Psychedelics are a subclass ofhallucinogenic drugs whose primary effect is to triggernon-ordinary mental states (known aspsychedelic experiences or "trips") and a perceived "expansion of consciousness".[1][2] Also referred to asclassic hallucinogens orserotonergic hallucinogens, the termpsychedelic is sometimes used more broadly to include various other types of hallucinogens as well, such as those which are atypical or adjacent topsychedelia likesalvia andMDMA, respectively.[3]
Many psychedelic drugs are illegal to possess without lawful authorisation, exemption or license worldwide under theUN conventions, with occasional exceptions for religious use or research contexts. Despite these controls,recreational use of psychedelics is common.[19][20] There is also a long history of use of naturally occurring psychedelics asentheogens dating back thousands of years. Legal barriers have made thescientific study of psychedelics more difficult. Research has been conducted, however, and studies show that psychedelics are physiologicallysafe and rarely lead toaddiction.[21][22] Studies conducted using psilocybin in apsychotherapeutic setting reveal that psychedelic drugs may assist with treatingdepression,anxiety,alcohol addiction, andnicotine addiction.[5][23] Although further research is needed, existing results suggest that psychedelics could be effective treatments for certainmental health conditions.[24][25][26][20] A 2022 survey byYouGov found that 28% of Americans had used a psychedelic at some point in their life.[27]
Mescaline (3,4,5-trimethoxyphenethylamine) is aphenethylamine alkaloid found in various species of cacti, the best-known of these beingpeyote (Lophophora williamsii) and theSan Pedro cactus (Echinopsis pachanoi, syn.Trichocereus macrogonus var.pachanoi). Mescaline has effects comparable to those of LSD and psilocybin.[31][page needed] Ceremonial San Pedro use seems to be characterized by relatively strong spiritual experiences, and low incidence of challenging experiences.[32]
DMT (N,N-dimethyltryptamine) is anindole alkaloid found in various species of plants. Traditionally, it is consumed by tribes inSouth America in the form ofayahuasca. A brew is used that consists of DMT-containing plants as well as plants containingMAOIs, specificallyharmaline, which allows DMT to be consumed orally without being rendered inactive bymonoamine oxidase enzymes in the digestive system.[33] A pharmaceutical version of ayahuasca is calledpharmahuasca.[34] 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.[35] Particularly in vaporised form, DMT has the ability to cause users to enter a hallucinatory realm fully detached from reality, being typically characterised byhyperbolic geometry, and described as defying visual or verbal description.[36] Users have also reported encountering and communicating with entities within this hallucinatory state.[37] DMT is the archetypalsubstituted tryptamine, being the structural scaffold of psilocybin and, to a lesser extent, the lysergamides.
2C-B (2,5-dimethoxy-4-bromophenethylamine) is asubstituted phenethylamine first synthesized in 1974 byAlexander Shulgin.[38][page needed] 2C-B has been described as both a psychedelic and a mildentactogen, with its psychedelic effects increasing and its entactogenic effects decreasing with dose.[39][40][41][42] 2C-B is the most well-known compound in the2C family, theirgeneral structure being discovered as a result of modifying the structure of mescaline.[38][page needed] It is also the most widely used synthetic phenethylamine psychedelic.
MDMA ("ecstasy") is sometimes said to also have weak psychedelic effects, but it acts and is classified mainly as anentactogen rather than as a hallucinogen.[43] Certain related drugs likeMDA andMMDA have greater psychedelic effects however.[38]
Syntheticmescaline. This psychedelic was the first to be isolated.[44]
Recreational use of psychedelics has been common since thepsychedelic era of the mid-1960s and continues to feature at festivals and events such asBurning Man.[19][20] A 2013 survey found that 13.4% of American adults had used a psychedelic at some point in their lives.[45]
A June 2024 report by theRAND 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 forLSD, whereasMDMA (ecstasy) showed lower lifetime use at 7.6%. Fewer than 1% of adults reported using any psychedelic in the past month.[46]
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.[47] 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.
Preparation ofAyahuasca, province ofPastaza, EcuadorReligious statues involving Psilocybe MushroomsEchinopsis pachanoi in Peru
A number of frequently mentioned or traditional psychedelics such asAyahuasca (which containsDMT),San Pedro,Peyote, andPeruvian torch (which all containmescaline),Psilocybe mushrooms (which containpsilocin/psilocybin) andTabernanthe iboga (which contains the unique psychedelicibogaine) all have a long and extensive history ofspiritual,shamanic and traditional usage byindigenous peoples in various world regions, particularly in Latin America, but alsoGabon, Africa in the case of iboga.[48] 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 nativeMazatec people ofOaxaca, Mexico[49] or the use of the ayahuasca brew in theAmazon basin, particularly in Peru for spiritual and physical healing as well as for religious festivals.[50] Peyote has also been used for several thousand years in theRio Grande Valley in North America by native tribes as anentheogen.[51] In theAndean region of South America, the San Pedro cactus (Echinopsis pachanoi) has a long history of use, possibly as atraditional medicine. Archaeological studies have found evidence of use going back two thousand years, toMoche culture,[52]Nazca culture,[53] andChavín culture. Although authorities of theRoman Catholic church attempted to suppress its use after the Spanish conquest,[54] 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."[55] In 2022, the Peruvian Ministry of Culture declared the traditional use of San Pedro cactus in northern Peru ascultural heritage.[56]
Although people ofWestern culture have tended to use psychedelics for eitherpsychotherapeutic orrecreational reasons, most indigenous cultures, particularly in South America, have seemingly tended to use psychedelics for moresupernatural reasons such asdivination. 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 ofsorcery.[57] In some cultures and regions, even psychedelics themselves, such as ayahuasca and the psychedeliclichen of eastern Ecuador (Dictyonema huaorani) that supposedly contains both5-MeO-DMT and psilocybin, have also been used by witches and sorcerers to conduct theirmalicious magic, similarly tonightshadedeliriants likebrugmansia andlatua.[57][citation needed]
Psychedelic therapy (or psychedelic-assisted therapy) is the proposed use of psychedelic drugs to treatmental disorders.[58] As of 2021, psychedelic drugs are controlled substances in most countries and psychedelic therapy is not legally available outside clinical trials, with some exceptions.[59][60]
The procedure for psychedelic therapy differs from that of therapies using conventionalpsychiatric 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.[61] The therapeutic team prepares the patient for the experience beforehand and helps them integrate insights from the drug experience afterwards.[62][63][64] 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.[62][63]
As of 2022, the body of high-quality evidence on psychedelic therapy remains relatively small and more, larger studies are needed to reliably show the effectiveness and safety of psychedelic therapy's various forms and applications.[24][25] On the basis of favorable early results, ongoing research is examining proposed psychedelic therapies for conditions includingmajor depressive disorder,[24][65] andanxiety and depression linked toterminal illness.[24][66] The United StatesFood and Drug Administration has grantedbreakthrough therapy status, which expedites the assessment of promising drug therapies for potential approval, to psilocybin therapy for treatment-resistant depression and major depressive disorder.[59]
It has been proposed that psychedelics used for therapeutic purposes may act asactive "superplacebos".[67][68][69]
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.[70][71] The practice of microdosing has become more widespread in the 21st century with more people claiming long-term benefits from the practice.[72][73]
A 2022 study recognized signatures of psilocybin microdosing innatural language and concluded that low amount of psychedelics have potential for application, and ecological observation of microdosing schedules.[74][75]
The table below provides doses of major serotonergic psychedelics as well as theentactogen and mild psychedelicMDMA ("ecstasy") that have been determined on the basis ofclinical studies.[76][77][78][79][80][81][82] Other dosing schemes have also been reported.[78]
