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Psychedelic drug

Psychedelics are a subclass of hallucinogenic drugs whose primary effect is to trigger non-ordinary mental states and a perceived "expansion of consciousness". Also referred to as classic hallucinogens or serotonergic hallucinogens, the term psychedelic is sometimes used more broadly to include various other types of hallucinogens as well, such as those which are atypical or adjacent to psychedelia like ketamine and MDMA, respectively.

Examples
Some major examples of, and among the most well-known serotonergic psychedelics, include: Drugs like ALD-52 (1A-LSD), 1P-LSD, and 1V-LSD are prodrugs of LSD. • Psilocin (4-HO-DMT) is the dephosphorylated active metabolite of the indole alkaloid psilocybin (4-PO-DMT) and a substituted tryptamine, which is produced by hundreds of species of psilocybin-containing mushrooms. Of the classical psychedelics, psilocybin has attracted the greatest academic interest regarding its ability to manifest mystical experiences, although all psychedelics are capable of doing so to variable degrees. 4-AcO-DMT (O-acetylpsilocin or psilacetin) is a synthetic acetylated analogue of psilocin and is a prodrug of psilocin similarly to psilocybin. • Mescaline (3,4,5-trimethoxyphenethylamine) is a phenethylamine alkaloid found in various species of cacti, the best-known of these being peyote (Lophophora williamsii) and the San Pedro cactus (Echinopsis pachanoi, syn. Trichocereus macrogonus var. pachanoi). Mescaline has effects comparable to those of LSD and psilocybin. Ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences. • DMT (N,N-dimethyltryptamine) is an indole alkaloid found in various species of plants. A pharmaceutical version of ayahuasca is called pharmahuasca. 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 much more intense. Particularly in smoked or 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. Users have also reported encountering and communicating with entities within this hallucinatory state. DMT is the archetypal substituted tryptamine, being the structural scaffold of psilocybin and, to a lesser extent, the lysergamides. • 5-MeO-DMT (5-methoxy-N,N-dimethyltryptamine; mebufotenin) is a naturally occurring substituted 5-methoxytryptamine which was first identified as having psychedelic effects in the 1960s. It is found in certain hallucinogenic snuffs and in Incilius alvarius (Bufo alvarius; Colorado River toad) toad venom. 5-MeO-DMT is about 5- to 20-fold more potent by weight than DMT. It produces atypical psychedelic effects, including powerful experiences but a relative absence of visual effects, with these experiences often described as "whiteouts". Certain closely related drugs like MDA and MMDA, while much less common, have greater psychedelic effects however. In addition to the above-listed psychedelics, there are hundreds of other much lesser-known psychedelic drugs. Some research suggests that there may be more than 100,000 unique possible serotonergic psychedelics. ==Uses==
Uses
Recreational Recreational use of psychedelics has been common since the psychedelic era of the mid-1960s and continues to feature at festivals and events such as Burning Man. A June 2024 report by the RAND Corporation indicated that psilocybin mushrooms are currently the most widely used psychedelic drug among U.S. adults. According to the RAND national survey, 3.1% of adults reported psilocybin use in the past year, while about 12% reported lifetime use. Similar lifetime prevalence was reported for LSD, whereas MDMA (ecstasy) showed lower lifetime use at 7.6%. Fewer than 1% of adults reported using any psychedelic in the past month. A nationwide survey of 11,299 adults in Germany, published in 2025, found that 5.0% of respondents reported lifetime psychedelic use, with 0.7% reporting use within the past six months. Approximately 3% of respondents had used LSD, LSD analogues, psilocybin, or related substances at least once in their lifetime, and 0.5% had done so within the past six months. Lifetime prevalence of medium-to-high dosing (3.9%) was higher than microdosing (2.7%). Usage patterns varied by sociodemographic characteristics, including sex, age, residence, income, and marital status. Traditional , province of Pastaza, Ecuador A number of frequently mentioned or traditional psychedelics such as ayahuasca (which contains DMT), San Pedro, peyote, and Peruvian torch (which all contain mescaline), psilocybin-containing mushrooms (which contain psilocin and psilocybin) and Tabernanthe iboga (which contains the unique hallucinogen 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 also Gabon, Africa in the case of iboga. Different countries and/or regions have come to be associated with traditional or spiritual use of particular psychedelics, such as the ancient and entheogenic use of psilocybe mushrooms by the native Mazatec people of Oaxaca, Mexico or the use of the ayahuasca brew in the Amazon basin, particularly in Peru for spiritual and physical healing as well as for religious festivals. Peyote has also been used for several thousand years in the Rio Grande Valley in North America by native tribes as an entheogen. In