Synthetic mescaline. Normally biosynthesized from peyote and some other cacti, mescaline was the first psychedelic compound to be extracted and isolated.^[1]

Psychedelics are a class of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips").^[2][3][4] This causes specific psychological, visual and auditory changes, and often a substantially altered state of consciousness.^[5][6][3][7] The "classical" psychedelics, the psychedelics with the largest scientific and cultural influence, are mescaline, LSD, psilocybin, and DMT.^{[8][9][10][11]}

Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides and many tend to act via serotonin 2A receptor agonism. When compounds bind to serotonin 5-HT_2A receptors,^[12] they modulate the activity of key circuits in the brain involved with sensory perception and cognition, however the exact nature of how psychedelics induce changes in perception and cognition via the 5-HT_2A receptor is still unknown, although the fact that psychedelics reduce default mode network activity and increased connectivity between regions in the brain as a result is likely one of the most relevant pharmacological mechanisms underpinning the psychedelic experience,^[13][14] particularly ego death.^[15] The psychedelic experience is often compared to non-ordinary forms of consciousness such as those experienced in meditation,^[16][3] mystical experiences,^[17][7] and near-death experiences,^[7] which also appear to be partially underpinned by altered default mode network activity.^[18][19] The phenomenon of ego death is often described as a key feature of the psychedelic experience.^[16][3][7]

Many psychedelic drugs are illegal worldwide under the UN conventions, with occasional exceptions for religious use or research contexts. Despite these controls, recreational use of psychedelics is common.^[20][21] Legal barriers have made the scientific study of psychedelics more difficult. Research has been conducted, however, and studies show that psychedelics are physiologically safe and do not lead to addiction.^[22][23] Studies conducted using psilocybin in a psychotherapeutic setting reveal that psychedelic drugs may assist with treating depression and alcohol addiction, and possibly also nicotine addiction.^[24][25] Although further research is needed, existing results are showing that psychedelics may be useful for treating certain forms of psychopathology.^[26][27][21]

Etymology and nomenclature

5-HT_2A receptor

The term psychedelic was coined by the psychiatrist Humphrey Osmond during written correspondence with author Aldous Huxley and presented to the New York Academy of Sciences by Osmond in 1957.^[28] It is irregularly^[29] derived from the Greek words ψυχή psychḗ 'soul, mind' and δηλείν dēleín 'to manifest', with the intended meaning "mind manifesting," the implication being that psychedelics can develop unused potentials of the human mind.^[30] The term was loathed by American ethnobotanist Richard Schultes but championed by American psychologist Timothy Leary.^[31]

Aldous Huxley had suggested his own coinage phanerothyme (Greek phaneroein- "visible" and Greek thymos "soul", thus "visible soul") to Osmond in 1956.^[32] Recently, the term entheogenic has come into use to denote the use of psychedelic drugs, as well as various other types of psychoactive substances, in a religious, spiritual, and mystical context.^[33]

In 2004, David E. Nichols wrote the following about the nomenclature used for psychedelic drugs:

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.^[33]

Robin Carhart-Harris and Guy Goodwin write that the term psychedelic is preferable to hallucinogen for describing classical psychedelics because of the term hallucinogen's "arguably misleading emphasis on these compounds' hallucinogenic properties."^[34]

Examples

Doses of lysergic acid diethylamide (LSD)

• LSD (Lysergic acid diethylamide) is a derivative of lysergic acid, which is obtained from the hydrolysis of ergotamine. Ergotamine is an alkaloid found in the fungus claviceps purpurea, which primarily infects rye. LSD is both the prototypical psychedelic and the prototypical lysergamide. As a lysergamide, LSD contains both a tryptamine and phenethylamine group within its structure. As a result of containing a phenethylamine group LSD agonises dopamine receptors as well as serotonin receptors,^[35] making it more energetic in effect in contrast to the more sedating effects of psilocin, which isn't a dopamine agonist.^[36]
• Psilocin (4-HO-DMT) is the dephosphorylated active metabolite of the indole alkaloid psilocybin and a substituted tryptamine, which is produced in over 200 species of fungi. Of the Classical psychedelics psilocybin has attracted the greatest academic interest regarding its ability to manifest mystical experiences.^[37] Although all psychedelics are capable of doing so to variable degrees.
• Mescaline (3,4,5-trimethoxyphenethylamine) is a phenthylamine alkaloid found in various species of cacti, the most well known being Peyote (Lophophora williamsii). Mescaline has effects comparable to those of LSD and psilocybin, Albeit with a greater emphasis on colors and patterns.^[38]
• DMT (N,N-dimethyltryptamine) is an indole alkaloid found in various species of plants. Traditionally it is consumed by tribes in South America in the form of ayahuasca. A brew is used that consists of DMT-containing plants as well as plants containing MAOIs, specifically harmaline, which allows DMT to be consumed orally without being rendered inactive by monoamine oxidase enzymes in the digestive system.^[39] In the Western world DMT is more commonly consumed via the vaporisation of freebase DMT. Whereas Ayahuasca typically lasts for several hours, inhalation has an onset measured in seconds and has effects measured in minutes, being significantly more intense.^[40] Particularly in vaporised form, DMT has the ability to cause users to enter a hallucinatory realm fully detached from reality, being typically characterised by hyperbolic geometry, and described as defying visual or verbal description.^[41] Users have also reported encountering and communicating with entitites within this hallucinatory state.^[42] DMT is the archeypal substituted tryptamine, being the structural scaffold of psilocybin and - to a lesser extent - the lysergamides.
• 2C-B (2,5-dimethoxy-4-bromophenethylamine) is a substituted phenthylamine first synthesised in 1974 by Alexander Shulgin.^[43] 2C-B is both a psychedelic and a mild entactogen, with its psychedelic effects increasing and its entactogenic effects decreasing with dosage. 2C-B is the most well known compound in the 2C family, their general structure being discovered as a result of modifying the structure of mescaline.^[43]