Notes: (1) All doses are fororal administration unless otherwise indicated. (2) For the psychedelics, doses are considered to be roughly equivalent in terms of peak or overall response.Footnotes:a = As LSDfree base (100μg LSD base = 146μg LSDtartrate).b = As mescalinehydrochloride.c = As DMTfumarate given as constant infusions for >30minutes.d = As MDMA hydrochloride.Refs:[76][77][79][80][81][82]
In the case of driedpsilocybin-containing mushrooms, microdoses are 0.1g to 0.3g and psychedelic doses are 1.0g to 3.5–5.0g.[83][84][85] The preceding 1.0 to 5.0g range corresponds to psilocybin doses of about 10 to 50mg.[85] Psilocybin-containing mushrooms vary in their psilocybin andpsilocin content, but are typically around 1% of the dried weight of the mushrooms (in terms of total or combined psilocybin and psilocin content).[84][86][87][85][88][89][90][91] Psilocybin and psilocin are similar inpotency and dose but psilocin is about 1.4-fold more active, this being related to the difference inmolecular weight between the two compounds.[87][92][93]
Some psychedelics, such as2C-B,2C-E,2C-P, and4-HO-DiPT among others, have been said to have steepdose–response curves, meaning that the difference in dose between a light experience and an overwhelming disconnection from reality can be small.[38]: 506, 518 [94]: 467 Conversely,2C-D is described as having an unusually wide and gradual dose range.[38][95]
Although several attempts have been made, starting in the 19th and 20th centuries, to define commonphenomenological structures of the effects produced by classic psychedelics, a universally accepted taxonomy does not yet exist.[96][97] 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 orform constants are common as well. Higher doses often cause intense and fundamental alterations of sensory (notablyvisual) perception, such assynesthesia or the experience of additional spatial or temporal dimensions.[98] Tryptamines are well documented to cause classic psychedelic states, such as increasedempathy, visual distortions (drifting, morphing, breathing, melting of various surfaces and objects), auditory hallucinations, ego dissolution orego 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.[99]Luis Luna describes psychedelic experiences as having a distinctlygnosis-like quality, and says that they offer "learning experiences that elevate consciousness and can make a profound contribution topersonal development."[100] Czech psychiatristStanislav Grof studied the effects of psychedelics like LSD early in his career and said of the experience, that it commonly includes "complexrevelatoryinsights 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."[citation needed] Traditionally, the standard model for thesubjective phenomenological effects of psychedelics has typically been based on LSD, with anything that is considered "psychedelic" evidently being compared to it andits specific effects.[5]
Good trips are reportedly deeply pleasurable, and typically involve intense joy or euphoria, a greater appreciation for life, reduced anxiety, a sense of spiritual enlightenment, and a sense of belonging or interconnectedness with the universe.[101][102] 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.[103] 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.[104][105] 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.[106]
In 1898, the English writer and intellectualHavelock 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.[134] The term "psychedelic afterglow" was first formally coined in the 1960s.[127]Albert Hofmann, the discoverer of LSD, said the following about the aftermath of his first full LSD experience in his 1980 bookLSD: My Problem Child:[135]
Exhausted, I then slept, to awake next morning refreshed, with a clear head, though still somewhat tired physically. A sensation of well-being and renewed life flowed through me. Breakfast tasted delicious and gave me extraordinary pleasure. When I later walked out into the garden, in which the sun shone now after a spring rain, everything glistened and sparkled in a fresh light. The world was as if newly created. All my senses vibrated in a condition of highest sensitivity, which persisted for the entire day.
During a speech on his 100th birthday in 2006, Hofmann additionally said of LSD:[136]
It gave me an inner joy, an open mindedness, a gratefulness, open eyes and an internal sensitivity for the miracles of creation... I think that in human evolution it has never been as necessary to have this substance LSD. It is just a tool to turn us into what we are supposed to be.
Psychedelic drugs are addictive psychologically, with little to no physical addiction in classical psychedelics.[21][22][5]
Risks do exist during an unsupervised psychedelic experience, however;Ira Byock wrote in 2018 in theJournal 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 impairedhand-eye coordination andfine motor control.[137] In some cases, individuals taking psychedelics have performed dangerous or fatal acts because they believed they possessed superhuman powers.[5]
Psilocybin-induced states of mind share features with states experienced inpsychosis, 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.[138] 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.[139] Apopulation 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.[140] 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 withschizophrenia.[141]
Using psychedelics poses certain risks of re-experiencing of the drug's effects, including flashbacks andhallucinogen persisting perception disorder (HPPD).[138] These non-psychotic effects are poorly studied, but the permanent symptoms (also called "endless trip") are considered to be rare.[142]
Serotonergic psychedelics areagonists not only of theserotonin5-HT2A receptor but also of the serotonin5-HT2B receptor and otherserotonin receptors.[143][144] A potential risk of frequent repeated use of serotonergic psychedelics iscardiac fibrosis andvalvulopathy caused by serotonin 5-HT2B receptor activation.[143][144] However, single high doses or widely spaced doses (e.g., months) are widely thought to be safe and concerns about cardiac toxicity apply more to chronicpsychedelic microdosing or very frequent use (e.g., weekly).[143][144]Selective serotonin 5-HT2A receptor agonists that do not activate the serotonin 5-HT2B receptor or other serotonin receptors, such as25CN-NBOH,DMBMPP, andLPH-5, have been developed and are being studied.[145][146][147] Selective serotonin 5-HT2A receptor agonists are expected to avoid the cardiac risks of serotonin 5-HT2B receptor activation.[147]
There have been a handful of cases of fataloverdose withLSD,psilocybin, andmescaline.[148][149] There have also been cases of death withdimethyltryptamine (DMT),5-MeO-DMT,2C-B,Bromo-DragonFLY,NBOMes like25I-NBOMe, and other psychedelics.[148][150] 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 especiallytoxic and uniquely linked toserotonin syndrome-type symptoms.[148] Major psychedelics like LSD and psilocybin do not cause serotonin syndrome, which is thought to be due to the fact that they act aspartial agonists of the serotonin 5-HT2A receptor.[151][148][152] Conversely, psychedelics like NBOMes have higheractivational efficacy at this receptor.[151][152] In terms of extrapolated humanlethal doses based onanimal studies and humancase 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 (asayahuasca), and 24-fold for mescaline.[148] Estimates for other psychedelics, like 5-MeO-DMT and 2C-B, could not be made.[148]
The serotonin5-HT1A receptorpartial agonistbuspirone has been found to markedly reduce the hallucinogenic effects of psilocybin in humans.[153][159][160] Conversely, the serotonin 5-HT1A receptor antagonistpindolol has been found to potentiate the hallucinogenic effects of DMT by 2- to 3-fold in humans.[160][161] Serotonin 5-HT1A receptor agonism may modify and self-inhibit the effects of psychedelics that possess this property.[107][162][159][163][164][165] A particularly notable example is5-methoxytryptaminederivatives such as5-MeO-DMT, which are morepotent serotonin 5-HT1A receptor agonists than other psychedelics and have qualitatively unique and differing hallucinogenic effects.[107][165][166]
Some serotonergic psychedelics, for instancedimethyltryptamine (DMT) and5-MeO-DMT, are highly susceptiblesubstrates formonoamine oxidase (MAO), specificallyMAO-A, and hence can be greatly potentiated bymonoamine oxidase inhibitors (MAOIs).[153][177][178] An example of this isayahuasca, in which plants containing both DMT andharmala alkaloids acting as MAOIs such asharmine andharmaline are combined.[177] This allows DMT to becomeorally active and to have a much longerduration of action than usual.[177] The2C psychedelics, such as2C-B,2C-I, and2C-E, are also substrates of both MAO-A andMAO-B, and may likewise be greatly potentiated by MAOIs.[179][180] Examples of MAOIs that may potentiate psychedelics behaving as MAO-A and/or MAO-B substrates includephenelzine,tranylcypromine,isocarboxazid,moclobemide, andselegiline.[153] Combination of MAO-substrate psychedelics with MAOIs can result inoverdose and serioustoxicity, including death.[153][179] Other psychedelics, such asLSD, are not substrates of MAO and are not potentiated by MAOIs.[153] The extent to whichpsilocin (and by extensionpsilocybin) is metabolized by MAO, specifically MAO-A, is not fully clear, but has ranged from 4% to 33% in different studies based onmetaboliteexcretion.[181][81][87] However, circulating levels of the deaminated metabolite of psilocin are far higher than those of free unmetabolized psilocin with psilocybin administration.[182][183] An early clinical study of psilocybin in combination with short-term tranylcypromine pretreatment found that tranylcypromine marginally potentiated theperipheral effects of psilocybin, includingpressor effects andmydriasis, 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.[184][185][186]