the Andean region of South America, the San Pedro cactus (Echinopsis pachanoi) has a long history of use, possibly as a traditional medicine. Archaeological studies have found evidence of use going back two thousand years, to Moche culture, Nazca culture, and Chavín culture. Although authorities of the Roman Catholic church attempted to suppress its use after the Spanish conquest, this failed, as shown by the Christian element in the common name "San Pedro cactus" – Saint Peter cactus. The name has its origin in the belief that just as St Peter holds the keys to heaven, the effects of the cactus allow users "to reach heaven while still on earth." In 2022, the Peruvian Ministry of Culture declared the traditional use of San Pedro cactus in northern Peru as cultural heritage. Although people of Western culture have tended to use psychedelics for either psychotherapeutic or recreational reasons, most indigenous cultures, particularly in South America, have seemingly tended to use psychedelics for more supernatural reasons such as divination. This can often be related to "healing" or health as well but typically in the context of finding out what is wrong with the individual, such as using psychedelic states to "identify" a disease and/or its cause, locate lost objects, and identify a victim or even perpetrator of sorcery. In some cultures and regions, even psychedelics themselves, such as ayahuasca and the psychedelic lichen of eastern Ecuador (Dictyonema huaorani) that supposedly contains both 5-MeO-DMT and psilocybin, have also been used by witches and sorcerers to conduct their malicious magic, similarly to nightshade deliriants like brugmansia and latua. As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials. However, certain psychedelics like psilocybin and LSD are legally approved and/or used for treatment of conditions like treatment-resistant depression under special access programs in several countries including Australia, Switzerland, Canada, and Israel. The procedure for psychedelic therapy differs from that of therapies using conventional psychiatric medications. While conventional medications are usually taken without supervision at least once daily, in contemporary psychedelic therapy the drug is administered in a single session (or sometimes up to three sessions) in a therapeutic context. The therapeutic team prepares the patient for the experience beforehand and helps them integrate insights from the drug experience afterwards. After ingesting the drug, the patient normally wears eyeshades and listens to music to facilitate focus on the psychedelic experience, with the therapeutic team interrupting only to provide reassurance if adverse effects such as anxiety or disorientation arise. and anxiety and depression linked to terminal illness. The United States Food and Drug Administration has granted breakthrough therapy status, which expedites the assessment of promising drug therapies for potential approval, to psilocybin therapy for treatment-resistant depression and major depressive disorder. On the other hand, the inverse placebo effect (or "knowcebo" effect) caused by blinding failure may create an illusion of large effect sizes with psychedelics. 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. The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice. A 2022 study recognized signatures of psilocybin microdosing in natural language and concluded that low amount of psychedelics have potential for application, and ecological observation of microdosing schedules. Dosing The table below provides doses of major serotonergic psychedelics as well as the entactogen and mild psychedelic MDMA ("ecstasy") that have been determined on the basis of clinical studies. Other dosing schemes have also been reported. In the case of dried psilocybin-containing mushrooms, microdoses are 0.1g to 0.3g and psychedelic doses are 1.0g to 3.5–5.0g. The preceding 1.0 to 5.0g range corresponds to psilocybin doses of about 10 to 50mg. Psilocybin and psilocin are similar in potency and dose but psilocin is about 1.4-fold more active, this being related to the difference in molecular weight between the two compounds. Some psychedelics, such as 2C-B, 2C-E, 2C-P, methallylescaline (MAL), and 4-HO-DiPT among others, have been said to have steep dose–response curves, meaning that the difference in dose between a light experience and an overwhelming disconnection from reality can be small. Conversely, 2C-D is described as having an unusually wide and gradual dose range. Durations The typical durations of major psychedelics are as follows: • Psilocybin oral: 5–6 hours • Dimethyltryptamine (DMT) inhaled: 5–20 minutes • 5-MeO-DMT inhaled: 5–20 minutes The shortest-acting oral psychedelics are the less-well-known ASR-3001 (5-MeO-iPALT) (1.5–2.5 hours) and 4-HO-DiPT (2–3 hours), ==Effects==
Effects