Uses

Traditional

Psychedelics have a long history of use in traditional medicine and traditional religion, for their perceived ability to promote physical and mental healing. In this context, they are often known as entheogens. Native American practitioners using mescaline-containing cacti (most notably peyote, San Pedro, and Peruvian torch) have reported success in treating alcoholism, and Mazatec practitioners routinely use psilocybin mushrooms for divination and healing.^{[citation needed]} The psychoactive brew ayahuasca is used in Peru and other parts of South America for spiritual and physical healing as well as in religious festivals.^[44]

Psychedelic therapy

Many of the currently known psychedelics are classified as having no accepted medical use in the United States.^[45] However, in 2018 the United States Food and Drug Administration (FDA) granted breakthrough therapy designation for psilocybin-assisted therapy for treatment-resistant major depressive disorder.^[46] In 2019, the FDA also granted breakthrough therapy designation for psilocybin therapy treating major depressive disorder more generally.^[47][48]

Recreational

Recreational use of psychedelics is common.^[20][21]

Microdosing

Psychedelic microdosing is the practice of using sub-threshold doses (microdoses) of psychedelics in an attempt to improve creativity, boost physical energy level, emotional balance, increase performance on problems-solving tasks and to treat anxiety, depression and addiction.^[49][50] The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice.^[51][52]

Pharmacology

Psychedelics are 5-HT_2A receptor agonists (serotonin 2A receptor agonists).^[53][54]

N,N-DMT

Tryptamines

Tryptamine, along with other trace amines, is found in the central nervous system of mammals. It is hypothesized to play a role as a neuromodulator on classical monoamine neurotransmitters, such as dopamine, serotonin, and norepinephrine (epinephrine). Tryptamine acts as a non-selective serotonin receptor agonist to activate serotonin receptors, and a serotonin–norepinephrine–dopamine releasing agent (SNDRA) to release more monoamine neurotransmitter, with a preference for evoking serotonin and dopamine release over norepinephrine (epinephrine) release.^[55][56][57] Psychedelic tryptamines found in nature include psilocin, DMT, 5-MeO-DMT, and tryptamines that have been synthesized in the laboratory include 4-HO-MET and 5-MeO-DALT.^[58]

Mescaline

Phenethylamines

Phenethylamine is also a trace amine but to a lesser extent acts as a neurotransmitter in the human central nervous system (CNS). Phenethylamine instead regulates monoamine neurotransmission by binding to trace amine-associated receptor 1 (TAAR1), which plays a significant role in regulating neurotransmission in dopamine, norepinephrine, and serotonin neurons in the CNS and inhibiting vesicular monoamine transporter 2 (VMAT2) in monoamine neurons.^[59][60] When VMAT2 is inhibited monoamine neurotransmitters such as dopamine cannot be released into the synapse via typical release mechanisms.^[61] Mescaline is a naturally occurring psychedelic protoalkaloid of the substituted phenethylamine class.

Lysergamides

Lysergic acid diethylamide (LSD)

Amides of lysergic acid are collectively known as lysergamides, and include a number of compounds with potent agonist and/or antagonist activity at various serotonin and dopamine receptors. LSD is one of many lysergamides. A wide range of lysergamides have emerged in recent years, inspired by existing scientific literature. Others, have appeared from chemical research.^[62] 1P-LSD is a derivative and functional analogue of LSD and a homologue of ALD-52. It modifies the LSD molecule by adding a propionyl group to the nitrogen molecule of LSD's indole.^[63]

Psychedelic experiences

Although several attempts have been made, starting in the 19th and 20th centuries, to define common phenomenological structures of the effects produced by classic psychedelics, a universally accepted taxonomy does not yet exist.^[64][65] At lower doses, features of psychedelic experiences include sensory alterations, such as the warping of surfaces, shape suggestibility, and color variations. Users often report intense colors that they have not previously experienced, and repetitive geometric shapes are common. Higher doses often cause intense and fundamental alterations of sensory perception, such as synesthesia or the experience of additional spatial or temporal dimensions.^[66]

