Hallucinogen

Albert Hofmann

Hallucinogens [huh-loo-suh-nuh-juhns] are drugs which can cause hallucinations (seeing, hearing, or otherwise perceiving things that are not real). They are a general group of pharmacological agents that can be divided into three broad categories: psychedelics (drugs with perception-altering effects), dissociatives (drugs that produce feelings of detachment – dissociation – from the environment and self), and deliriants (drugs that induce a state of delirium in the user).

These classes of psychoactive drugs have in common that they can cause subjective changes in perception, thought, emotion and consciousness. Unlike other psychoactive drugs, such as stimulants and opioids, these drugs do not merely amplify familiar states of mind, but rather induce experiences that are qualitatively different from those of ordinary consciousness. These experiences are often compared to non-ordinary forms of consciousness such as trance, meditation, dreams, or insanity.

Hallucinogens have several common characteristics, for example, in proportion to other effects, changes in thought, perception, and mood should predominate; intellectual or memory impairment should be minimal; stupor, narcosis, or excessive stimulation should not be an integral effect; autonomic (involuntary) nervous system side effects should be minimal; and addictive craving should be absent. Not all drugs produce the same effect and even the same drug can produce different effects in the same individual on different occasions. The term ‘hallucinogen’ is a misnomer because these drugs do not cause hallucinations at typical doses. Hallucinations, strictly speaking, are perceptions that have no basis in reality, but that appear entirely realistic. A typical ‘hallucination’ induced by a psychedelic drug is more accurately described as a modification of regular perception, and the subject is usually quite aware of the illusory and personal nature of their perceptions. Deliriants, such as diphenhydramine and atropine, may cause hallucinations in the proper sense.

Psychedelics, dissociatives, and deliriants have a long history of use within medicinal and religious traditions around the world. They are used in shamanic forms of ritual healing and divination, in initiation rites, and in the religious rituals of syncretistic movements such as the Native American Church. When used in religious practice, psychedelic drugs, as well as other substances like tobacco, are referred to as ‘entheogens.’ Also, in some states and on some reservations, certain drugs like peyote are classified as part of a recognized religious ceremony, and if used in said ceremonies, are considered legal. Starting in the mid-20th century, psychedelic drugs have been the object of extensive attention in the Western world. They have been and are being explored as potential therapeutic agents in treating depression, posttraumatic stress disorder, obsessive–compulsive disorder, alcoholism, opiate addiction, cluster headaches, and other ailments. Early military research focused on their use as incapacitating agents. Intelligence agencies tested these drugs in the hope that they would provide an effective means of interrogation, with little success.

Yet the most popular, and at the same time most stigmatized, use of psychedelics in Western culture has been associated with the search for direct religious experience, enhanced creativity, personal development, and ‘mind expansion.’ The use of psychedelic drugs was a major element of the 1960s counterculture, where it became associated with various social movements and a general atmosphere of rebellion and strife between generations. Despite prohibition, the recreational, spiritual, and medical use of psychedelics continues today. Organizations, such as MAPS (Multidisciplinary Association for Psychedelic Studies) and the Heffter Research Institute, have arisen to foster research into their safety and efficacy, while advocacy groups such as the Center for Cognitive Liberty and Ethics push for their legalization. In addition to this activity by proponents, hallucinogens are also widely used in basic science research to understand the mind and brain. However, ever since hallucinogenic experimentation was discontinued in the late 1960s, research into the therapeutic applications of such drugs have been almost nonexistent, that is until this last decade where research has finally been allowed to resume. In some cases, this includes research in humans, like that conducted by Roland Griffiths and colleagues.

The word ‘psychedelic’ (‘mind/soul; manifest/reveal’) was coined to express the idea of a drug that makes manifest a hidden but real aspect of the mind. It is commonly applied to any drug with perception-altering effects. The term ‘psychedelic’ is used interchangeably with ‘psychotomimetic’ and ‘hallucinogen,’ thus it can refer to a large number of drugs such as classical hallucinogens (LSD, psilocybin, mescaline, etc.), empathogen-entactogens (e.g. MDMA), cannabinoids, and some dissociative drugs (e.g. Salvia divinorum and ketamine). The classical hallucinogens are considered to be the representative psychedelics and LSD is generally considered the prototypical psychedelic. In order to refer to the LSD-like psychedelics, scientific authors have used the term ‘classical hallucinogen’ to refer to serotonergic hallucinogens.