Psychedelic effects 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. At lower doses, features of psychedelic experiences include sensory alterations, such as the warping of surfaces, shape suggestibility, pareidolia, and color variations. Users often report intense colors that they have not previously experienced, and repetitive geometric shapes or form constants are common as well. Higher doses often cause intense and fundamental alterations of sensory (notably visual) perception, such as synesthesia or the experience of additional spatial or temporal dimensions. Tryptamines are well documented to cause classic psychedelic states, such as increased empathy, visual distortions (drifting, morphing, breathing, melting of various surfaces and objects), auditory hallucinations, ego dissolution or ego death with high enough dose, mystical, transpersonal and spiritual experiences, autonomous "entity" encounters, time distortion, closed eye hallucinations and complete detachment from reality with a high enough dose. Luis Luna describes psychedelic experiences as having a distinctly gnosis-like quality, and says that they offer "learning experiences that elevate consciousness and can make a profound contribution to personal development." Czech psychiatrist Stanislav Grof studied the effects of psychedelics like LSD early in his career and said of the experience, that it commonly includes "complex revelatory insights into the nature of existence… typically accompanied by a sense of certainty that this knowledge is ultimately more relevant and 'real' than the perceptions and beliefs we share in everyday life." Traditionally, the standard model for the subjective phenomenological effects of psychedelics has typically been based on LSD, with anything that is considered "psychedelic" evidently being compared to it and its specific effects. Negative experiences, colloquially known as "bad trips," evoke an array of dark emotions, such as irrational fear, anxiety, panic, paranoia, dread, distrustfulness, hopelessness, and even suicidal ideation. While it is impossible to predict when a bad trip will occur, one's mood, surroundings, sleep, hydration, social setting, and other factors can be controlled (colloquially referred to as "set and setting") to minimize the risk of a bad trip. The concept of "set and setting" also generally appears to be more applicable to psychedelics than to other types of hallucinogens such as deliriants, hypnotics and dissociative anesthetics. Psychedelics include naturally occurring tryptamines like psilocybin and DMT, the naturally occurring phenethylamine mescaline, and naturally occurring lysergamides like ergine (lysergic acid amide; LSA), as well as synthetic analogues and derivatives like LSD and 2C-B. Many of these psychedelics cause remarkably similar effects, despite their different chemical structures. However, many users anecdotally report that the three major families have subjectively different qualities in the "feel" of the experience, which are difficult to describe. There can also be very substantial differences between the drugs; for instance, 5-MeO-DMT rarely produces the visual effects typical of other psychedelics. As additional examples, DiPT is said to primarily affect the auditory sense, are said to produce psychedelic effects on thinking or "head space" with few or no visuals, and N-methyltryptamine (NMT) is said to be a spatial psychedelic. The visuals of psychedelics have been reproduced, with these creations known as psychedelic replications. Some rare individuals do not experience hallucinogenic effects with serotonergic psychedelics. Other psychoactive effects Some psychedelics have been associated with other psychoactive effects in addition to their hallucinogenic effects. Some psychedelics and related drugs, like DOET (low doses), Ariadne, and ASR-2001 (2CB-5PrO), have been investigated specifically for such effects. These effects include reduction in psychopathology and increased well-being, mood, mindfulness, social functioning, spirituality, and executive functioning, and positive behavioral changes. Both psychological and pharmacological effects may be involved in the afterglow phenomenon. In 1898, the English writer and intellectual Havelock Ellis reported a heightened perceptual sensitivity to "the more delicate phenomena of light and shade and color" for a prolonged period of time after his exposure to mescaline. The term "psychedelic afterglow" was first formally coined in the 1960s. During a speech on his 100th birthday in 2006, Hofmann additionally said of LSD: ==Contraindications==
Adverse effects
Psychedelic drugs are addictive psychologically, with little to no physical addiction in classical psychedelics. In some cases, individuals taking psychedelics have performed dangerous or fatal acts because they believed they possessed superhuman powers. A 2023 international survey found 14% of respondents felt more anxious for an extended period following ingestion., 9% of users reported functional impairment lasting at least 24 hours beyond the trip itself. In another survey of 608 people who all reported post-psychedelic difficulties, one third of the dataset said the difficulties lasted longer than a year, and one fifth said the difficulties lasted longer than three years. The most commonly-reported post-psychedelic difficulties in that study were anxiety, feeling traumatized by the experience or uncovering earlier trauma, social isolation, derealization/depersonalization, visual distortions and existential confusion. Most people recover from these difficulties with the help of accurate information, social support, and therapy. 