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 subset of hallucinogenic drugs whose primary effect is to trigger non-ordinary states of consciousness (known as psychedelic experiences or "trips" ) via serotonin 2A receptor agonism. This causes specific psychological, visual and auditory changes, and often a substantially altered state of consciousness. The "Classical" psychedelics, the psychedelics with the largest scientific and cultural influence, are mescaline, LSD, psilocybin, and DMT.

Most psychedelic drugs fall into one of the three families of chemical compounds: tryptamines, phenethylamines, or lysergamides. These chemicals all bind to serotonin 5-HT_2A receptors,^[2] which 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 reduced default mode network activity is likely a primary mechanism of action.^[3][4] The psychedelic experience is often compared to non-ordinary forms of consciousness such as those experienced in meditation,^[5][6]mystical experiences,^[7][8] and near-death experiences.^[8] The phenomenon of ego dissolution is often described as a key feature of the psychedelic experience.^[5][6][8]

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.^[9][10] 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.^[11][12] 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.^[13][14] Although further research is needed, existing results are showing that psychedelics may be useful for treating certain forms of psychopathology.^[15][16][10]

Origin of the term

5-HT_2A receptor

The term psychedelic is derived from the Greek words ? (psyche, "soul, mind") and (deloun, "to manifest"), hence "mind manifesting", the implication being that psychedelics can develop unused potentials of the human mind.^[17] The word was coined in 1956 by British psychiatrist Humphry Osmond; the term was loathed by American ethnobotanist Richard Schultes but championed by American psychologist Timothy Leary.^[18]

Aldous Huxley had suggested his own coinage phanerothyme (Greek phaneroein- "visible" and Greek thymos "soul", thus "visible soul") to Osmond in 1956.^[19] 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.^[20]

Examples

Doses of lysergic acid diethylamide (LSD)

• LSD (Lysergic acid diethylamide, a.k.a. acid) is made from a substance found in ergot, which is a fungus that infects rye.
• Psilocin is a naturally occurring substance found in psilocybin mushrooms and is found in many parts of the world.
• O-Acetylpsilocin is believed to be a prodrug of psilocin.^[21]
• Mescaline is derived from the Mexican peyote and San Pedro cactus and produces similar effects to LSD.
• DMT (N,N-Dimethyltryptamine) is structurally similar to psilocin, an alkaloid found in psilocybin mushrooms. It can be synthesised in the laboratory but is also a naturally occurring component of several plants.
• DOM is a member of the DOx family of compounds which are known for their high potency, long duration, and mixture of psychedelic and stimulant effects.
• 2C-B (4-Bromo-2,5-dimethoxyphenethylamine) is a psychedelic drug first synthesised in 1974. 2C-B is considered both a psychedelic and a mild empathogen/entactogen. 'Entactogen' means 'touching within' and is a term used by psychiatrists to classify MDMA and related drugs.
• Peyote (Lophophora williamsii) is the most well-known and potent psychedelic cactus, although the smallest and slowest growing. Instead of growing upward to form a column, it grows as 'buttons' low to the ground. It has been used by Native Americans for over 5000 years.
• 25-NBOMe (N-methoxybenzyl) is the name for a series of drugs that have psychedelics effects. Reports indicate that there are a number of different versions of NBOMe available - all with differing effects.

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. The psychoactive brew Ayahuasca contains the psychedelic DMT alongside a monoamine oxidase inhibitor (MAOI), which makes it orally active,^[22] is used in Peru and other parts of South America for spiritual and physical healing as well as in religious festivals.^[23]

Psychedelic therapy

Many of the currently known psychedelics are classified as having no accepted medical use in the United States.^[24] 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.^[25] In 2019, the FDA also granted breakthrough therapy designation for psilocybin therapy treating major depressive disorder more generally.^[26][27]

Recreational

Recreational use of psychedelics is common.^[9][10]

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.^[28][29] The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice.^[30][31]

Pharmacology

Psychedelics are 5-HT_2A receptor agonists (serotonin 2A receptor agonists).^[32][33]

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.^[34][35][36] 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.^[37]

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.^[38][39] When VMAT2 is inhibited monoamine neurotransmitters such as dopamine cannot be released into the synapse via typical release mechanisms.^[40] Mescaline is a naturally occurring psychedelic protoalkaloid of the substituted phenethylamine class.

Lysergamides

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.^[41]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.^[42]

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.^[43][44] 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.^[45]

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.^[] 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.^[46]

Potential adverse effects

Despite the contrary perception of much of the public, psychedelic drugs are not addictive and are physiologically safe.^[11][12][13] As of 2016, there have been no known deaths due to overdose of LSD, psilocybin, or mescaline.^[13]

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 are 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.^[47] In some cases, individuals taking psychedelics have performed dangerous or fatal acts because they believed they possessed superhuman powers.^[13]

The usage of psilocybin entails a risk of eliciting lasting flashbacks of the drug experience (see hallucinogen persisting perception disorder).^[48] 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.^[48] 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.^[49]

Potential therapeutic effects

Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline.^[16] During the 1950s and 1960s, lack of informed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants.^[16] 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.^[16] 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.^[10]

It has long been known that psychedelics promote neurite growth and synaptic plasticity.^[50][51][52] Psychedelics have also been shown to have potent anti-inflammatory activity and therapeutic effects in animal models of inflammatory diseases including asthma,^[53] and cardiovascular disease and diabetes.^[54]

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.^[55] 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.^[]

Surrounding culture

Psychedelic culture includes manifestations such as psychedelic music,^[56]psychedelic art,^[57]psychedelic literature,^[58]psychedelic film,^[59] and psychedelic festivals.^[60] An example of psychedelic music is that of the rock band Grateful Dead.^[61]

See also

Categories

Notes