Hallucinogens

This seminal review paper (2004) reviews the psychedelics literature up to this point. It specifically looks at how psychedelics influence the brain. The main conclusion is that psychedelics increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the psychedelic experience. The paper foreshadows the research on the practical uses of psychedelics for (mental) illnesses.

Abstract of Hallucinogens

“Hallucinogens (psychedelics) are psychoactive substances that powerfully alter perception, mood, and a host of cognitive processes. They are considered physiologically safe and do not produce dependence or addiction. Their origin predates written history, and they were employed by early cultures in a variety of sociocultural and ritual contexts. In the 1950s, after the virtually contemporaneous discovery of both serotonin (5-HT) and lysergic acid diethylamide (LSD-25), early brain research focused intensely on the possibility that LSD or other hallucinogens had a serotonergic basis of action and reinforced the idea that 5-HT was an important neurotransmitter in brain. These ideas were eventually proven, and today it is believed that hallucinogens stimulate 5-HT2A receptors, especially those expressed on neocortical pyramidal cells. Activation of 5-HT2A receptors also leads to increased cortical glutamate levels presumably by a presynaptic receptor-mediated release from thalamic afferents. These findings have led to comparisons of the effects of classical hallucinogens with certain aspects of acute psychosis and to a focus on thalamocortical interactions as key to understanding both the action of these substances and the neuroanatomical sites involved in altered states of consciousness (ASC). In vivo brain imaging in humans using [18F]fluorodeoxyglucose has shown that hallucinogens increase prefrontal cortical metabolism, and correlations have been developed between activity in specific brain areas and psychological elements of the ASC produced by hallucinogens. The 5-HT2A receptor clearly plays an essential role in cognitive processing, including working memory, and ligands for this receptor may be extremely useful tools for future cognitive neuroscience research. In addition, it appears entirely possible that utility may still emerge for the use of hallucinogens in treating alcoholism, substance abuse, and certain psychiatric disorders.”

Author: David E. Nichols

Notes on Hallucinogers

“Hallucinogens, for the purposes of this review, will mean only substances with psychopharmacology resembling that of the natural products mescaline and psilocybin and the semisynthetic substance known as lysergic acid diethylamide (LSD-25). More specifically, now that there is appreciation of their probable molecular mechanism of action, we shall review those substances that principally exert their central nervous system (CNS) effects by an agonist (or partial agonist) action at serotonin (5-HT)2A receptors.”

The author also prefers the term hallucinogens over psychedelics, later literature does use psychedelics more (as does this website).

In describing the history of psychedelics, the paper mentions their link to religions and the use of psychedelics from before recorded history. For further history of mescaline/peyote, see the book Mescaline.

Psychedelics have various effects on our perception of the world. The paper cites Jaffe (1990): “…the feature that distinguishes the psychedelic agents from other classes of drugs is their capacity reliably to induce states of altered perception, thought, and feeling that are not experienced otherwise except in dreams or at times of religious exaltation.” And at lower doses describes it as reliably doing the following:

1. Somatic symptoms: dizziness, weakness, tremors, nausea, drowsiness, paresthesias, and blurred vision
2. Perceptual symptoms: altered shapes and colors, difficulty in focusing on objects, sharpened sense of hearing, and rarely synesthesias
3. Psychic symptoms: alterations in mood (happy, sad, or irritable at varying times), tension, distorted time sense, difficulty in expressing thoughts, depersonalization, dreamlike feelings, and visual hallucinations

Psychedelics are not toxic to your body: “Hallucinogens are generally considered to be physiologically safe molecules whose principal effects are on consciousness. That is, hallucinogens are powerful in producing altered states of consciousness (ASC), but they do so at doses that are not toxic to mammalian organ systems.”

They are also not addictive: “In contrast to many other abused drugs, hallucinogens do not engender drug dependence or addiction and are not considered to be reinforcing substances.” Chemically this means they don’t influence our dopamine (reward) system.

There are dangers to using psychedelics. People have done stupid things while under the influence (e.g. driving). The concept of flashbacks is defined too broad/inconsistent, but the author concludes that the incidence is probably very low.

“Hallucinogens can catalyze the onset of psychosis or depression, which has sometimes led to suicide, and Cohen (1960) has estimated the incidence of LSD-related psychosis to be about 8 per 10,000 subjects. In another study, one case of psychosis was reported in a survey of 247 LSD users (McGlothlin & Arnold, 1971). Fortunately, however, these drugs do not appear to produce illness de novo in otherwise emotionally healthy persons, but these problems seem to be precipitated in predisposed individuals.” and “A search of Medline in early 2003 for case reports of LSD-induced psychosis found only three reports in the previous 20 years.”