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. Many of the persistent negative perceptions of psychological risks are unsupported by the currently available scientific evidence, with the majority of reported adverse effects not being observed in a regulated and/or medical context. 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. In any case, induction of psychosis has been associated with psychedelics in small percentages of individuals, and the rates appear to be higher in people with schizophrenia. Using psychedelics poses certain risks of re-experiencing of the drug's effects, including flashbacks and hallucinogen persisting perception disorder (HPPD). Some people with aphantasia have been reported to have acquired visual mental imagery after using psychedelics. While enhanced mental imagery may seem appealing, it may also pose risks such as increased risk of psychiatric disorders. It develops with a single dose and is present within hours to days. Tolerance has been shown to develop to numerous psychedelics in animals and/or humans. ayahuasca (which contains DMT), and 5-MeO-DMT. Similarly, the structurally related dipropyltryptamine (DPT) and diisopropyltryptamine (DiPT) did not show behavioral tolerance in rodents, in contrast to DOI and 2C-T-7. The reasons for the apparently reduced tolerance development with the preceding psychedelics is unclear. Contrary to earlier findings, subsequent clinical studies employing DMT by continuous intravenous infusion (also known as DMTx) have found rapid and moderate acute tolerance development. The mechanism of the tolerance with psychedelics is thought to be rapid serotonin 5-HT2A receptor downregulation with very slow recovery. Cardiovascular toxicity Serotonergic psychedelics are agonists not only of the serotonin 5-HT2A receptor but also of the serotonin 5-HT2B receptor and other serotonin receptors. A potential risk of frequent repeated use of serotonergic psychedelics is cardiac fibrosis and valvulopathy caused by serotonin 5-HT2B receptor activation. Selective serotonin 5-HT2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT2B receptor activation. ==Overdose==
Overdose
There have been a handful of cases of fatal overdose with LSD, psilocybin, and mescaline. There have also been cases of death with dimethyltryptamine (DMT), 5-MeO-DMT, 2C-B, Bromo-DragonFLY, NBOMes like 25I-NBOMe, and other psychedelics. LSD and psilocybin appear to have very wide margins of safety with overdose, whereas mescaline and 2C-B have much narrower margins, and NBOMes appear to be especially toxic and uniquely linked to serotonin syndrome-type symptoms. Conversely, psychedelics like NBOMes have higher activational efficacy at this receptor. In terms of extrapolated human lethal doses based on animal studies and human case reports, lethal doses of psychedelics relative to typical recreational doses are estimated to be 1,000-fold for LSD, 200-fold for psilocybin, 50-fold for oral DMT (as ayahuasca), and 24-fold for mescaline. Estimates for other psychedelics, like 5-MeO-DMT and 2C-B, could not be made. ==Interactions==
Interactions
Serotonin 5-HT2A receptor antagonists can block the subjective psychedelic effects of serotonergic psychedelics in humans. Numerous drugs act as serotonin 5-HT2A receptor antagonists, for instance antidepressants like trazodone and mirtazapine, antipsychotics like quetiapine, olanzapine, and risperidone, and other agents like ketanserin, pimavanserin, cyproheptadine, and pizotifen. Such drugs are sometimes referred to as "trip killers" due to their ability to prevent or abort the hallucinogenic effects of psychedelics. Besides serotonin 5-HT2A receptor antagonists, non-hallucinogenic serotonin 5-HT2A receptor partial agonists, such as lisuride, may also block the hallucinogenic effects of serotonergic psychedelics. The serotonin 5-HT1A receptor partial agonist buspirone has been found to markedly reduce the hallucinogenic effects of psilocybin in humans. Conversely, the serotonin 5-HT1A receptor antagonist pindolol has been found to potentiate the hallucinogenic effects of DMT by 2- to 3-fold in humans. Serotonin 5-HT1A receptor agonism may modify and self-inhibit the effects of psychedelics that possess this property. A particularly notable example is 5-methoxytryptamine derivatives such as 5-MeO-DMT, which are more potent serotonin 5-HT1A receptor agonists than other psychedelics and have qualitatively unique and differing hallucinogenic effects. Benzodiazepines, for example diazepam, alprazolam, clonazepam, and lorazepam, as well as alcohol, which act as GABAA receptor positive allosteric modulators, have been limitedly studied in combination with psychedelics and are not currently known to directly interact with them. As a result of this, benzodiazepines and alcohol are often used by recreational users as "trip killers" to manage difficult hallucinogenic experiences with psychedelics, for instance experiences with prominent anxiety. A clinical trial of psilocybin and midazolam coadministration found that midazolam clouded the effects of psilocybin