Some psychedelics are substrates ofcytochrome P450 (CYP450)enzymes, for instance LSD being a substrate ofCYP2D6 as well as of several other CYP450 enzymes.[153][187] As such, CYP450inhibitors may increaseexposure to CYP450-substrate psychedelics such as LSD and thereby potentiate their effects as well as risks.[153][187] A clinical study found that administration of LSD to people takingparoxetine, aselective serotonin reuptake inhibitor (SSRI) and strong CYP2D6 inhibitor, increased LSD exposure by about 1.5-fold.[187] The combination was well-tolerated and did not modify the pleasant subjective effects or physiological effects of LSD, whereas negative effects of LSD, including "bad drug effect",anxiety, andnausea, were reduced.[187] Similarly to the findings with a strong CYP2D6 inhibitor, apharmacogenomic clinical study with LSD found that LSD levels were 75% higher in people with non-functional CYP2D6 (poor metabolizers) compared to those with functional CYP2D6.[153][188]
A high rate ofseizures has been reported when people onlithium have taken serotonergic psychedelics.[184][193][194] In an analysis of online reports, 47% of 62accounts reported seizures when a psychedelic was taken while on lithium.[184][193][194] The mechanism of this interaction is unclear.[184][194]
In animals, potency forstimulus generalization to the psychedelicDOM indrug discrimination tests is strongly correlated with serotonin 5-HT2A receptor affinity.[196][11] Non-selective serotonin 5-HT2A receptor antagonists, like ketanserin andpirenperone, and selective serotonin 5-HT2A receptor antagonists, likevolinanserin (MDL-100907), abolish the stimulus generalization of psychedelics in drug discrimination tests.[196] Conversely, serotonin5-HT2B and5-HT2C receptor antagonists are ineffective.[196] The potencies of serotonin 5-HT2 receptor antagonists in blocking psychedelic substitution are strongly correlated with their serotonin 5-HT2A receptor affinities.[196] Highly selective serotonin 5-HT2A receptor agonists have recently been developed and show stimulus generalization to psychedelics, whereas selective serotonin 5-HT2C receptor agonists do not do so.[196] Thehead-twitch response (HTR) is induced by serotonergic psychedelics and is a behavioral proxy of psychedelic-like effects in animals.[196][198] The HTR is invariably induced by serotonergic psychedelics, is blocked by selective serotonin 5-HT2A receptor antagonists, and is abolished in serotonin 5-HT2A receptorknockout mice.[196][11] In addition, there is a strong correlation between hallucinogenic potency in humans and potency in the HTR assay.[11][199] 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 aslisuride.[196] In accordance with the preceding animal and human findings, it has been said that the evidence that the serotonin 5-HT2A receptor mediates the hallucinogenic effects of serotonergic psychedelics is overwhelming.[11]
The serotonin 5-HT2A receptor activates several downstreamsignaling pathways.[11][200][201] These include theGq,β-arrestin2, and other pathways.[11][201] Activation of both the Gq and β-arrestin2 pathways have been implicated in mediating the hallucinogenic effects of serotonergic psychedelics.[11][200][202] However, subsequently, activation of the Gq pathway and not β-arrestin2 has been implicated.[201][200][202][131][203] Interestingly, Gq signaling appeared to mediate hallucinogenic-like effects, whereas β-arrestin2 mediatedreceptor downregulation andtachyphylaxis.[201][203] The lack of psychedelic effects with non-hallucinogenic serotonin 5-HT2A receptor agonists may be due topartial agonism of the serotonin 5-HT2A receptor withefficacy insufficient to produce psychedelic effects or may be due tobiased agonism of the serotonin 5-HT2A receptor.[196] There appears to be a threshold level of Gq activation (in terms ofintrinsic activity, withEmaxTooltip maximal efficacy >70%) required for production of hallucinogenic effects.[146][202][203]Full agonists andpartial agonists above this threshold are psychedelic 5-HT2A receptor agonists, whereas partial agonists below this threshold, such as lisuride,2-bromo-LSD,6-fluoro-DET,6-MeO-DMT, andAriadne, are non-hallucinogenic 5-HT2A receptor agonists.[146][203][158][157][123] In addition, biased agonists that activate β-arrestin2 signaling but not Gq signaling, such asITI-1549,IHCH-7086, and25N-N1-Nap, are non-hallucinogenic serotonin 5-HT2A receptor agonists.[146][203][204]
The hallucinogenic effects of serotonergic psychedelics may be critically mediated by serotonin 5-HT2A receptor activation in themedial prefrontal cortex (mPFC).[196]Layer Vpyramidal neurons in this area are especially discussed.[196][205] Activation of serotonin 5-HT2A receptors in the mPFC results in marked excitatory and inhibitory effects as well as increased release ofglutamate andGABA.[196] Direct injection of serotonin 5-HT2A receptor agonists into the mPFC produces the HTR.[196] Drugs that suppress glutamatergic activity in the mPFC, includingAMPA receptor antagonists,metabotropic glutamatemGlu2/3 receptor agonists,μ-opioid receptor agonists, andadenosineA1 receptor agonists, block or suppress many of the neurochemical and behavioral effects of serotonergic psychedelics, including the HTR.[196][206] Metabotropic glutamate mGlu2 receptors are primarily expressed aspresynapticautoreceptors and have inhibitory effects on glutamate release.[196][207] Serotonergic psychedelics have been found to producefrontal cortexhyperactivity in humans in PET andsingle-photon emission computed tomography (SPECT) imaging studies.[196] The PFC projects to many other cortical and subcortical brain areas, such as thelocus coeruleus,nucleus accumbens, andamygdala, among others, and activation of the PFC by serotonergic psychedelics may thereby indirectly modulate these areas.[196] In addition to the PFC, there is moderate to high expression of serotonin 5-HT2A receptors in theprimary visual cortex (V1), as well as expression of the serotonin 5-HT2A receptor in other visual areas, and activation of these receptors may contribute to or mediate the visual effects of serotonergic psychedelics.[196][11][208][209][210] Serotonergic psychedelics also directly or indirectly modulate a variety of other brain areas, like theclaustrum, and this may be involved in their effects as well.[11][211][212]
Serotonin, as well as drugs that increase serotonin levels, like theserotonin precursor5-hydroxytryptophan (5-HTP),serotonin reuptake inhibitors, andserotonin releasing agents, are non-hallucinogenic in humans despite increasing activation of serotonin 5-HT2A receptors.[207][213][214][215] Serotonin is ahydrophilic molecule which cannot easily crossbiological membranes withoutactive transport, and the serotonin 5-HT2A receptor is usually expressed as acell surface receptor that is readily accessible to extracellular serotonin.[213][215] The HTR, a behavioral proxy of psychedelic-like effects, appears to be mediated by activation ofintracellularlyexpressed serotonin 5-HT2A receptors in a population of mPFC neurons that do not also express theserotonin transporter (SERT) and hence cannot be activated by serotonin.[213][215] In contrast to serotonin, serotonergic psychedelics are morelipophilic than serotonin and are able to readily enter these neurons and activate the serotonin 5-HT2A receptors within them.[213][215] Artificial expression of the SERT in this population of neurons in animals resulted in a serotonin releasing agent that doesn't normally produce the HTR being able to do so.[215] Although serotonin itself is non-hallucinogenic, at very high concentrations achieved pharmacologically (e.g., injected into the brain or with massive doses of 5-HTP) it can produce psychedelic-like effects in animals by beingmetabolized byindolethylamineN-methyltransferase (INMT) into more lipophilicN-methylated tryptamines likeN-methylserotonin andbufotenin (N,N-dimethylserotonin).[216][198][207][217][213][215]
