Hallucinogen

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https://en.wikipedia.org/wiki/Hallucinogen

 

A hallucinogen is a psychoactive agent which most likely causes hallucinations, perceptual anomalies, and other substantial subjective changes in thoughts, emotion, and consciousness. The common types of hallucinogens are psychedelics, dissociatives and deliriants. Although hallucinations are a common symptom of amphetamine psychosis, amphetamines are not considered hallucinogens as they are not a primary effect of the drugs themselves. While hallucinations can occur when abusing stimulants, the nature of stimulant psychosis is not unlike delirium. 

Nomenclature

A debate persists on criteria which would easily differentiate a substance which is 'psychedelic' from one 'hallucinogenic'. Sir Thomas Browne in 1646 coined the term 'hallucination' from the Latin word "alucinari" meaning "to wander in the mind".

A 'hallucinogen' and a 'psychedelic' may refer correctly to the same substance. Psychedelics are considered by many to be the 'traditional' or 'classical hallucinogens'. A 'hallucinogen' in this sense broadly refers to any substance which causes changes in perception or hallucinations, while psychedelics also carry a connotation of psychedelic culture. 

Psychedelics (classical hallucinogens)

One "Blotter" sheet of 900 LSD doses.

 

The word psychedelic (From Ancient Greek ψυχή (psychê) mind, soul + δηλος (dêlos) manifest, reveal + -ic) 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 such as LSD and other ergotamine derivatives, DMT and other tryptamines including the alkaloids of Psilocybe spp., mescaline and other phenethylamines.

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" in the sense defined by Glennon (1999): "The classical hallucinogens are agents that meet Hollister's original definition, but are also agents that: (a) bind at 5-HT2 serotonin receptors, and (b) are recognized by animals trained to discriminate 1-(2,5-dimethoxy-4-methylphenyl)-2-aminopropane (DOM) from vehicle. Otherwise, when the term 'psychedelic' is used to refer only to the LSD-like psychedelics (a.k.a. the classical hallucinogens), authors explicitly point that they intend 'psychedelic' to be understood according to this more restrictive interpretation (e.g. see Nichols, 2004).

One explanatory model for the experiences provoked by psychedelics 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. 

While possessing a unique mechanism of action, cannabis or marijuana has historically been regarded alongside the classic psychedelics.

Research chemicals and designer drugs

A designer drug is a structural or functional analog of a controlled substance that has been designed to mimic the pharmacological effects of the original drug while at the same time avoid being classified as illegal (by specification as a research chemical) and/or avoid detection in standard drug tests. Many designer drugs and research chemicals are hallucinogenic in nature, such as those in the 2C and 25-NB (NBOMe) families.

Dissociatives

Salvia divinorum

 

Dissociatives produce analgesia, amnesia and catalepsy at anesthetic doses. They also produce a sense of detachment from the surrounding environment, hence "the state has been designated as dissociative anesthesia since the patient truly seems disassociated from his 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, vague or unreal. Other dissociative experiences include depersonalization, which includes feeling dissociated from one's personality; feeling unreal; feeling able to observe one's actions but not actively take control; being unable to associate with 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 classical dissociatives achieve their effect through blocking the signals received by the NMDA receptor set (NMDA receptor antagonism) and include ketamine, methoxetamine (MXE), phencyclidine (PCP), dextromethorphan (DXM), and nitrous oxide. However, dissociation is also remarkably administered by salvinorin A's (the active constituent in Salvia divinorum shown to the left) potent κ-opioid receptor agonism, though sometimes described as an atypical psychedelic.

Some dissociatives can have CNS 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.

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, John Olney discovered that neuronal vacuolation and other cytotoxic changes ("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

Datura innoxia in flower.

 

Attractive but highly toxic berry of Atropa belladonna

 

Flowers and foliage of Nicotiana tabacum, the cultivated tobacco.

 

Single fruiting body of Amanita muscaria

 

Myristica fragrans fruit, halved, showing within the brown seed (nutmeg) enclosed in its red aril (mace).

 

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. The term was introduced by David F. Duncan and Robert S. Gold to distinguish these drugs from psychedelics and dissociatives, such as LSD and ketamine respectively, due to their primary effect of causing delirium, as opposed to the more lucid states produced by the other hallucinogens.

Despite the fully legal status of several common deliriant plants, deliriants are largely unpopular as recreational drugs due to the severe, generally unpleasant and often dangerous nature of the hallucinations produced.

Typical or classical deliriants are those which block the muscarinic acetylcholine receptors (antagonism). These are said to be anticholinergic. Many of these compounds are produced naturally by plant genera belonging to the nightshade family Solanaceae, such as Datura, Brugmansia and Latua in the New World and Atropa, Hyoscyamus and Mandragora in the Old World. These tropane alkaloids are poisonous and can cause death due to tachycardia-induced heart failure and hyperthermia even in small doses. Additionally, over-the-counter antihistamines such as diphenhydramine (brand name Benadryl) and dimenhydrinate (brand name Dramamine) also have an anticholinergic effect.

Uncured tobacco is also a deliriant due to its intoxicatingly high levels of nicotine.