and impaired memory of the experience. Benzodiazepines might interfere with the therapeutic effects of psychedelics, such as sustained antidepressant effects. Some serotonergic psychedelics, for instance dimethyltryptamine (DMT) and 5-MeO-DMT, are highly susceptible substrates for monoamine oxidase (MAO), specifically MAO-A, and hence can be greatly potentiated by monoamine oxidase inhibitors (MAOIs). Examples of MAOIs that may potentiate psychedelics behaving as MAO-A and/or MAO-B substrates include phenelzine, tranylcypromine, isocarboxazid, moclobemide, and selegiline. However, circulating levels of the deaminated metabolite of psilocin are far higher than those of free unmetabolized psilocin with psilocybin administration. An early clinical study of psilocybin in combination with short-term tranylcypromine pretreatment found that tranylcypromine marginally potentiated the peripheral effects of psilocybin, including pressor effects and mydriasis, but overall did not significantly modify the psychoactive and hallucinogenic effects of the psilocybin, although some of its emotional effects were said to be reduced and some of its perceptual effects were said to be amplified. Some psychedelics are substrates of cytochrome P450 (CYP450) enzymes, for instance LSD being a substrate of CYP2D6 as well as of several other CYP450 enzymes. As such, CYP450 inhibitors may increase exposure to CYP450-substrate psychedelics such as LSD and thereby potentiate their effects as well as risks. Serotonin syndrome can be caused by combining psychedelics with other serotonergic drugs, including certain antidepressants, opioids, psychostimulants (e.g. MDMA), serotonin 5-HT1 receptor agonists (e.g. triptans), herbs or supplements, and others. A high rate of seizures has been reported when people on lithium have taken serotonergic psychedelics. In an analysis of online reports, 47% of 62accounts reported seizures when a psychedelic was taken while on lithium. The mechanism of this interaction is unclear. ==Pharmacology==
Pharmacology
Mechanism of action Most serotonergic psychedelics act as non-selective agonists of serotonin receptors, including of the serotonin 5-HT2 receptors, but often also of other serotonin receptors, such as the serotonin 5-HT1 receptors. They are thought to mediate their hallucinogenic effects specifically by activation of serotonin 5-HT2A receptors. There is a very strong correlation between 5-HT2A receptor affinity and human hallucinogenic potency. 5-HT2A receptor. In animals, potency for stimulus generalization to the psychedelic DOM in drug discrimination tests is strongly correlated with serotonin 5-HT2A receptor affinity. The HTR is invariably induced by serotonergic psychedelics, is blocked by selective serotonin 5-HT2A receptor antagonists, and is abolished in serotonin 5-HT2A receptor knockout mice. Moreover, the HTR paradigm is one of the only animal tests that can distinguish between hallucinogenic serotonin 5-HT2A receptor agonists and non-hallucinogenic serotonin 5-HT2A receptor agonists, such as lisuride. Interestingly, Gq signaling appeared to mediate hallucinogenic-like effects, whereas β-arrestin2 mediated receptor downregulation and tachyphylaxis. The hallucinogenic effects of serotonergic psychedelics may be critically mediated by serotonin 5-HT2A receptor activation in the medial prefrontal cortex (mPFC). Activation of serotonin 5-HT2A receptors in the mPFC results in marked excitatory and inhibitory effects as well as increased release of glutamate and GABA. Metabotropic glutamate mGlu2 receptors are primarily expressed as presynaptic autoreceptors and have inhibitory effects on glutamate release. Serotonergic psychedelics also directly or indirectly modulate a variety of other brain areas, like the claustrum, and this may be involved in their effects as well. Psychedelics may work in part by disrupting the default mode network (DMN), a collection of interconnected brain areas which has high serotonin 5-HT2A receptor expression and is said to construct our sense of space, time, and self. Serotonin is a hydrophilic molecule which cannot easily cross biological membranes without active transport, and the serotonin 5-HT2A receptor is usually expressed as a cell surface receptor that is readily accessible to extracellular serotonin. antidepressant, empathy-enhancing or prosocial effects, anti-obsessional, anti-addictive, anti-inflammatory and immunomodulatory effects, analgesic effects, and/or antimigraine effects. While psychedelics themselves are also being clinically evaluated for these potential therapeutic benefits, non-hallucinogenic serotonin 5-HT2A receptor agonists, which are often analogues of serotonergic psychedelics, have been developed and are being studied for potential use in medicine in an attempt to provide some such benefits without hallucinogenic effects. Although the hallucinogenic effects of serotonergic psychedelics are thought to be mediated by serotonin 5-HT2A receptor activation, interactions with other receptors, such as the serotonin 5-HT1A, 5-HT1B, 5-HT2B, and 5-HT2C receptors among many others, may additionally contribute to and modulate their effects. Many psychedelics show pronounced