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 serotonin5-HT1A,5-HT1B, 5-HT2B, and 5-HT2C receptors among many others, may additionally contribute to and modulate their effects.[196][250] Certain psychedelics, including LSD and psilocin, have been reported to act as highlypotentpositive allosteric modulators of thetropomyosin receptor kinase B (TrkB), one of the signaling receptors ofbrain-derived neurotrophic factor (BDNF).[221][251][250][252] However, subsequent studies failed to reproduce these findings and instead found no interaction of LSD or psilocin with TrkB.[253] Moreover, the psychoplastogenic effects of serotonergic psychedelics, includingdendritogenesis,spinogenesis, andsynaptogenesis, appear to be mediated by activation of serotonin 5-HT2A receptors, whereas psychedelics do not generally stimulateneurogenesis.[221][220][250]
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 oroff-target activity; (2) differences infunctional selectivity for different serotonin 5-HT2A receptor downstream signaling pathways; and (3) differences in patterns or balances ofdistribution to different brain areas.[13][4][107][254]
Lysergamides areergoline derivatives related to theergot alkaloids. They are notable in containing both tryptamine and phenethylamine within theirchemical structures. As such, ergolines and lysergamides may be considered structurally related to the monoamine neurotransmitters. Many ergolines and lysergamides act as highly promiscuous ligands ofmonoamine receptors, including ofserotonin,dopamine, andadrenergic receptors. Some lysergamides are efficacious serotonin 5-HT2A receptor agonists and thereby produce psychedelic effects. Examples of psychedelic lysergamides includelysergic acid diethylamide (LSD),ergine (lysergic acid amide; LSA),isoergine (isolysergic acid amide; iso-LSA),ETH-LAD,AL-LAD,1P-LSD,1S-LSD,ALD-52 (1A-LSD),LA-SS-Az (LSZ),ergonovine (ergometrine; lysergic acid propanolamide),methylergometrine (methylergonovine), andmethysergide (methylmethylergonovine), among others.[13] Ergine, isoergine, and ergonovine occur naturally inmorning glories and certainfungi likeergot andPeriglandula species, while others like LSD aresynthetic. LSD is among the mostpotent psychedelics, as well as psychoactive drugs in general, that are known.[13]
Austrian anthropologist andethnobotanist Blas Pablo Reko, traveling throughCentral andSouth America, wrote of the use of teonanacatl by native Mexican people inOaxaca in 1919.[271] Reko subsequently sent samples of teonanacatl (Psilocybe mexicana) as well asIpomoea violacea (morning glory) seeds toSwedish anthropologistHenry Wassén in 1937.[271] Reko had obtained the mushroom sample from AustrianengineerRobert Weitlaner who was working inMexico.[271] Eventually, Wassén forwarded Reko and Weitlaner's mushroom sample toHarvard University, where the mushrooms came to the attention of American ethnobotanistRichard Evans Schultes.[271][88] However, they had decomposed so badly that they could not be identified.[271][88] Prior to Wassén obtaining specimens around 1936, the existence of teonanacatl was very controversial and was debated and even denied by some.[88] In 1938, a small group of Westerners, which included Weitlaner's daughter and American anthropologistJean Basset Johnson, attended a mushroom ceremony.[271][88] They were the first Westerners known to do so and described the event.[271][88] Schultes published reviews of teonanacatl being a hallucinogenic mushroom in the late 1930s.[271][290] Schultes obtained specimens of three of the hallucinogenic mushrooms used in ceremonies, includingPsilocybe caerulescens,Panaeolus campanulatus, andStropharia cubensis, but further investigations of the mushrooms were interrupted byWorld War II.[88]
Schultes described the indigenous and shamanic use ofdimethyltryptamine (DMT)-containing psychedelic plants in 1954 and also described the use of hallucinogenicmorning glories in the 1950s.[271] The psychedelic effects of synthesized DMT were described byHungarian chemist and psychiatristStephen Szára in 1956.[279][300][271][301][302] Osmond described the hallucinogenic and other effects of morning glory seeds in clinical studies in 1955.[254] Hofmann identified and described ergine and isoergine as the active constituents of morning glory seeds in 1960.[270][303][304][305] Their hallucinogenic effects were first described by Hofmann in 1963.[254][304]
In 1952, couple and amateurethnomycologistsR. Gordon Wasson andValentina Wasson learned of the ritual use of hallucinogenic mushrooms in the 16th century in Mexico from the published work of Schultes.[88][306] They made several trips to Mexico in search of the mushrooms.[88][306] In mid-1955, the Wassons participated in a mushroom ceremony withMazateccuranderaMaria Sabina inHuautla de Jiménez, Oaxaca, Mexico.[88][306] Gordon Wasson published his experience in an article forLife magazine titled "Seeking the Magic Mushroom" in 1957, while Valentina Wasson published her experience as "I Ate the Sacred Mushroom" inThis Week magazine the same year.[88][306] Later in 1957, a second expedition was made by the Wassons to Mexico withFrench mycologistRoger Heim.[88] Heim identified several of the mushrooms as belonging to thegenusPsilocybe.[88] They collected samples of the mushrooms and Heim sent a sample to Hofmann.[88] Hofmann identified psilocybin as the active constituent in 1958 and developed achemical synthesis for it.[88][279][271] Sandoz Pharmaceuticals began distributingtablets of psilocybin under the brand name Indocybin in 1960.[88]
French scientistsCésaire Phisalix and Gabriel Bertrand isolatedbufotenin fromBufo toads in 1893 and named it.[307][308][309] The compound was first isolated to purity by Austrian chemist Hans Handovsky in 1920.[307] Clinical studies assessed the effects of bufotenin and were published starting in 1956.[307][310][178] However, the findings of these studies were conflicting, and bufotenin developed a long-standing reputation of being inactive and toxic.[307][310][178] American ethnobotanistJonathan Ott and colleagues subsequently showed in 2001 that bufotenin is in fact a psychedelic and does not necessarily produce major adverse effects, although markednausea andvomiting are prominent.[178][311][312] The related psychedelic5-MeO-DMT was first synthesized byJapanese chemists Toshio Hoshino and Kenya Shimodaira in 1935.[313][314] It was later isolated fromDictyoloma incanescens in 1959.[314] Subsequently, 5-MeO-DMT was isolated from numerous other plants and fungi.[314][313] The compound was isolated from the skin of toads, specifically theColorado River toad (Incilius alvarius, formerlyBufo alvarius), byItalian chemist and pharmacologistVittorio Erspamer in 1967.[313][314][315] A 1984 pamphlet by Albert Most (real name Ken Nelson), titledBufo 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.[316][317][314]
Mid-20th-century research, popularization, and prohibition
Extensive clinical research on almost exclusively LSD, mescaline, and psilocybin was conducted in the 1950s and 1960s.[279] However, the amount of research done on psilocybin was nowhere near that of LSD.[279] Psychedelics like LSD started to become more visible in the mainstream sphere in the 1950s.[279]English writerAldous Huxley tried mescaline, which he had obtained from English psychiatristHumphry Osmond, in 1953, and described its effects in his 1954 bookThe Doors of Perception.[279][318][319]British politicianChristopher Mayhew tried mescaline in 1955 and this was reported on in the media.[270] Osmond, in correspondence with Huxley, coined the term "psychedelic", meaning "mind-manifesting", in 1956.[320][319]
Psychedelics became widelyrecreationally used by the public, for instance by thehippies, during thecounterculture of the 1960s.[271] Harvard psychologistsTimothy Leary andRichard Alpert began studying LSD and psilocybin in the early 1960s and ended up being fired from the university in 1963.[279] Sandoz Laboratories ceased distribution of Delysid in 1965.[279] Psychedelics becamecontrolled substances in theUnited States and internationally in the 1960s and 1970s.[279][270] By the end of the 1960s, psychedelic clinical research throughout the world had largely ceased.[271]
Alexander Shulgin, an American chemist working atDow Chemical Company, tried mescaline by 1960.[121][337] 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.[121][337] Starting in the 1960s, Shulginsynthesized and gradually described hundreds of novel synthetic psychedelics as well as entactogens inscientific publications and published books such asPiHKAL (1991) andTiHKAL (1997).[279][270][121] Notable major examples of these drugs have included theDOx psychedelicDOM, the2C psychedelic2C-B, and theMDxx entactogenMDMA, among others.[270][43][324] 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.[338][339][324] Instead, Shulgin had merely served to help popularize and spread awareness about MDMA and its unique effects.[338][339][324]
MDMA became outlawed in the mid-1980s.[270][340] In response to this, theMultidisciplinary Association for Psychedelic Studies (MAPS) was founded byRick Doblin in 1986 and began efforts to develop MDMA and other psychedelics as medicines.[340] American chemistDavid E. Nichols has developed numerous novel psychedelics and entactogens from the 1970s to present.[341][342][343]Swiss chemistDaniel Trachsel, sometimes referred to as the "German Shulgin", has also developed and published numerous novel psychedelics as well as entactogens since the 1990s.[344][345]