Common herbal and fungal sources of psychedelics include psilocybin mushrooms, various ingredients of ayahuasca preparations (a South American entheogen), and peyote. One explanatory model for the experiences provoked by hallucinogens is the ‘reducing valve’ concept, first articulated in Aldous Huxley’s book ‘The Doors of Perception.’ In this view, the drugs disable the brain’s ‘filtering’ ability to selectively prevent certain perceptions, emotions, memories and thoughts from ever reaching the conscious mind. This effect has been described as mind expanding, or consciousness expanding, for the drug ‘expands’ the realm of experience available to conscious awareness.

Psychedelic effects can vary depending on the precise drug and dosage, as well as the set and setting. ‘Trips’ range between the short but intense effects of intravenous DMT to the protracted ibogaine experience, which can last for days. Appropriate dosage ranges from extremely low (LSD) to rather high (mescaline). Some drugs, like the auditory hallucinogen DiPT, act specifically to distort a single sense, and others have more diffuse effects on cognition generally. Some are more conducive to solitary experiences (entactogenic) while others are conducive to social, bonding experiences (empathogenic). Though the natural drugs have a long history of use and usually have an extensive study profile aside from the mortality rates of the drugs, in recent times there has been large production of hundreds of virtually unstudied psychedelics (many created by Alexander Shulgin and documented in his books ‘PiHKAL’ and ‘TiHKAL’) that may be potentially harmful. This is especially the case with the designer drugs in the psychedelic-amphetamine class. Because of this factor, one should not make the generalization that all psychedelics cannot be potentially harmful at normal doses.

Dissociatives produce analgesia, amnesia and catalepsy at anesthetic doses. They also produce a sense of detachment from the surrounding environment. Dissociative symptoms include the disruption or compartmentalization of ‘…the usually integrated functions of consciousness, memory, identity or perception.’ Dissociation of sensory input can cause derealization, the perception of the outside world as being dream-like or unreal. Other dissociative experiences include depersonalization, which includes feeling detached from one’s body; feeling unreal; feeling able to observe one’s actions but not actively take control; being unable to recognize one’s self in the mirror while maintaining rational awareness that the image in the mirror is the same person. Simeon (2004) offered ‘…common descriptions of depersonalisation experiences: watching oneself from a distance (similar to watching a movie); candid out-of-body experiences; a sense of just going through the motions; one part of the self acting/participating while the other part is observing;….’ The primary dissociatives achieve their effect through blocking the signals received by the NMDA receptor set and include ketamine, phencyclidine (PCP), dextromethorphan (DXM, cough syrup), and nitrous oxide. However, dissociation is also remarkably administered by Salvia divinorum and is notably the most potent psychoactive chemical harnessed directly from the plant kingdom.

Some dissociatives can have CNS (central nervous system) depressant effects, thereby carrying similar risks as opioids, which can slow breathing or heart rate to levels resulting in death (when using very high doses). DXM in higher doses can increase heart rate and blood pressure and still depress respiration. Inversely, PCP can have more unpredictable effects and has often been classified as a stimulant and a depressant in some texts along with being as a dissociative. While many have reported that they ‘feel no pain’ while under the effects of PCP, DXM and Ketamine, this does not fall under the usual classification of anesthetics in recreational doses (anesthetic doses of DXM may be dangerous). Rather, true to their name, they process pain as a kind of ‘far away’ sensation; pain, although present, becomes a disembodied experience and there is much less emotion associated with it. As for probably the most common dissociative, nitrous oxide, the principal risk seems to be due to oxygen deprivation. Injury from falling is also a danger, as nitrous oxide may cause sudden loss of consciousness, an effect of oxygen deprivation. Because of the high level of physical activity and relative imperviousness to pain induced by PCP, some deaths have been reported due to the release of myoglobin from ruptured muscle cells. High amounts of myoglobin can induce renal shutdown. None of the dissociatives have any physically addictive properties, though psychological addiction has been observed.