biased agonism at the serotonin 5-HT2C receptor. Certain psychedelics, including LSD and psilocin, have been reported to act as highly potent positive allosteric modulators of the tropomyosin receptor kinase B (TrkB), one of the signaling receptors of brain-derived neurotrophic factor (BDNF). However, subsequent studies failed to reproduce these findings and instead found no interaction of LSD or psilocin with TrkB. Moreover, the psychoplastogenic effects of serotonergic psychedelics, including dendritogenesis, spinogenesis, and synaptogenesis, appear to be mediated by activation of multiple serotonin receptors as well as non‑serotonergic targets, whereas psychedelics do not generally stimulate neurogenesis. The factors responsible for differences in psychoactive and hallucinogenic effects between different psychedelics are incompletely understood but may include (1) differences in selectivity for the serotonin 5-HT2A receptor or off-target activity; (2) differences in functional selectivity for different serotonin 5-HT2A receptor downstream signaling pathways; and (3) differences in patterns or balances of distribution to different brain areas. Examples include allometric scaling formulas and receptor occupancy studies. These psychedelics have included DOI, 2C-B, 25B-NBOMe, 25C-NBOMe, 5-MeO-DiPT, 5-MeO-MiPT, methallylescaline (MAL), and BOD, among others. DOM is known to metabolize into 2,5-DDM-DOM (2-O-,5-O-didesmethyl-DOM; 2,5-dihydroxy-4-methylamphetamine), which bears a close resemblance to 6-hydroxydopamine (6-OHDA; 2,4,5-trihydroxyphenethylamine) and has been found to be a potent neurotoxin similarly. Other related phenethylamine psychedelics may also undergo similar metabolism and form analogous potentially neurotoxic metabolites. Chronic administration of LSD has been associated with long-lasting schizophrenia-like behavioral changes in rodents, which was not blocked by serotonin 5-HT2A receptor antagonism but may instead be related to LSD's dopamine D2-like receptor agonism. Single macrodoses of LSD do not produce such changes in rodents, but the preceding findings may have implications for continuous psychedelic microdosing with LSD. ==Chemistry==
Chemistry
The three major chemical groups of serotonergic psychedelics include the tryptamines, phenethylamines, and lysergamides, which each have different profiles of pharmacological activity. Harmala alkaloids like harmaline and iboga-type alkaloids like ibogaine are cyclized tryptamines and may also be considered hallucinogenic tryptamines. Phenethylamines . Phenethylamines, as well as amphetamines (α-methylphenethylamines), are derivatives of β-phenethylamine and are structurally related to the monoamine neurotransmitters dopamine, norepinephrine, and epinephrine. Some phenethylamines and amphetamines, particularly those with methoxy and other substitions on the phenyl ring, are potent serotonin 5-HT2 receptor agonists, including of the serotonin 5-HT2A receptor, and can produce psychedelic effects. In contrast to phenethylamines and amphetamines generally, most psychedelic phenethylamines are not monoamine releasing agents. Examples of psychedelic phenethylamines and amphetamines include mescaline and other scalines like trimethoxyamphetamine (TMA) and escaline, the 2C drugs like 2C-B, 2C-E, and 2C-I, the DOx drugs like DOM, DOB, DOI, certain MDxx drugs like MDA and MDMA (weak psychedelics), FLY drugs like 2C-B-FLY and Bromo-DragonFLY, and the NBOMe (25x-NBx) drugs like 25I-NBOMe, among others. the antiretroviral drug efavirenz, and simplified or partial lysergamides (which are also conformationally constrained tryptamines and/or phenethylamines) like NDTDI (9-nor-LSD; 8,10-seco-LSD) and DEMPDHPCA (dides-B,C-LSD). Comparison (a tryptamine), 2C-B (a phenethylamine), and LSD (a lysergamide or cyclized tryptamine and phenethylamine). Note the structural parallels and overlap between the different groups of compounds. ==History==
History
Early history Psychedelics occurring in plants, fungi, and animals have been used by indigenous peoples throughout the world for thousands of years. Western characterization Psychedelics were discovered by the Western world and the scientific community relatively late. The first written description of an observed psychedelic experience, with cohoba, was published by Ramon Pane in 1511. Spanish explorers observed the use of psilocybin-containing mushrooms (teonanacatl) in Mexico as early as 1519 with the arrival of Hernán Cortés. He obtained mescal buttons from Mexico and published a journal article about trying a very low dose of them in May 1887. After reading Mitchell's article, others, including psychologist and sexologist Havelock Ellis, American psychologist William James, and German pharmacologist, chemist, and Lewin rival Arthur Heffter, among others, tried peyote and described their experiences. Heffter isolated and ingested mescaline from peyote, experiencing psychedelic effects with the pure compound, in 1897, and published his findings in 1898. Austrian chemist Ernst Späth synthesized mescaline for the first time in 1919. German–American psychologist Heinrich Klüver published his monograph, Mescal: The Divine Plant and Its