The fly agaric mushroom, Amanita muscaria, is often informally lumped with the nightshade plants as a deliriant, though regarded as a dissociative with some regularity as well. This may be explained by the familiarity of both A. muscaria and Atropa belladonna to European culture, their formal statuses as deadly poisons, and their generally undesirable, unpleasant, and dangerous nature, with the potential for death from physical and behavioral toxicity a possibility even when dosages are carefully considered. 

Nutmeg has deliriant and hallucinogenic effects as well due to some of its psychoactive chemicals, such as myristicin, which may be anticholinergic like the tropane alkaloids of the nightshade plants, or as suggested by Alexander Shulgin, partially metabolized into the empathogen-entactogen MMDA.

History of use

Psychedelics, dissociatives, and deliriants have a long history of use within medicinal and religious traditions around the world including shamanic forms of ritual healing and divination, initiation rites, and rituals of syncretistic movements such as União do Vegetal, Santo Daime, and the Native American Church. 

In the context of religious practice, psychedelic drug use, as well as other substances such as tobacco (hypnotic), are referred to as entheogens. In some places peyote is classified as 'sacrament' for part of religious ceremonies, and is legally condoned for such use.

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.

Traditional religious and shamanic use

Historically, hallucinogens have been commonly used in religious or shamanic rituals. In this context they are referred to as entheogens, and 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 Ancient Egyptian, Mycenaean, Ancient Greek, Vedic, Maya, Inca and Aztec cultures. The Upper Amazon is home to the strongest extant entheogenic tradition; the Urarina of the Peruvian Amazon, for instance, continue to practice an elaborate system of ayahuasca shamanism, coupled with an animistic belief system.

Shamans consume hallucinogenic substances in order to induce a trance. Once in this trance, shamans believe that they are able to communicate with the spirit world, and can 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 try to discover and remove the darts from their patients.

Concerning lycanthropy (werewolves) and the use of hallucinogenic drugs, Frida G. Surawicz and Richard Banta wrote "In the first case, this was brought on by LSD and strychnine and continued casual marijuana use... Concerning drugs as causative agents, it is interesting to note that opium has been mentioned in a dual capacity, namely as a drug which can cause lycanthropy as well as a drug for its treatment."

Early scientific investigations

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.

Hallucinogens after World War II

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 (see psychedelic psychotherapy), 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 to more than 1000 articles. 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 to the general public in 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 (Nichols 2004: 164)." 

Starting in the mid-20th century, psychedelic drugs has 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, drug 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 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. 

Legal status and attitudes

In Canada, mescaline is listed as prohibited under schedule III of the Controlled Drugs and Substances Acts, but peyote is specifically exempt and legally available.

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 October 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 Salvia divinorum, and until the ban of psilocybin mushrooms took effect, they were still available for purchase in smartshops as well.

Despite being scheduled as a controlled substance in the mid-1980s, MDMA's popularity has been growing since that time in western Europe and in the United States.

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. Some of these have been successful, for example the Native American Church in the United States, and Santo Daime in Brazil. 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 reasons for the use of hallucinogens including spiritual, introspective, psychotherapeutic, recreational and even hedonistic motives, each subject to some degree of social disapproval, have all been defended as the legitimate exercising of civil liberties and freedom of thought.

Several medical and scientific experts, including the late Albert Hofmann, advocate the drugs should not be banned, but should be strongly regulated and warn they can be dangerous without proper psychological supervision.

Psychedelics and mental illnesses in long-term users

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 possibly formed from neurotransmitters released from the synaptic vesicle. 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. 

A large epidemiological study in the U.S. found that other than personality disorders and other substance use disorders, lifetime hallucinogen use was not associated with other mental disorders, and that risk of developing a hallucinogen use disorder was very low.

How hallucinogens affect the brain

LSD, mescaline, psilocybin, and PCP are drugs that cause hallucinations, which can alter a person's perception of reality. LSD, mescaline, and psilocybin cause their effects by initially disrupting the interaction of nerve cells and the neurotransmitter serotonin. It is distributed throughout the brain and spinal cord, where the serotonin system is involved with controlling of the behavioral, perceptual, and regulatory systems. This also includes mood, hunger, body temperature, sexual behavior, muscle control, and sensory perception. Certain hallucinogens, such as PCP, act through a glutamate receptor in the brain which is important for perception of pain, responses to the environment, and learning and memory. Thus far, there have been no properly controlled research studies on the specific effects of these drugs on the human brain, but smaller studies have shown some of the documented effects associated with the use of hallucinogens.

Naming and taxonomy

Psychedelic nomenclature

The class of drugs described in this article has been described by a profusion of names, most of which are associated with a particular theory of their nature. 

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, phanerothyme, psychedelic, psychotomimetic, psychogenic, schizophrenogenic, cataleptogenic, mysticomimetic, psychodysleptic, 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." 

The word psychedelic was coined by Humphrey Osmond and has the rather mysterious but at least somewhat value-neutral meaning of "mind manifesting". The word entheogen, on the other hand, which is often used to describe the religious and ritual use of psychedelic drugs in anthropological studies, is associated with the idea that it could be relevant to religion. The words entactogen, empathogen, dissociative and deliriant, at last, have all been coined to refer to classes of drugs similar to the classical psychedelics that seemed deserving of a name of their own.