Many users of dissociatives have been concerned about the possibility of NMDA antagonist neurotoxicity (NAN). This concern is partly due to William E. White, the author of the DXM FAQ, who claimed that dissociatives definitely cause brain damage. The argument was criticized on the basis of lack of evidence and White retracted his claim. White’s claims and the ensuing criticism surrounded original research by John Olney. In 1989, Olney discovered lesions occurred in brains of rats administered NMDA antagonists, including PCP and ketamine. Repeated doses of NMDA antagonists led to cellular tolerance and hence continuous exposure to NMDA antagonists did not lead to cumulative neurotoxic effects. Antihistamines such as diphenhydramine, barbiturates and even diazepam have been found to prevent NAN. LSD and DOB have also been found to prevent NAN.

Deliriants, as their name implies, induce a state of delirium in the user, characterized by extreme confusion and an inability to control one’s actions. They are called deliriants because their subjective effects are similar to the experiences of people with delirious fevers. Included in this group are such plants as belladonna (deadly nightshade), Angel’s Trumpet, Datura (Jimson weed), henbane, mandrake, and nutmeg, as well as a number of pharmaceutical drugs, when taken in very high doses, such as diphenhydramine (Benadryl) and its close relative dimenhydrinate (Dramamine). Uncured tobacco is also a deliriant due to its intoxicatingly high levels of nicotine. In addition to the dangers of being far more disconnected from reality than with other drugs and retaining a truly fragmented dissociation from regular consciousness without being immobilized, the anticholinergics (substance that blocks the neurotransmitter acetylcholine) are toxic, carry the risk of death by overdose, and also include a number of uncomfortable side effects.

Most modern-day psychonauts who use deliriants report similar or identical hallucinations and challenges. For example, diphenhydramine, as well as dimenhydrinate, when taken in a high enough dosage, often are reported to evoke vivid, dark, and entity-like hallucinations, peripheral disturbances, feelings of being alone but simultaneously of being watched, and hallucinations of real things ceasing to exist. Deliriants also may cause confusion or even rage, and thus have been used by ancient peoples as a stimulant before going into battle.

Hallucinogenic substances are among the oldest drugs used by human kind, as hallucinogenic substances naturally occur in mushrooms, cacti and a variety of other plants. Numerous cultures worldwide have endorsed the use of hallucinogens in medicine, religion and recreation, to varying extents, while some cultures have regulated or outright prohibited their use. In most developed countries today, the possession of many hallucinogens, even those found commonly in nature, is considered a crime punishable by fines, imprisonment or even death. In some countries, such as the United States and the Netherlands, partial deference may be granted to traditional religious use by members of indigenous ethnic minorities such as the Native American Church and the Santo Daime Church. Recently the União do Vegetal, a Christian-based religious sect whose composition is not primarily ethnicity-based, won a United States Supreme Court decision authorizing its use of ayahuasca. However, in Brazil, ayahuasca use in a religious context has been legal since 1987. In fact, it is a common belief among members of the União do Vegetal that ayahuasca presents no risk for adolescents within the church, as long as they take it within a religious context.

Historically, hallucinogens have been most commonly used in religious or shamanic rituals. In this context they are referred to as entheogens, and they are used to facilitate healing, divination, communication with spirits, and coming-of-age ceremonies. Evidence exists for the use of entheogens in prehistoric times, as well as in numerous ancient cultures, including the Rus’, Ancient Egyptian, Mycenaean, Ancient Greek, Vedic, Maya, Inca and Aztec cultures. The Upper Amazon is home to the strongest extant entheogenic tradition; the Urarina people of Peruvian Amazonia, for instance, continue to practice an elaborate system of Ayahuasca shamanism, coupled with an animistic belief system (belief of ‘spiritual beings’). Shamans consume hallucinogenic substances in order to induce a trance. Once in this trance, they are able to communicate with the spirit world, and can often see what is causing their patients illness. The Aguaruna of Peru believe that many illnesses are caused by the darts of sorcerers. Under the influence of yaji, a hallucinogenic drink, Aguaruna shamans are able to discover and remove darts from their patients.