Psychological Effects, in English in 1928. He is said to have been the first to attempt to provide a phenomenological description of the psychedelic experience. Schultes obtained specimens of three of the hallucinogenic mushrooms used in ceremonies, including Psilocybe caerulescens, Panaeolus campanulatus, and Stropharia cubensis, but further investigations of the mushrooms were interrupted by World War II. In 1938, Swiss chemist Albert Hofmann, working at Sandoz Laboratories, synthesized lysergic acid diethylamide (LSD), a synthetic derivative of ergine, while developing new oxytocic drugs derived from ergot. Hofmann and his colleague, psychiatrist Werner Stoll, first described LSD in 1943 and first described its psychedelic effects in 1947. LSD began being distributed by Sandoz Laboratories for research purposes under the brand name Delysid in 1949. Schultes described the indigenous and shamanic use of dimethyltryptamine (DMT)-containing psychedelic plants in 1954 and also described the use of hallucinogenic morning glories in the 1950s. Osmond described the hallucinogenic and other effects of morning glory seeds in clinical studies in 1955. Their hallucinogenic effects were first described by Hofmann in 1963. In 1952, couple and amateur ethnomycologists R. Gordon Wasson and Valentina Wasson learned of the ritual use of hallucinogenic mushrooms in the 16th century in Mexico from the published work of Schultes. They made several trips to Mexico in search of the mushrooms. The compound was first isolated to purity by Austrian chemist Hans Handovsky in 1920. The related psychedelic 5-MeO-DMT was first synthesized by Japanese chemists Toshio Hoshino and Kenya Shimodaira in 1936. A 1984 pamphlet by Albert Most (real name Ken Nelson), titled Bufo Alvarius: the Psychedelic Toad of the Sonoran Desert, described how to obtain and use Colorado River toad secretions as a psychedelic drug, and this started its recreational use. However, the amount of research done on psilocybin was nowhere near that of LSD. British politician Christopher Mayhew tried mescaline in 1955 and this was reported on in the media. Creation of other synthetic psychedelics The synthetic mescaline analogue 2,6-dibromomescaline was described by Arthur Heffter in 1901, although he is not known to have tested it and its psychedelic effects weren't reported until much later. The psychedelic effects of 3,4-methylenedioxyamphetamine (MDA), a synthetic analogue of mescaline that had been derived from amphetamine in 1910, were discovered by American chemist and pharmacologist Gordon Alles in 1930, but weren't subsequently published until 1959. 3,4,5-Trimethoxyamphetamine (TMA), another synthetic mescaline analogue, was first described in 1947 and its psychedelic effects were described in 1955. 2,4,5-Trimethoxyphenethylamine (2C-O), a synthetic positional isomer of mescaline, was synthesized and claimed to be psychedelic similarly to mescaline in 1931, but later trials found it to be inactive. Various synthetic tryptamine psychedelics, such as diethyltryptamine (DET), 4-PO-DET (CEY-19), and 4-HO-DET (CZ-74), were developed in the late 1950s. In addition, the synthetic α-alkyltryptamine analogues α-methyltryptamine (AMT; Indopan) and α-ethyltryptamine (AET; Monase), which are psychedelics and/or entactogens, were marketed and clinically used at non-hallucinogenic doses as antidepressants in the early 1960s, but were quickly withdrawn due to physical toxicity. Numerous synthetic psychedelic tryptamines were known by the mid-1970s. This experience has been described as "the most consequential mescaline trip of the sixties", as it caused Shulgin to redirect his focus and life's work to psychedelic chemistry. However, MDMA was not an original creation of Shulgin's but had previously been first synthesized in 1912 and had surfaced as a recreational drug related to MDA by the mid- to late-1960s. American chemist David E. Nichols has developed numerous novel psychedelics and entactogens from the 1970s to present. Swiss chemist Daniel Trachsel, sometimes referred to as the "German Shulgin", has also developed and published numerous novel psychedelics as well as entactogens since the 1990s. The NBOMe drugs were subsequently encountered as novel recreational drugs by 2010, and by 2012 had eclipsed other psychedelics like LSD and psilocybin-containing mushrooms in popularity, at least for a time. Psychedelics, serotonin, and their actions Serotonin, also known as 5-hydroxytryptamine (5-HT) and originally called enteramine, was discovered by Vittorio Erspamer in the 1930s Serotonin was discovered in the brain by Betty Twarog and Irvine Page in 1953. It was quickly noticed that LSD contains the serotonin-like tryptamine scaffold within its chemical structure. It was first proposed that LSD may be acting as an agonist of serotonin receptors by N. E. Andén and colleagues in 1968. The serotonin receptors, including the serotonin 5-HT2 receptors, were identified by the late 1970s. Mediation of the hallucinogenic effects of psychedelics specifically by serotonin 5-HT2 receptor agonism was proposed by Richard Glennon and other researchers by the early 1980s. The human serotonin 5-HT2A receptor was first