions is intensified.

It turned out that after taking psychedelics the connection between the amygdala complex and the cortex is weakened. Hence the shift towards positive emotions. Moreover, in depressed patients such changes persist significantly longer than in healthy volunteers. Feelings such as the splitting of the self, the removal of self-limitations, and the emergence of a sense of unity with everything and everyone, often observed when taking psychedelics, are already more difficult to describe in terms of any single neural pathway. A variety of studies have shown that in the brain there are large-scale changes in a variety of neural networks within the cortex and between the cortex and the limbic structures. In other words, connectivity is enhanced. Changes in self-perception entail changes in communication with other people. A frequent effect of taking psychedelics is an increase in empathy and social interaction, both with the therapist and with other people; altruistic behavior is strengthened.

Why did the term "winner's curse" appear?
Many promising drugs that showed fantastic results in preclinical and pilot clinical trials eventually failed in large-scale trials. This is what has become known as the "winner's curse.

In fact, trials of psychedelics have moved only one step forward from those old, unreliable studies of half a century ago. There are good reasons for this (small samples don't count). So, serious reason #1 is the lack of an adequate placebo. The peculiarity of psychedelics, as we already know, is their specific effects, which are difficult to disguise with anything. Of course, attempts are being made. As we have seen, they use niacin, or simply tinted water (in the case of Ayahuasca), Benadryl. In studies where a "crossover" was used, the blinding effect disappeared in a flash when patients were switched from placebo to psychedelics, and vice versa - so noticeable was the difference from taking the two substances. Particularly unfortunate here is the use of low doses as placebos. For the patient, the low dose may not be subjectively noticeable, but it will have a positive effect on the symptoms of depression, albeit a shorter-term one. This can by no means be called a placebo!

Reason #2 - is the lack of a clear idea of the optimal dosage of drugs. How many psychedelics do we need in order to have the maximum effect on the condition of patients, but to avoid adverse reactions? Analyzing data from clinical trials, the impression is that psychedelics are effective in any dose. The minimum dose of psilocybin that will have no effect at all has been found to be 0.028 mg/kg. Since small doses of psychedelics, chosen as placebos, have proven unexpectedly good in several trials, there was immediate interest in using just small doses - microdosing. However, analysis of the same clinical trials shows that the higher the dose, the better the effect. Some have even noted that the mystical experience experienced by patients is positively correlated with a reduction in anxiety and depressive symptoms. That is, twenty milligrams of psilocybin is better than one milligram. But one milligram does not cause hallucinations, and the duration of the effects can be increased by repeated ingestions. Only a comparative study can solve this dilemma. But to do this, there must also be a placebo control for a high dose of psychedelic, and we return to reason #1. In clinical trials of most drugs, by the second phase of the trial an idea of the required dosages is usually already formed. This is not the case with psychedelics.


Serious reason #3 - is the selection of subjects. Very often test participants have a history of psychedelic use. Since recruitment often takes place through Internet sites where psychonaut communities discuss personal experiences with recreational drugs, it is suspected that some volunteers readily agree to trials in order to legally obtain a new dose of unforgettable sensations. For example, in the previously mentioned double-blind psilocybin trial on patients with terminal cancer, 55% of the subjects had prior experience with psychedelic substances. In the pioneering Carhartt-Harris trials on patients with therapeutically resistant depression, five out of twenty subjects found and used psilocybin during the observation period and evaluation of the duration of effects after taking their last dose (the study design was indeed open-label and controlled. The problem is not only that the subjects with experience of using psychedelics know very well what to expect from them (psychedelics), so they "spoil" the objectivity of the study with their expectations. Those who have had negative experiences with use will simply avoid such trials. In addition, the samples are very homogeneous. As a rule, they are educated middle-aged Europeans. Many of them have positive experiences with psychedelic substances. And many feel good after a short course of psilocybin, ayahuasca or LSD.

Reason #4 - which also merits discussion, is the presence of psychotherapy in the design of all trials. This component in itself can contribute very much to the results and confuse researchers. In a recent meta-analysis of six randomized trials, cognitive behavioral psychotherapy, widely used in the treatment of depression, was shown to be effective in reducing symptom severity and achieving remission. The effect of psychotherapy lasts for at least six months. Interestingly, the effects of psychedelics are often observed within a similar time interval. It is worth saying that taking psychedelics is highly context dependent and requires many conditions to be met. It is well known that a patient can easily get a bad trip from a psychedelic if he is in a bad emotional mood and in an anxious environment.

You will say, why did you have to build the "building" of psychedelic therapy so diligently for two chapters, only to take a sledgehammer and blow it to pieces in the end?

The answer is that I didn't tear anything down, I only pointed out that the foundation of the "building" has cracks and defects.

I share the optimism about psychedelics and have had several experiences with LSD and psilocybin myself. Yes, psychedelic substances do have some potential, but the existing data is clearly insufficient for psychedelics to be decriminalized and widely accepted in medical practice. Many proponents of psychedelic therapy see legislative restrictions as a major brake on progress. But even with all the restrictions, research on psychedelics was and is still being conducted. Interested researchers should make every effort to make the results more reliable. Not emotion or inflated expectations of a "magic bullet," but only painstaking scientific work will answer the question: "Are psychedelics super effective antidepressants and is it possible to legalize psychedelics around the world without the accompanying danger to people?".


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Expert Pharmacologist
Jul 6, 2021
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thx, bro!
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