Nichols then goes on to discuss the chemical structure of psychedelics. He makes the following distinction:

1. Tryptamines
   1. simple tryptamines (e.g. DMT, 5-MeO-DMT, psilocybin/psilocin)
   2. ergolines (e.g. LSD)
2. Phenethylamines (e.g. mescaline)

See TiHKaL and PiHKaL for much more on these.

The set and setting are important determinants of the psychedelic experience (unlike/more-so than with other drugs). The dose of a psychedelic has some effects that become enlarged with a higher dose, others that are only present in higher doses (i.e. peak/mystical experiences).

Most people don’t use psychedelics often and for a prolonged period: “Because hallucinogens do not produce the type of reinforcing effects that occur after use of substances such as cocaine or amphetamine, an interesting question that can be asked is: What is the motivation for continued use of hallucinogens, once an ‘‘experimentation’’ phase has ended? It must be kept in mind that hallucinogen use is generally not compulsive and long-lasting and that these substances do not produce dependence. Their use is more often episodic, and most people do not continue to use hallucinogens on a long-term basis after some initial experimentation. Surveys have shown that hallucinogen use is most likely to occur in the late teens and into the early 20s but does not usually continue after users reach their late 20s.” Those who do continue do this for “… personal or spiritual development and increased understanding and self-discovery, that their use seems important to them, and that often they feel they gain important personal, religious, or philosophical insights.”

Psychedelics work by increasing brain 5-HT levels and/or decreasing the turnover of 5-HT (specifically 5-HT_2a but 5-HT_2c is also possibly involved). There is also rapid tolerance for psychedelics (i.e. take a high dose for several days and you won’t feel the effects anymore), this is caused by a down-regulation of the 5-HT_2a receptor. The paper does discuss in detail the way that LSD doesn’t seem to have much affinity for the receptor and so proposes that there may be other ways it works.

The paper discusses the validity of animal models and the influence psychedelics have on the brain’s metabolism. “Increased release of glutamate in response to hallucinogen administration would be expected to enhance cortical metabolic activity.” It is now known that this is true for most regions of the brain, although there is less activity in the default mode network (DMN). Psychedelics may also influence gene expression during the experience (arc/c-fos/Nor1).

Psychedelics were not actively studied after the 1960s and have only found a place in research again around the year 2000. One thing that makes the studies from that time not that usable is the lack of adequate controls and other treatment methods that are standard today. Much of the research that had been done focussed on the comparison between LSD and psychosis.

Nichols identifies two broad areas in which psychedelics are being/can be used:

1. Treating certain psychiatric disorders (e.g. terminal illness and existential dread, alcoholism/substance abuse, OCD)
2. Research tools for cognitive neuroscience (studies with DMT started again in 1994)

“Scientists can no longer see them as ‘‘magic’’ drugs but rather as 5-HT2A receptor-specific molecules that affect membrane potentials, neuronal firing frequencies, and neurotransmitter release in particular areas of the brain. One can now begin to speculate in reasonable ways about how these cellular changes transform our perceptions of reality and produce ASC [altered states of consciousness].”

In conclusion, the author makes another link to consciousness research (since psychedelics influence the areas of the brain that are specifically interesting to that research). And rightly foreshadows the resurgence of research happening now: “It is quite unfortunate that legal restrictions have kept these extremely interesting substances from receiving more extensive clinical study, but there are hopeful recent signs that this situation may be changing.”

Summary of Hallucinogens

Hallucinogens are a catchall category of pharmacological substances that alter consciousness, often in dramatic and unpredictable ways, and may produce delirium, true hallucinations, loss of contact with reality, and sometimes death.

Ecstasy, a popular recreational drug, has subjective effects that are to a certain degree similar to hallucinogens. MDMA has unique psychopharmacology, however, and does not properly fit within the hallucinogen classification.

Hallucinogens are substances with psychopharmacology resembling that of mescaline, psilocybin, and lysergic acid diethylamide. They exert their effects by an agonist action at serotonin 5HT2A receptors.

Many different names have been proposed over the years for this drug class, including hallucinogen, psychotomimetic, and psychedelic. The term entheogen, derived from the Greek word entheos, has seen increasing use in popular media and on internet sites.

There is only a meagre amount of factual information about hallucinogenic drugs among the general public today, and the scientific and medical communities know almost nothing about them. They remain pharmacological curiosities with no demonstrated therapeutic utility.

Despite their physiological safety and lack of dependence liability, hallucinogens have been branded by law enforcement officials as among the most dangerous drugs that exist, being placed into Schedule I of the Controlled Substances Act. This has led to a resurgence of research interest in these substances.

What is it about psychedelics that makes them so fearsome? The answer lies beyond hard science and within a complex sociological and political agenda.