Many different names have been proposed over the years for this drug class. The famous German toxicologist Louis Lewin used the name phantastica earlier in this century, and as we shall see later, such a descriptor is not so farfetched. The most popular names—hallucinogen, psychotomimetic, and psychedelic ("mind manifesting")—have often been used interchangeably. Hallucinogen is now, however, the most common designation in the scientific literature, although it is an inaccurate descriptor of the actual effects of these drugs. In the lay press, the term psychedelic is still the most popular and has held sway for nearly four decades. Most recently, there has been a movement in nonscientific circles to recognize the ability of these substances to provoke mystical experiences and evoke feelings of spiritual significance. Thus, the term entheogen, derived from the Greek word entheos, which means "god within", was introduced by Ruck et al. and has seen increasing use. This term suggests that these substances reveal or allow a connection to the "divine within". Although it seems unlikely that this name will ever be accepted in formal scientific circles, its use has dramatically increased in the popular media and on internet sites. Indeed, in much of the counterculture that uses these substances, entheogen has replaced psychedelic as the name of choice and we may expect to see this trend continue.

Taxonomy

Hallucinogens can be classified by their subjective effects, mechanisms of action, and chemical structure. These classifications often correlate to some extent. In this article, they are classified as psychedelics, dissociatives, and deliriants, preferably entirely to the exclusion of the inaccurate word hallucinogen, but the reader is well advised to consider that this particular classification is not universally accepted. The taxonomy used here attempts to blend these three approaches in order to provide as clear and accessible an overview as possible.

Almost all hallucinogens contain nitrogen and are therefore classified as alkaloids. THC and salvinorin A 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. 

Leo Hollister's five criteria for establishing that a drug is hallucinogenic are as follows:

(1) in proportion to other effects, changes in thought, perception, and mood should predominate; (2) intellectual or memory impairment should be minimal; (3) stupor, narcosis, or excessive stimulation should not be an integral effect; (4) autonomic nervous system side effects should be minimal; and (5) addictive craving should be absent.

Lewin's classes

A classical classification, mainly of historical interest, is that of Lewin (Phantastica, 1928):

Class I Phantastica roughly correspond to the psychedelics, which is a more modern term usually used as synonym to "hallucinogen" by people with positive attitudes towards them. Here the term is used a bit differently to discriminate one particular class of hallucinogens which it seems to describe best. They typically have no sedative effects (sometimes the opposite) and there is usually a clearcut memory to their effects. These drugs have also been referred to as the "classical" hallucinogens.

Class II Phantastica correspond to the other classes in our scheme. They tend to sedate in addition to their hallucinogenic properties and there often is an impaired memory trace after the effects wear off.

Pharmacological classes of hallucinogens

One possible way of classifying the hallucinogens is by their chemical structure and that of the receptors they act on. In this vein, the following categories are often used:

• Psychedelics
  • Serotonergics (5-HT_2A receptor agonists or classical psychedelics) such as mescaline from peyote (Lophophora williamsii)
    • Indoles / Tryptamines such as psilocybin from "magic" mushrooms (Psilocybe)
      • Ergolines such as lysergol from morning glory (Convolvulaceae)
        • Lysergamides such as LSD ("acid"), derived from ergot (Claviceps purpurea)
      • Beta-carbolines (monoamine oxidase inhibitors or MAOIs, specifically reversible inhibitors of monoamine oxidase A or RIMAs) such as harmala alkaloids such as norharman from ayahuasca (Banisteriopsis caapi)
      • Complexly substituted tryptamines such as ibogaine from iboga (Tabernanthe iboga)
    • Phenethylamines such as mescaline
      • Empathogen–entactogens such as MDA
        • Substituted methylenedioxyphenethylamines (serotonin releasing agents) such as MDMA ("ecstasy")
  • Cannabinoidergics (CB-1 receptor agonists or atypical psychedelics) such as THC from cannabis (Cannabis)
• Dissociatives
  • Antiglutamatergics (NMDA receptor antagonists or classical dissociatives) such as "laughing gas" (nitrous oxide) and ketamine
  • Opioidergics (sometimes regarded as atypical psychedelics) (κ-Opioid receptor agonists or atypical dissociatives) such as salvinorin A from Salvia divinorum and pentazocine
• Deliriants
  • Anticholinergics (muscarinic acetylcholine receptor antagonists or classical deliriants) such as tropane alkaloids such as atropine from deadly nightshade (Atropa belladonna) and diphenhydramine (Benadryl)
  • GABAergics (sometimes regarded as atypical dissociatives) (GABA_A receptor agonists, and some positive allosteric modulators of the GABA_A receptor, or atypical deliriants) such as muscimol from fly agaric (Amanita muscaria) and zolpidem (Ambien)

Problems 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 MDMA, 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.

Even so, in many cases structure-based frameworks are still very useful, and the identification of a biologically active pharmacophore and synthesis of analogues of known active substances remains an integral part of modern medicinal chemistry.