Although natural hallucinogenic drugs have been known to mankind for millennia, it was not until the early 20th century that they received extensive attention from Western science. Earlier beginnings include scientific studies of nitrous oxide in the late 18th century, and initial studies of the constituents of the peyote cactus in the late 19th century. Starting in 1927 with Kurt Beringer’s ‘Der Meskalinrausch’ (‘The Mescaline Intoxication’), more intensive effort began to be focused on studies of psychoactive plants. Around the same time, Louis Lewin published his extensive survey of psychoactive plants, ‘Phantastica’ (1928). Important developments in the years that followed included the re-discovery of Mexican psilocybin mushrooms (in 1936 by Robert J. Weitlaner) and Christmas vine (in 1939 by Richard Evans Schultes). Arguably the most important pre-World War II development was by Albert Hofmann’s 1938 discovery of the semi-synthetic drug LSD, which was later discovered to produce hallucinogenic effects in 1943.

After World War II there was an explosion of interest in hallucinogenic drugs in psychiatry, owing mainly to the invention of LSD. Interest in the drugs tended to focus on either the potential for psychotherapeutic applications of the drugs, or on the use of hallucinogens to produce a ‘controlled psychosis,’ in order to understand psychotic disorders such as schizophrenia. By 1951, more than 100 articles on LSD had appeared in medical journals, and by 1961, the number had increased tenfold. Hallucinogens were also researched in several countries for their potential as agents of chemical warfare. Most famously, several incidents associated with the CIA’s MK-ULTRA mind control research project have been the topic of media attention and lawsuits.

At the beginning of the 1950s, the existence of hallucinogenic drugs was virtually unknown among the general public of the West. However this soon changed as several influential figures were introduced to the hallucinogenic experience. Aldous Huxley’s 1953 essay ‘The Doors of Perception,’ describing his experiences with mescaline, and R. Gordon Wasson’s 1957 ‘Life’ magazine article (‘Seeking the Magic Mushroom’) brought the topic into the public limelight. In the early 1960s, counterculture icons such as Jerry Garcia, Timothy Leary, Allen Ginsberg, and Ken Kesey advocated the drugs for their psychedelic effects, and a large subculture of psychedelic drug users was spawned. Psychedelic drugs played a major role in catalyzing the vast social changes initiated in the 1960s. As a result of the growing popularity of LSD and disdain for the hippies with whom it was heavily associated, LSD was banned in the United States in 1967. This greatly reduced the clinical research about LSD, although limited experiments continued to take place, such as those conducted by Reese Jones in San Francisco.

As early as the 1960s, research into the medicinal properties of LSD was being conducted. It has been found that LSD is a fairly effective treatment for mental disorders such as obsessive compulsive disorder (OCD). ‘Savage et al. (1962) provided the earliest report of efficacy for a hallucinogen in OCD, where after two doses of LSD, a patient who suffered from depression and violent obsessive sexual thoughts experienced dramatic and permanent improvement.” LSD, along with other hallucinogens, possesses a considerable amount of medicinal properties, which is why further research on the medical uses of hallucinogens is paramount.

As of 2008, most well known hallucinogens (aside from dextromethorphan, diphenhydramine and dimenhydrinate) are illegal in most Western countries. In the United States hallucinogens are classified as a schedule 1 drug. The 3-pronged test for schedule 1 drugs is as follows. The drug has no currently accepted medical use, there is a lack of safety for the use of the drug under medical supervision, and the substance has a high potential for abuse. One notable exception to the current criminalization trend is in parts of Western Europe, especially in the Netherlands, where cannabis is considered to be a ‘soft drug.’ Previously included were hallucinogenic mushrooms, but as of 2007 the Netherlands officials have moved to ban their sale following several widely publicized incidents involving tourists. While the possession of soft drugs is technically illegal, the Dutch government has decided that using law enforcement to combat their use is largely a waste of resources. As a result, public ‘coffeeshops’ in the Netherlands openly sell cannabis for personal use, and ‘smart shops’ sell drugs like Ayahuasca and Salvia divinorum.