NBOMe psychedelics such as25I-NBOMe, derived fromstructural modification of 2C psychedelics, were first described by Ralf Heim and colleagues by 2000.[346][347][348] 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.[349][350][351]
Serotonin, also known as 5-hydroxytryptamine (5-HT) and originally called enteramine, was discovered byVittorio Erspamer in the 1930s[352] and its structural identity was fully characterized in the late 1940s and early 1950s.[352][353][354] Serotonin was discovered in thebrain byBetty Twarog andIrvine Page in 1953.[352][353][355] It was quickly noticed that LSD contains the serotonin-liketryptamine scaffold within itschemical structure.[352][353] Shortly thereafter, it was found that LSD showed serotonin-like effects and couldantagonize serotonin in certainassays.[352][353] Studies in the 1960s and 1970s showed that variousserotonin antagonists could block the behavioral effects of psychedelics in animals.[356][4][357][358][359] Theserotonin receptors, including the serotonin5-HT2 receptors, were elucidated by the late 1970s.[352][353][360] Mediation of the hallucinogenic effects of psychedelics by serotonin 5-HT2 receptoragonism was proposed byRichard Glennon and other researchers by the early 1980s.[356][196][4][361][362] The human serotonin5-HT2A receptor was firstcloned in 1990.[352][363] The hallucinogenic effects of psilocybin in humans were shown to be blocked by theselective serotonin 5-HT2A receptor antagonistketanserin 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.[352][364]
Since the prohibition of the 1960s and 1970s, clinical research into psychedelics started to resume by the 1990s, for instance the studies of DMT byRick Strassman, and they have once again started to be developed aspharmaceutical drugs for potential medical use.[273][279][300][365] A so-called "psychedelic renaissance", in which interest in psychedelics has resurged, began in the late 2010s and early 2020s.[366][367][368]Michael Pollan's 2018 bookHow to Change Your Mind, which was alsoadapted into a Netflix series in 2022, was especially impactful in terms of increasing mainstream awareness and interest in psychedelics.[369][370][371] More than 100clinical trials of four major psychedelics, including psilocybin,LSD,ayahuasca, andMDMA, were identified as being underway in 2024.[370][372]
The termpsychedelic was coined by the psychiatristHumphrey Osmond during written correspondence with authorAldous Huxley (written in a rhyme: "To fathom Hell or soar angelic/Just take a pinch of psychedelic."[373]) and presented to the New York Academy of Sciences by Osmond in 1957.[374] It is irregularly[375] derived from theGreek 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.[376] The term was loathed by AmericanethnobotanistRichard Schultes but championed by American psychologistTimothy Leary.[377]
Aldous Huxley had suggested his own coinagephanerothyme (Greekphaneroein- "to make manifest or visible" and Greekthymos "soul", thus "to reveal the soul") to Osmond in 1956.[378] Recently, the termentheogen (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.[4]
In 2004,David E. Nichols wrote the following about the nomenclature used for psychedelic drugs:[4]
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 termpsychedelic 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 termentheogen, derived from the Greek wordentheos, 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.
Robin Carhart-Harris andGuy Goodwin write that the termpsychedelic is preferable tohallucinogen for describing classical psychedelics because of the termhallucinogen's "arguably misleading emphasis on these compounds' hallucinogenic properties."[379]
While the termpsychedelic is most commonly used to refer only to serotonergic hallucinogens,[5][13][380][59] it is sometimes used for a much broader range of drugs, includingentactogens,dissociatives, and atypical hallucinogens/psychoactives such asAmanita muscaria,Cannabis sativa,Nymphaea nouchali andSalvia divinorum.[25][381] Thus, the termserotonergic psychedelic is sometimes used for the narrower class.[382][383] It is important to check the definition of a given source.[4] This article uses the more common, narrower definition ofpsychedelic.
Many psychedelics are classified under Schedule I of the United NationsConvention on Psychotropic Substances of 1971 as drugs with the greatest potential to cause harm and no acceptable medical uses.[390] In addition, many countries have analogue laws; for example, in the United States, theFederal Analogue Act of 1986 automatically forbids any drugs sharing similar chemical structures or chemical formulas to prohibited substances if sold for human consumption.[391]
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.[392]
U.S. states such as Oregon and Colorado have also instituted decriminalization and legalization measures for accessing psychedelics[393] and states like New Hampshire are attempting to do the same.[394] 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 withalcohol andcannabis).[395]
Psychedelic substances which may have therapeutic uses include psilocybin, LSD, and mescaline.[26] During the 1950s and 1960s, lack ofinformed consent in some scientific trials on psychedelics led to significant, long-lasting harm to some participants.[26] 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.[26] Psychedelics, particularly psilocybin, show potential therapeutic benefits for depression, anxiety, and other mental disorders, with generally mild and transient adverse effects.[396]
It has long been known that psychedelics promote neurite growth andneuroplasticity and are potentpsychoplastogens.[397][398][399] There is evidence that psychedelics induce molecular and cellular adaptations related to neuroplasticity and that these could potentially underlie therapeutic benefits.[400][401]
TheBritishcritical psychiatristJoanna Moncrieff has critiqued the use and study of psychedelic and related drugs likepsilocybin,MDMA, andketamine for treatment of psychiatric disorders, highlighting concerns including excessive hype around these drugs, questionable biologically-based theories of benefit, blurred lines between medical and recreational use, flawed clinical trial findings, financial conflicts of interest, strong expectancy effects and large placebo responses, small and short-term benefits over placebo, and their potential for difficult experiences and adverse effects.[402]
^abR. R. Griffiths, W. A. Richards, U. McCann, R. Jesse (7 July 2006). "Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance".Psychopharmacology.187 (3):268–283.doi:10.1007/s00213-006-0457-5.PMID16826400.S2CID7845214.
^McKenna, Terence (1992).Food of the Gods: The Search for the Original Tree of Knowledge A Radical History of Plants, Drugs, and Human Evolution
^W. Davis (1996),One River: Explorations and Discoveries in the Amazon Rain Forest. New York, Simon and Schuster, Inc. p. 120.
^abcdefghNichols DE (2018).Chemistry and Structure-Activity Relationships of Psychedelics. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 1–43.doi:10.1007/7854_2017_475.ISBN978-3-662-55878-2.PMID28401524.Although LSD is the most well-known psychedelic, only a very few structural modifications can be made to its structure, and nearly all of those attenuate its activity by about an order of magnitude. In addition, there is a paucity of structure–activity data for ergolines, principally due to the synthetic difficulty inherent in their chemistry. [...] Although LSD is the most potent psychedelic agent in humans, its affinity and potency at the human 5-HT2A receptor is rather unremarkable compared with much simpler molecules such as DOI. [...] Because of its structural complexity and tedious approaches to its total synthesis, only a few structural modifications of LSD have been reported. [...] Unfortunately, only a few of them have been assessed in human psychopharmacology, most being much less active than LSD itself.
^Siegel GJ (11 November 2005).Basic neurochemistry: Molecular, cellular and medical aspects (7th ed.). Amsterdam: Elsevier Science.ISBN978-0-08-047207-2.OCLC123438340.
^abLe Dain G (1971).The Non-medical Use of Drugs: Interim Report of the Canadian Government's Commission of Inquiry. p. 106.Physical dependence does not develop to LSD
^abcdBender D, Hellerstein DJ (2022). "Assessing the risk–benefit profile of classical psychedelics: a clinical review of second-wave psychedelic research".Psychopharmacology.239 (6):1907–1932.doi:10.1007/s00213-021-06049-6.PMID35022823.S2CID245906937.
^abcReiff CM, Richman EE, Nemeroff CB, Carpenter LL, Widge AS, Rodriguez CI, et al. (May 2020). "Psychedelics and Psychedelic-Assisted Psychotherapy".The American Journal of Psychiatry.177 (5):391–410.doi:10.1176/appi.ajp.2019.19010035.PMID32098487.S2CID211524704.
^Freye E (2009).Pharmacology and abuse of cocaine, amphetamines, ecstasy and related designer drugs: a comprehensive review on their mode of action, treatment of abuse and intoxication. Dordrecht: Springer.ISBN978-90-481-2448-0.OCLC489218895.