cloned in 1990. The hallucinogenic effects of psilocybin in humans were shown to be blocked by the selective serotonin 5-HT2A receptor antagonist ketanserin by Franz Vollenweider and colleagues in 1998, solidifying theoretical notions that agonism of the serotonin 5-HT2A receptor mediates the hallucinogenic effects of serotonergic psychedelics. Psychedelic renaissance Since the prohibition of the 1960s and 1970s, clinical research into psychedelics started to resume by the 1990s, for instance the studies of DMT by Rick Strassman, and they have once again started to be developed as pharmaceutical drugs for potential medical use. A so-called "psychedelic renaissance", in which interest in psychedelics has resurged, began in the late 2010s and early 2020s. Michael Pollan's 2018 book How to Change Your Mind, which was also adapted into a Netflix series in 2022, was especially impactful in terms of increasing mainstream awareness and interest in psychedelics. More than 100clinical trials of four major psychedelics, including psilocybin, LSD, ayahuasca, and MDMA, were identified as being underway in 2024. ==Society and culture==
Society and culture
Etymology and nomenclature The term psychedelic was coined by the psychiatrist Humphrey Osmond during written correspondence with author Aldous Huxley (written in a rhyme: "To fathom Hell or soar angelic/Just take a pinch of psychedelic.") and presented to the New York Academy of Sciences by Osmond in 1957. It is irregularly derived from the Greek words ψυχή (psychḗ, meaning 'mind, soul') and δηλείν (dēleín, meaning 'to manifest'), with the intended meaning "mind manifesting" or alternatively "soul manifesting", and the implication that psychedelics can reveal unused potentials of the human mind. The term was loathed by American ethnobotanist Richard Schultes but championed by American psychologist Timothy Leary. Aldous Huxley had suggested his own coinage phanerothyme (Greek phaneroein- "to make manifest or visible" and Greek thymos "soul", thus "to reveal the soul") to Osmond in 1956. Recently, the term entheogen (meaning "that which produces the divine within") 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. While the term psychedelic is most commonly used to refer only to serotonergic hallucinogens, it is sometimes used for a much broader range of drugs, including entactogens, dissociatives, and atypical hallucinogens/psychoactives such as Amanita muscaria, Cannabis sativa, Nymphaea nouchali and Salvia divinorum. Thus, the term serotonergic psychedelic is sometimes used for the narrower class. It is important to check the definition of a given source. Surrounding culture band Jefferson Airplane in 1967 Psychedelic culture includes manifestations such as psychedelic music, psychedelic art, psychedelic literature, psychedelic film, and psychedelic festivals. Examples of psychedelic music are found in the work of 1960s rock bands like the Grateful Dead, Jefferson Airplane, The 13th Floor Elevators, and Syd Barrett-era Pink Floyd. Many psychedelic bands and elements of the psychedelic subculture originated in San Francisco during the mid to late 1960s. Usage prevalence A September 2025 national survey of American adults conducted by the RAND Corporation found that the most commonly used psychedelics and related drugs (past-year use) were psilocybin (4.3%), MDMA or MDA (1.8%), Amanita muscaria (1.3%), ketamine (1.3%), LSD (1.1%), DMT (0.84%), mescaline (0.53%), 2C-B (0.46%), Salvia divinorum (0.43%), ibogaine or iboga (0.36%), and 5-MeO-DMT (0.30%). The survey also found that about 3.7% of adults had microdosed in the past year, with the most frequent drugs being psilocybin, MDMA, and LSD. 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 prohibited substances if sold for human consumption. In July 2022, though, under the United States Food and Drug Administration, the drug psilocybin was on track to be approved of as a treatment for depression, and MDMA as a treatment for post-traumatic stress disorder. U.S. states such as Oregon and Colorado have also instituted decriminalization and legalization measures for accessing psychedelics and states like New Hampshire are attempting to do the same. J.D. Tuccille argues that increasing rates of use of psychedelics in defiance of the law are likely to result in more widespread legalization and decriminalization of access to the substances in the United States (as has happened with alcohol and cannabis). ==Research==
Research
Therapeutic effects . Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline. During the 1950s and 1960s, lack of informed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants. It has long been known that psychedelics promote neurite growth and neuroplasticity and are potent psychoplastogens. There is evidence that psychedelics induce molecular and cellular adaptations related to neuroplasticity and that these could potentially underlie therapeutic benefits. The British critical psychiatrist Joanna Moncrieff has critiqued the use and study of psychedelic and related drugs like psilocybin, MDMA, and ketamine for treatment of psychiatric disorders. ==See also==
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