Classic psychedelics are considered to be those found in nature like psilocybin, DMT, mescaline, and LSD which is derived from naturally occurring ergotamine, and non-classic psychedelics are considered to be newer analogs and derivatives of pharmacophore lysergamides, tryptamine, and phenethylamine structures like 2C-B. Many of these psychedelics cause remarkably similar effects, despite their different chemical structure. However, many users report that the three major families have subjectively different qualities in the "feel" of the experience, which are difficult to describe. Some compounds, such as 2C-B, have extremely tight "dose curves", meaning the difference in dose between a non-event and an overwhelming disconnection from reality can be very slight. There can also be very substantial differences between the drugs; for instance, 5-MeO-DMT rarely produces the visual effects typical of other psychedelics.^{[citation needed]} Tryptamines are well documented to cause classic psychedelic states, such as increased empathy, visual distorsions (drifting, morphing, breathing, melting of various surfaces and objects), auditory hallucinations, ego dissolution or ego death with high enough dose, mystical and spiritual experiences, closed eye hallucinations and complete detachment from reality with a high enough dose.^[67]

Potential adverse effects

Despite the contrary perception of much of the public, psychedelic drugs are not addictive and are physiologically safe.^[22][23][24] As of 2016, there have been no known deaths due to overdose of LSD, psilocybin, or mescaline.^[24]

Risks do exist during an unsupervised psychedelic experience, however; Ira Byock wrote in 2018 in the Journal of Palliative Medicine that psilocybin is safe when administered to a properly screened patient and supervised by a qualified professional with appropriate set and setting. However, he called for an "abundance of caution" because in the absence of these conditions a range of negative reactions is possible, including "fear, a prolonged sense of dread, or full panic." He notes that driving or even walking in public can be dangerous during a psychedelic experience because of impaired hand-eye coordination and fine motor control.^[68] In some cases, individuals taking psychedelics have performed dangerous or fatal acts because they believed they possessed superhuman powers.^[24]

The usage of most psychedelics entails some risk of eliciting flashbacks of the drug experience even after the effects have worn off, albeit rarely.^[69] HPPD or other after-effects may also occur. Psilocybin-induced states of mind share features with states experienced in psychosis, and while a causal relationship between psilocybin and the onset of psychosis has not been established as of 2011, researchers have called for investigation of the relationship.^[69] A population study on associations between psychedelic use and mental illness published in 2013 found no evidence that psychedelic use was associated with increased prevalence of any mental illness.^[70]

Potential therapeutic effects

Psilocybin session at Johns Hopkins

Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline.^[27] During the 1950s and 1960s, lack of informed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants.^[27] Since then, research regarding the effectiveness of psychedelic therapy has been conducted under strict ethical guidelines, with fully informed consent and a pre-screening to avoid people with psychosis taking part.^[27] Although the history behind these substances has hindered research into their potential medicinal value, scientists are now able to conduct studies and renew research that was halted in the 1970s. Some research has shown that these substances have helped people with such mental disorders as obsessive-compulsive disorder (OCD), post-traumatic stress disorder (PTSD), alcoholism, depression, and cluster headaches.^[21]

It has long been known that psychedelics promote neurite growth and synaptic plasticity.^[71][72][73] There is evidence that psychedelics induce molecular and cellular adaptations related to neuroplasticity and that these could potentially underlie therapeutic benefits.^[74] Psychedelics have also been shown to have potent anti-inflammatory activity and therapeutic effects in animal models of inflammatory diseases including asthma,^[75] and cardiovascular disease and diabetes.^[76]

Shamanic, spiritual and religious use

Preparation of Ayahuasca, Province of Pastaza, Ecuador.

A number of frequently mentioned or traditional psychedelics such as Ayahuasca (which contains DMT), San Pedro (which contains mescaline), Psilocybe mushrooms (which contain psilocin/psilocybin) and Tabernanthe iboga (which contains the unique psychedelic ibogaine) all have a long and extensive history of spiritual, shamanic and traditional usage by indigenous peoples in various world regions, particularly in Latin America but in the case of iboga, Gabon, Africa.^{[citation needed]}

Different countries have come to be associated with particular psychedelic entheogens such as ayahuasca's spiritual importance in regions of Peru near the Amazon Basin^[77] and the entheogenic use of psilocybe mushrooms by the native Mazatec people of Oaxaca, Mexico.^{[citation needed]}

Surrounding culture

Psychedelic rock band Jefferson Airplane in 1967

Psychedelic culture includes manifestations such as psychedelic music,^[78] psychedelic art,^[79] psychedelic literature,^[80] psychedelic film,^[81] and psychedelic festivals.^[82] Examples of psychedelic music would be rock bands like the Grateful Dead and Jefferson Airplane. Many psychedelic bands and elements of the psychedelic subculture originated in San Francisco during the mid to late 1960s^[83]

Legal status

Many psychedelics are classified under Schedule I of the United Nations Convention on Psychotropic Substances of 1971 as drugs with the greatest potential to cause harm and no acceptable medical uses.^[84] In addition, many countries have analogue laws; for example, in the United States, the Federal Analogue Act of 1986 automatically forbids any drugs sharing similar chemical structures or chemical formulas to illicit or prohibited substances if sold for human consumption.^{[citation needed]}