^Strassman RJ, Qualls CR, Uhlenhuth EH, Kellner R (1994-02-01). "Dose-Response Study of N,N-Dimethyltryptamine in Humans: II. Subjective Effects and Preliminary Results of a New Rating Scale".Archives of General Psychiatry.51 (2):98–108.doi:10.1001/archpsyc.1994.03950020022002.ISSN0003-990X.PMID8297217.
^abLuethi D, Liechti ME (April 2020)."Designer drugs: mechanism of action and adverse effects".Arch Toxicol.94 (4):1085–1133.Bibcode:2020ArTox..94.1085L.doi:10.1007/s00204-020-02693-7.PMC7225206.PMID32249347.In one of the few clinical studies of a designer drug, 4-bromo-2,5-dimethoxyphenylethylamine (2C-B) was shown to induce euphoria, well-being, and changes in perception, and to have mild stimulant properties (Gonzalez et al. 2015). 2C-B may thus be classified as a psychedelic with entactogenic properties, an effect profile that is similar to various other phenethylamine psychedelics (Shulgin and Shulgin 1995).
^abWills B, Erickson T (9 March 2012). "Psychoactive Phenethylamine, Piperazine, and Pyrrolidinophenone Derivatives". In Barceloux DG (ed.).Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. Wiley. pp. 156–192.doi:10.1002/9781118105955.ch10.ISBN978-0-471-72760-6.DOSE EFFECT: Anecdotal data suggests that recreational doses of 2C-B range from 4—30 mg with lower doses (4—10 mg) producing entactogenic effects, whereas high doses (10— 20 mg) cause psychedelic and sympathomimetic effects.
^abcdeOeri HE (May 2021)."Beyond ecstasy: Alternative entactogens to 3,4-methylenedioxymethamphetamine with potential applications in psychotherapy".Journal of Psychopharmacology.35 (5):512–536.doi:10.1177/0269881120920420.PMC8155739.PMID32909493.While an argument can be made that compounds like 4-bromo-2,5-dimethoxyphenethylamine (2CB) or N,N-diisopropyl-5-methoxytryptamine (5-MeO-DiPT) are also entactogenic, and they have been described as such in the past (González et al., 2015; Palamar and Acosta, 2020; Schifano et al., 2019), they were also excluded due to their high affinity as agonists at post-synaptic 5-HT2 and 5-HT1A receptors (Fantegrossi et al., 2006; Nugteren-van Lonkhuyzen et al., 2015; Taylor et al., 1986; Villalobos et al., 2004), which would indicate that their effects also include a marked psychedelic component.
^Ismael Eduardo Apud Peláez. (2020).Ayahuasca: Between Cognition and Culture. Publicacions Universitat Rovira i Virgili.ISBN978-84-8424-834-7.OCLC1229544084.
^Romeo B, Karila L, Martelli C, Benyamina A (2020). "Efficacy of psychedelic treatments on depressive symptoms: A meta-analysis".Journal of Psychopharmacology.34 (10):1079–1085.doi:10.1177/0269881120919957.PMID32448048.S2CID218873949.
^Dupuis D, Veissière S (October 2022). "Culture, context, and ethics in the therapeutic use of hallucinogens: Psychedelics as active super-placebos?".Transcult Psychiatry.59 (5):571–578.doi:10.1177/13634615221131465.PMID36263513.
^van Elk M, Yaden DB (September 2022). "Pharmacological, neural, and psychological mechanisms underlying psychedelics: A critical review".Neurosci Biobehav Rev.140 104793.doi:10.1016/j.neubiorev.2022.104793.hdl:1887/3515020.PMID35878791.In addition, the strong prior expectations that many people have about psychedelics directly contribute to the psychedelic experience and as a consequence it has been suggested that psychedelics may act as a 'super-placebo' (Hartogsohn, 2016). Specifically, strong prior expectations (e.g., that a specific intervention will likely trigger a mystical experience) will increase the likelihood of having e.g., a mystical-type experience (Maij et al., 2019), and this placebo-effect is further boosted by the psychedelic-induced suggestibility.
^Kozlowska U, Nichols C, Wiatr K, Figiel M (July 2022). "From psychiatry to neurology: Psychedelics as prospective therapeutics for neurodegenerative disorders".J Neurochem.162 (1):89–108.doi:10.1111/jnc.15509.PMID34519052.One dosing method of psychedelics is the use of so called "microdoses"—very low concentrations of various psychedelics that do not reach the threshold of perceivable behavioral effects. This is usually 10% of active recreational doses (e.g., 10–15 µg of LSD, or 0.1–0.3 g of dry "magic mushrooms") taken up to three times per week.
^Pepe M, Hesami M, de la Cerda KA, Perreault ML, Hsiang T, Jones AM (December 2023). "A journey with psychedelic mushrooms: From historical relevance to biology, cultivation, medicinal uses, biotechnology, and beyond".Biotechnol Adv.69 108247.doi:10.1016/j.biotechadv.2023.108247.PMID37659744.
^abcdefghijklmnopqrNichols DE (October 2020)."Psilocybin: from ancient magic to modern medicine".J Antibiot (Tokyo).73 (10):679–686.doi:10.1038/s41429-020-0311-8.PMID32398764.Total psilocybin and psilocin levels in species known to be used recreationally varied from 0.1% to nearly 2% by dry weight [8]. The medium oral dose of psilocybin is 4–8 mg, which elicits the same symptoms as the consumption of about 2 g of dried Psilocybe Mexicana [9].
^Goff R, Smith M, Islam S, Sisley S, Ferguson J, Kuzdzal S, et al. (February 2024). "Determination of psilocybin and psilocin content in multiple Psilocybe cubensis mushroom strains using liquid chromatography - tandem mass spectrometry".Anal Chim Acta.1288 342161.Bibcode:2024AcAC.128842161G.doi:10.1016/j.aca.2023.342161.PMID38220293.A method for clinical potency determination of psilocybin and psilocin in hallucinogenic mushroom species Psilocybe cubensis was developed using liquid chromatography with tandem mass spectrometry (LC-MS/MS). Five strains of dried, intact mushrooms were obtained and analyzed: Blue Meanie, Creeper, B-Plus, Texas Yellow, and Thai Cubensis. [...] From most to least potent, the study found that the average total psilocybin and psilocin concentrations for the Creeper, Blue Meanie, B+, Texas Yellow, and Thai Cubensis strains were 1.36, 1.221, 1.134, 1.103, and 0.879 % (w/w), respectively.
^Wolbach AB, Miner EJ, Isbell H (1962). "Comparison of psilocin with psilocybin, mescaline and LSD-25".Psychopharmacologia.3 (3):219–223.doi:10.1007/BF00412109.PMID14007905.Psilocin is approximately 1.4 times as potent as psilocybin. This ratio is the same as that of the molecular weights of the two drugs.
^Preller KH, Vollenweider FX (2016). "Phenomenology, Structure, and Dynamic of Psychedelic States". In Adam L. Halberstadt, Franz X. Vollenweider, David E. Nichols (eds.).Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. Berlin, Heidelberg: Springer Berlin Heidelberg. pp. 221–256.doi:10.1007/7854_2016_459.ISBN978-3-662-55878-2.PMID28025814.
^Rogge T (May 21, 2014),Substance use – LSD, MedlinePlus, U.S. National Library of Medicine,archived from the original on July 28, 2016, retrievedJuly 14, 2016
^CESAR (29 October 2013),LSD, Center for Substance Abuse Research, University of Maryland, archived fromthe original on July 15, 2016, retrieved14 July 2016
^abKuypers KP (2024)."Microdosing Psychedelics as a Promising New Pharmacotherapeutic".Modern CNS Drug Discovery. Cham: Springer Nature Switzerland. pp. 407–436.doi:10.1007/978-3-031-61992-2_26.ISBN978-3-031-61991-5. Retrieved28 May 2025.Interestingly, users sometimes attribute other effects to different psychedelics, in which LSD is more associated with cognitive and/or stimulant effects and psilocybin with emotional or well-being effects (Anderson et al. 2019b; Johnstad 2018). This stronger stimulant character of LSD compared to psilocybin was seen by some as an advantage while others experienced it as uncomfortable (Johnstad 2018). [...] Additionally, McGlothlin et al. (1967) showed that LSD (25 mcg) indeed induces stimulant effects, as the effects were similar to those of amphetamine (20 mg) (McGlothlin et al. 1967). Notwithstanding this does not confirm that psilocybin and LSD would have dissimilar effects; it rather supports the claims by users that LSD in low doses has stimulant effects (Johnstad 2018; Anderson et al. 2019a). [...] Decades earlier, Albert Hofmann, the "discoverer" of LSD and its hallucinogenic effects, mentioned that "very small doses, perhaps 25 micrograms," could be useful as an antidepressant (Ghose 2015; Horowitz 1976) or as a substitute for Ritalin (Fadiman 2017; Horowitz 1976).
