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 hallucinogenic class of psychoactive drug whose primary effect is to trigger non-ordinary states of consciousness and psychedelic experiences via serotonin 2A receptor agonism.^[2] This causes specific psychological, visual and auditory changes, and often a substantially altered state of consciousness. "Classical" psychedelic drugs include 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 activate serotonin 5-HT_2A receptors, 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 through the 5-HT_2A receptor is still unknown. The psychedelic experience is often compared to non-ordinary forms of consciousness such as those experienced in meditation,^[3][4]mystical experiences,^[5][6] and near-death experiences.^[6] The phenomenon of ego dissolution is often described as a key feature of the psychedelic experience.^[3][4][6]

Many psychedelic drugs are illegal worldwide under the UN conventions, occasionally excepting use in a religious or research context. Despite these controls, recreational use of psychedelics is common.^[7][8] 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.^[9][10] Studies conducted using psilocybin in a psychotheraputic setting reveal that psychedelic drugs may assist with treating depression and alcohol addiction, and possibly also nicotine addiction.^[11][12] Although further research is needed, existing results are showing that psychedelics may be useful for treating certain forms of psychopathology.^[13][14][8]

Origin of the term

The term psychedelic is derived from the Greek words ? (psyche, "soul, mind") and (delein, "to manifest"), hence "mind manifesting", the implication being that psychedelics can develop unused potentials of the human mind.^[15] The word was coined in 1956 by British psychiatrist, Humphry Osmond, the spelling loathed by American ethnobotanist Richard Schultes, but championed by the American psychologist, Timothy Leary.^[16]

Aldous Huxley had suggested to Humphry Osmond in 1956 his own coinage phanerothyme (Greek phaneroein- "visible" and Greek thymos "soul", thus "visible soul").^[17] Recently, the term entheogenic has come into use to denote the use of psychedelic drugs in a religious, spiritual, and mystical context.

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.
• Mescaline is derived from the Mexican peyote and San Pedro cactus and produces similar effects to LSD.
• DMT (Diemethyltryptamine) 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.²
• 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 entactogenic. 'Entactogen' means 'touching within' and is a term used by psychiatrists to classify MDMA and related drugs.³
• 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.⁴
• 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.⁵

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 against alcoholism, and Mazatec practitioners routinely use psilocybin mushrooms for divination and healing. Ayahuasca, which contains the potent psychedelic DMT, is used in Peru and other parts of South America for spiritual and physical healing as well as in religious festivals.^[]

Psychedelic therapy

Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline.^[14] During the 1950s and 1960s, lack of informed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants.^[14] 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.^[14] 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, post-traumatic stress disorder (PTSD), alcoholism, depression, and cluster headaches.^[8]

Many of the currently known psychedelics are classified as having no accepted medical use in the United States.^[18] However, in 2018 the United States Food and Drug Administration (FDA) granted Breakthrough Therapy Designation for psilocybin-assisted therapy for treatment-resistant depression.^[19] In 2019, the FDA also granted Breakthrough Therapy Designation for psilocybin therapy treating major depressive disorder.^[20] In 2017, a Phase II clinical trial of MDMA-assisted psychotherapy for PTSD led to a designation of breakthrough therapy status by the FDA.^[21] The Multidisciplinary Association for Psychedelic Studies and the FDA have agreed on the design for the Phase III trial, and if the trial is successful the treatment could be approved as early as 2021.^[22]

Recreational

Recreational use of psychedelics is common.^[7][8]

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.^[23][24] The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice.^[25][26]

Chemical family vs characteristic effects

Tryptamine

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 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.^[27][28][29] This chemical class is 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.^[30] Psychedelic tryptamines that could be found in nature are psilocin, DMT, 5-MeO-DMT or they could be synthesised in a laboratory like 4-HO-MET or 5-MeO-DALT.

Phenethylamine

Phenethylamine is also a trace amine but to a lesser extent acts as a neurotransmitter in the human central nervous system. 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.^[31][32] When VMAT2 is inhibited monoamine neurotransmitters such as dopamine cannot be released into the synapse via typical release mechanisms.^[33]

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 dopaminereceptors. 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.^[34]

Pharmacological classes and effects

Psychedelics (5-HT_2A receptor agonists)

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. At lower doses, these 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.^[35] 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 be very substantial differences between the drugs, however. For instance, 5-MeO-DMT rarely produces the visual effects typical of other psychedelics. It has long been known that psychedelics promote neurite growth and synaptic plasticity.^[36][37][38] Psychedelics have also been shown to have potent anti-inflammatory activity and therapeutic effects in animal models of inflammatory diseases including asthma,^[39] and cardiovascular disease and diabetes.^[40]

Empathogen-entactogens (serotonin releasers)

Although not pharmacologically considered psychedelics, empathogen-entactogens are phenethylamines of the MDxx class such as MDMA, MDEA, and MDA have some overlap in the behaviors that they elicit with psychedelics. Their effects are characterized by feelings of openness, euphoria, empathy, love, heightened self-awareness, and by mild audio and visual distortions (an overall enhancement of sensory experience is often reported). Their adoption by the rave subculture is probably due to the enhancement of the overall social and musical experience.

Other

Salvia divinorum is a dissociative that is sometimes classified as an atypical psychedelic with some overlap in its perceptual effects with serotonergic psychedelics. The active molecule in the plant, salvinorin A, is a kappa opioid receptor agonist, working on a part of the brain that deals with pain. Activation of this receptor is also linked to the dysphoria sometimes experienced by users of opioids either therapeutically or recreationally. An unusual feature of S. divinorum is its high potency (dosage is in the microgram range) and extremely disorienting effects, which often include "entity contact", complete loss of reality-perception and user's experiencing their consciousness as being housed in different objects, for example a pane of glass or a pencil. Cannabis (containing THC), particularly when taken in edible form is commonly referred to as a mild psychedelic, and produces behavioral effects with some similarity to true psychedelics.

Potential adverse effects

Psychedelic drugs are not addictive.^[9][10] There is also no evidence that they cause long-term harm to mental health.^[41]

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.^[42]

Legal status

Many psychedelic drugs have been declared illegal under the UN Convention on Psychotropic Substances of 1971. In addition, many countries have analogue acts that automatically forbid any drugs sharing similar chemical structures to common illicit substances regardless of whether or not they are harmful.

Surrounding culture

Psychedelic culture includes manifestations such as psychedelic music,^[43]psychedelic art,^[44]psychedelic literature,^[45]psychedelic film,^[46][47] and psychedelic festivals.^[48]

See also

Categories

Notes