Attitudes towards hallucinogens other than cannabis have been slower to change. Several attempts to change the law on the grounds of freedom of religion have been made. However, some people argue that a religious setting should not be necessary for the legitimacy of hallucinogenic drug use, and for this reason also criticize the euphemistic use of the term ‘entheogen.’ Non-religious use of hallucinogens (for spiritual, introspective, psychotherapeutic, recreational and even hedonistic motives) is often subject to social disapproval, but has also been defended as the legitimate exercise of civil liberties, including freedom of thought and freedom of self-harm. Some people connect the idea of being ‘high’ or going through a psychedelic state, as having brain damage or going crazy. This is due to the effect of the drug which, in some cases, can be overwhelming. Effects of these drugs may mimic psychological conditions such as psychosis, schizophrenia, and thought disorder, but there have not yet been studies confirming any real similarities between these different states of mind. Several medical and scientific experts, including the late Albert Hofmann, advocate against banning these drugs, and for strong regulation instead and warn they can be dangerous without proper psychological supervision.

Most psychedelics are not known to have long-term physical toxicity. However, entactogens such as MDMA that release neurotransmitters may stimulate increased formation of free radicals. Free radicals are associated with cell damage in other contexts, and have been suggested to be involved in many types of mental conditions including Parkinson’s disease, senility, schizophrenia, and Alzheimer’s. Research on this question has not reached a firm conclusion. The same concerns do not apply to psychedelics that do not release neurotransmitters, such as LSD, nor to dissociatives or deliriants. No clear connection has been made between psychedelic drugs and organic brain damage. However, hallucinogen persisting perception disorder (HPPD) is a diagnosed condition wherein certain visual effects of drugs persist for a long time, sometimes permanently, although science and medicine have yet to determine what causes the condition.

Louis Lewin started out in 1928 by using the word ‘phantastica’ as the title of his ground-breaking monograph about plants that, in his words, ‘bring about evident cerebral excitation in the form of hallucinations, illusions and visions […] followed by unconsciousness or other symptoms of altered cerebral functioning.’ But no sooner had the term been invented, or Lewin complained that the word ‘does not cover all that I should wish it to convey,’ and indeed with the proliferation of research following the discovery of LSD came numerous attempts to improve on it, such as ‘hallucinogen,’ ‘psychedelic, psychotomimetic,’ and ‘entheogenic.’ The word ‘psychotomimetic,’ meaning ‘mimicking psychosis,’ reflects the hypothesis of early researchers that the effects of psychedelic drugs are similar to naturally-occurring symptoms of schizophrenia, though it has since been discovered that some psychedelics resemble endogenous psychoses better than others. PCP and ketamine are known to better resemble endogenous psychoses because they reproduce both positive and negative symptoms of psychoses, while psilocybin and related hallucinogens typically produce effects resembling only the positive symptoms of schizophrenia.

While the serotonergic psychedelics (LSD, psilocybin, mescaline, etc.) do produce subjective effects distinct from NMDA antagonist dissociatives (PCP, ketamine, dextrorphan), there is obvious overlap in the mental processes that these drugs affect and research has discovered that there is overlap in the mechanisms by which both types of psychedelics mimic psychotic symptoms. One double-blind study examining the differences between DMT and ketamine hypothesized that classically psychedelic drugs most resemble paranoid schizophrenia while dissociative drugs best mimicked catatonic subtypes or otherwise undifferentiated schizophrenia. The researchers expressed the view that ‘a heterogeneous disorder like schizophrenia is unlikely to be modeled accurately by a single pharmacological agent.’

Almost all hallucinogens contain nitrogen and are therefore classified as alkaloids. THC and salvinorin A (Salvia) are exceptions. Many hallucinogens have chemical structures similar to those of human neurotransmitters, such as serotonin, and temporarily modify the action of neurotransmitters and/or receptor sites. However, the problem with structure-based frameworks is that the same structural motif can include a wide variety of drugs which have substantially different effects. For example, both methamphetamine and MDMA are substituted amphetamines, but methamphetamine has a much stronger stimulant action than ecstasy, with none of the latter’s empathogenic effects. Also, drugs commonly act on more than one receptor; DXM, for instance, is primarily dissociative in high doses, but also acts as a serotonin reuptake inhibitor, similar to many phenethylamines and in fact, the phenethylamine moiety is embedded in the structure of DXM. LSD also contains both the indole backbone and the phenethylamine moiety. Even so, in many cases structure-based frameworks are still very useful, and the identification of a biologically active pharmacophore (description of molecular features) and synthesis of analogues of known active substances remains an integral part of modern medicinal chemistry.

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