^abcdefBaggott MJ (1 October 2023)."Learning about STP: A Forgotten Psychedelic from the Summer of Love"(PDF).History of Pharmacy and Pharmaceuticals.65 (1):93–116.doi:10.3368/hopp.65.1.93.ISSN2694-3034. Retrieved26 January 2025.The Grateful Dead learned they could use small amounts as a stimulant, an effect they used extensively during the recording of the album Aoxomoxoa in 1968 and 1969.143 The use of lower doses of DOM echoed DOET's "psychic energizer" effects and may be the first documented use of subpsychedelic doses of a psychedelic for cognitive enhancement, a practice that is now called microdosing.144
^abMajić T, Schmidt TT, Gallinat J (March 2015). "Peak experiences and the afterglow phenomenon: when and how do therapeutic effects of hallucinogens depend on psychedelic experiences?".J Psychopharmacol.29 (3):241–253.doi:10.1177/0269881114568040.PMID25670401.
^abcChisamore N, Kaczmarek E, Le GH, Wong S, Orsini DK, Mansur R, et al. (26 April 2024). "Neurobiology of the Antidepressant Effects of Serotonergic Psychedelics: A Narrative Review".Current Treatment Options in Psychiatry.11 (2). Springer Science and Business Media LLC:90–105.doi:10.1007/s40501-024-00319-8.ISSN2196-3061.
^Kinderlehrer DA (2025)."Mushrooms, Microdosing, and Mental Illness: The Effect of Psilocybin on Neurotransmitters, Neuroinflammation, and Neuroplasticity".Neuropsychiatr Dis Treat.21:141–155.doi:10.2147/NDT.S500337.PMC11787777.PMID39897712.Mason et al studied the immune status of healthy humans after administration of oral psilocybin compared with placebo, and found an immediate reduction in the plasma concentration of TNF-α in the treatment group.Citation106 Although there was no immediate change in IL-6 and CRP, at seven days these levels were reduced while TNF-α concentrations had returned to baseline. They also documented an association between the degree of reduction of IL-6 and CRP and the positive effect on the participants' mood and social activity.
^abvan Amsterdam J, Opperhuizen A, van den Brink W (2011). "Harm potential of magic mushroom use: A review".Regulatory Toxicology and Pharmacology.59 (3):423–429.doi:10.1016/j.yrtph.2011.01.006.PMID21256914.
^Baggott MJ, Coyle JR, Erowid E, Erowid F, Robertson LC (1 March 2011). "Abnormal visual experiences in individuals with histories of hallucinogen use: A web-based questionnaire".Drug and Alcohol Dependence.114 (1):61–67.doi:10.1016/j.drugalcdep.2010.09.006.PMID21035275.
^abcTagen M, Mantuani D, van Heerden L, Holstein A, Klumpers LE, Knowles R (September 2023). "The risk of chronic psychedelic and MDMA microdosing for valvular heart disease".J Psychopharmacol.37 (9):876–890.doi:10.1177/02698811231190865.PMID37572027.
^Märcher Rørsted E, Jensen AA, Kristensen JL (November 2021). "25CN-NBOH: A Selective Agonist for in vitro and in vivo Investigations of the Serotonin 2A Receptor".ChemMedChem.16 (21):3263–3270.doi:10.1002/cmdc.202100395.PMID34288515.
^abcdefghDuan W, Cao D, Wang S, Cheng J (January 2024). "Serotonin 2A Receptor (5-HT2AR) Agonists: Psychedelics and Non-Hallucinogenic Analogues as Emerging Antidepressants".Chem Rev.124 (1):124–163.doi:10.1021/acs.chemrev.3c00375.PMID38033123.
^abPeplow M (2024). "Next-generation psychedelics: should new agents skip the trip?".Nature Biotechnology.42 (6):827–830.doi:10.1038/s41587-024-02285-1.ISSN1087-0156.PMID38831049.Another problem is that some classical psychedelics are also agonists of the 5-HT2B receptor, which is expressed in heart tissue and can cause long-term cardiac problems. Kristensen's company Lophora aims to solve that with its lead compound LPH-5, a phenylethylamine derivative with an extra molecular ring that makes it less flexible. LPH-5 has a 60-fold higher selectivity for 5-HT2A over 5-HT2B.
^abMalcolm B, Thomas K (June 2022). "Serotonin toxicity of serotonergic psychedelics".Psychopharmacology (Berl).239 (6):1881–1891.doi:10.1007/s00213-021-05876-x.PMID34251464.
^abTap SC, Thomas K, Páleníček T, Stenbæk DS, Oliveira-Maia AJ, van Dalfsen J, et al. (September 2025)."Concomitant use of antidepressants and classic psychedelics: A scoping review".J Psychopharmacol.39 (10) 02698811251368360: 2698811251368360.doi:10.1177/02698811251368360.PMC12572353.PMID40937732.Importantly, the idea of increased risk for developing serotonin syndrome and/or serotonin toxicity, when [antidepressants (ADs)] are co-administered with high doses of psychedelics, has recently been challenged, in part because classic psychedelics are partial agonists of the 5-HT2A receptor and would also compete for serotonin binding (Malcolm and Thomas, 2022; Rickli et al., 2016; Sarparast et al., 2022). Based on this clinical rationale, the concomitant use of ADs and classic psychedelics may be preferred, or patients could temporarily reduce the dose of ADs around dosing days with psychedelics to have minimal interactions. Simultaneously, the competition for 5-HT2A receptors could impede the biological action of psychedelics during concomitant use of ADs and potentially limit efficacy (Halman et al., 2024), particularly as the 5-HT2A receptor induces neuroplasticity (Cameron et al., 2023; Ly et al., 2018; Vargas et al., 2023).{{cite journal}}: CS1 maint: article number as page number (link)
^abcdSuran M (February 2024). "Study Finds Hundreds of Reddit Posts on "Trip-Killers" for Psychedelic Drugs".JAMA.331 (8):632–634.doi:10.1001/jama.2023.28257.PMID38294772.
^abBrandt SD, Kavanagh PV, Twamley B, Westphal F, Elliott SP, Wallach J, et al. (February 2018)."Return of the lysergamides. Part IV: Analytical and pharmacological characterization of lysergic acid morpholide (LSM-775)".Drug Test Anal.10 (2):310–322.doi:10.1002/dta.2222.PMC6230476.PMID28585392.Additionally, pretreatment with the 5‐HT1A agonist buspirone (20 mg p.o.) markedly attenuates the visual effects of psilocybin in human volunteers.59 Although buspirone failed to completely block the hallucinogenic effects of psilocybin, the limited inhibition is not necessarily surprising because buspirone is a low efficacy 5‐HT1A partial agonist.60 The level of 5‐HT1A activation produced by buspirone may not be sufficient to completely counteract the stimulation of 5‐HT2A receptors by psilocin (the active metabolite of psilocybin). Another consideration is that psilocin acts as a 5‐HT1A agonist.30 If 5‐HT1A activation by psilocin buffers its hallucinogenic effects similar to DMT58 then competition between psilocin and a weaker partial agonist such as buspirone would limit attenuation of the hallucinogenic response.
^abPokorny T, Preller KH, Kraehenmann R, Vollenweider FX (April 2016). "Modulatory effect of the 5-HT1A agonist buspirone and the mixed non-hallucinogenic 5-HT1A/2A agonist ergotamine on psilocybin-induced psychedelic experience".Eur Neuropsychopharmacol.26 (4):756–766.doi:10.1016/j.euroneuro.2016.01.005.PMID26875114.
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^Gartner HT, Wan HZ, Simmons RE, Sollee DR, Sheikh S (November 2024). "Psychedelic mushroom-containing chocolate exposures: Case series".Am J Emerg Med.85:208–213.doi:10.1016/j.ajem.2024.09.038.PMID39288500.
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^Vojtĕchovský M, Hort V, Safratová V (October 1968). "Ovlvinĕní experimntálních psychóz po psilocybinu inhibitory MAO" [Influence of MAO inhibitors on psilocybine induced psychosis].Act Nerv Super (Praha) (in Czech).10 (3):278–279.PMID5702524.
^Bijl D (October 2004). "The serotonin syndrome".Neth J Med.62 (9):309–13.PMID15635814.Mechanisms of serotonergic drugs implicated in serotonin syndrome... Stimulation of serotonin receptors... LSD
^abHolze F, Liechti ME, Müller F (July 2024). "Pharmacological Properties of Psychedelics with a Special Focus on Potential Harms".Current Topics in Behavioral Neurosciences. Curr Top Behav Neurosci.doi:10.1007/7854_2024_510.PMID39080236.
^abKozlenkov A, González-Maeso J (2013). "Animal Models and Hallucinogenic Drugs".The Neuroscience of Hallucinations. New York, NY: Springer New York. pp. 253–277.doi:10.1007/978-1-4614-4121-2_14.ISBN978-1-4614-4120-5.
^abcdGumpper RH, Nichols DE (October 2024). "Chemistry/structural biology of psychedelic drugs and their receptor(s)".Br J Pharmacol bph.17361.doi:10.1111/bph.17361.PMID39354889.
^Marek GJ (2018). "Interactions of Hallucinogens with the Glutamatergic System: Permissive Network Effects Mediated Through Cortical Layer V Pyramidal Neurons".Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 107–135.doi:10.1007/7854_2017_480.ISBN978-3-662-55878-2.PMID28831734.
^abcHalberstadt AL, Geyer MA (2018). "Effect of Hallucinogens on Unconditioned Behavior".Behavioral Neurobiology of Psychedelic Drugs. Current Topics in Behavioral Neurosciences. Vol. 36. pp. 159–199.doi:10.1007/7854_2016_466.ISBN978-3-662-55878-2.PMC5787039.PMID28224459.[...] the 5-HT releasing drugs fenfluramine and p-chloroamphetamine (PCA) do produce a robust HTR (Singleton and Marsden 1981; Darmani 1998a). Fenfluramine and PCA are thought to act indirectly, by increasing carrier-mediated release of 5-HT, because the response can be blocked by inhibition of the 5-HT transporter (Balsara et al. 1986; Darmani 1998a) or by depletion of 5-HT (Singleton and Marsden 1981; Balsara et al. 1986). [...] Because indirect 5-HT agonists such as fenfluramine, PCA, and 5-HTP are not hallucinogenic (Van Praag et al. 1971; Brauer et al. 1996; Turner et al. 2006), their effects on HTR can potentially be classified as false-positive responses.
^Aqil M, Roseman L (February 2023). "More than meets the eye: The role of sensory dimensions in psychedelic brain dynamics, experience, and therapeutics".Neuropharmacology.223 109300.doi:10.1016/j.neuropharm.2022.109300.PMID36334767.
^Császár-Nagy N, Kapócs G, Bókkon I (July 2019). "Classic psychedelics: the special role of the visual system".Rev Neurosci.30 (6):651–669.doi:10.1515/revneuro-2018-0092.PMID30939118.
^Bressloff PC, Cowan JD, Golubitsky M, Thomas PJ, Wiener MC (March 2002). "What geometric visual hallucinations tell us about the visual cortex".Neural Comput.14 (3):473–491.doi:10.1162/089976602317250861.PMID11860679.
^abcdefVargas MV, Dunlap LE, Dong C, Carter SJ, Tombari RJ, Jami SA, et al. (February 2023)."Psychedelics promote neuroplasticity through the activation of intracellular 5-HT2A receptors".Science.379 (6633):700–706.Bibcode:2023Sci...379..700V.doi:10.1126/science.adf0435.PMC10108900.PMID36795823.In addition to promoting psychedelic-induced structural neuroplasticity, the intracellular population of 5-HT2ARs might also contribute to the hallucinogenic effects of psychedelics. When we administered a serotonin-releasing agent to wild type mice, we did not observe a HTR. However, the same drug was able to induce a HTR in mice expressing SERT on cortical neurons of the mPFC—a brain region known to be essential for the HTR (49). Thus, activation of intracellular cortical 5-HT2ARs may play a role in the subjective effects of psychedelics. This hypothesis is further supported by previous work demonstrating that a high dose of the serotonin precursor 5-hydroxytryptophan (5-HTP) induces a HTR in WT mice, which can be blocked by an N-methyltransferase inhibitor that prevents the metabolism of 5-HTP to N-methyltryptamines (50). Inhibition of N-methyltransferase failed to block the HTR induced by 5-MeO-DMT (50). Taken together, this work emphasizes that accessing intracellular 5-HT2ARs is important for 5-HT2AR agonists to produce a HTR.
^Schmid CL, Bohn LM (2018). "βArrestins: Ligand-Directed Regulators of 5-HT2A Receptor Trafficking and Signaling Events".5-HT2A Receptors in the Central Nervous System. Cham: Springer International Publishing. pp. 31–55.doi:10.1007/978-3-319-70474-6_2.ISBN978-3-319-70472-2.
^Werle I, Bertoglio LJ (December 2024). "Psychedelics: A review of their effects on recalled aversive memories and fear/anxiety expression in rodents".Neurosci Biobehav Rev.167 105899.doi:10.1016/j.neubiorev.2024.105899.PMID39305969.
^Ehrmann K, Allen JJ, Moreno FA (2022). "Psilocybin for the Treatment of Obsessive-Compulsive Disorders".Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. Vol. 56. pp. 247–259.doi:10.1007/7854_2021_279.ISBN978-3-031-12183-8.PMID34784024.
^Gomez-Escolar A, Folch-Sanchez D, Stefaniuk J, Swithenbank Z, Nisa A, Braddick F, et al. (October 2024). "Current Perspectives on the Clinical Research and Medicalization of Psychedelic Drugs for Addiction Treatments: Safety, Efficacy, Limitations and Challenges".CNS Drugs.38 (10):771–789.doi:10.1007/s40263-024-01101-3.PMID39033264.
^Nichols DE, Johnson MW, Nichols CD (February 2017). "Psychedelics as Medicines: An Emerging New Paradigm".Clin Pharmacol Ther.101 (2):209–219.doi:10.1002/cpt.557.PMID28019026.
^Flanagan TW, Nichols CD (2022). "Psychedelics and Anti-inflammatory Activity in Animal Models".Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. Vol. 56. pp. 229–245.doi:10.1007/7854_2022_367.ISBN978-3-031-12183-8.PMID35546383.
^Castellanos JP, Woolley C, Bruno KA, Zeidan F, Halberstadt A, Furnish T (July 2020). "Chronic pain and psychedelics: a review and proposed mechanism of action".Reg Anesth Pain Med.45 (7):486–494.doi:10.1136/rapm-2020-101273.PMID32371500.
^Goel A, Rai Y, Sivadas S, Diep C, Clarke H, Shanthanna H, et al. (October 2023). "Use of Psychedelics for Pain: A Scoping Review".Anesthesiology.139 (4):523–536.doi:10.1097/ALN.0000000000004673.PMID37698433.
^Schindler EA (2022). "Psychedelics in the Treatment of Headache and Chronic Pain Disorders".Disruptive Psychopharmacology. Current Topics in Behavioral Neurosciences. Vol. 56. pp. 261–285.doi:10.1007/7854_2022_365.ISBN978-3-031-12183-8.PMID35546382.
^Schindler EA, Hendricks PS (2023). "Adapting psychedelic medicine for headache and chronic pain disorders".Expert Rev Neurother.23 (10):867–882.doi:10.1080/14737175.2023.2246655.PMID37652000.
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^Jain MK, Gumpper RH, Slocum ST, Schmitz GP, Madsen JS, Tummino TA, et al. (July 2025)."The polypharmacology of psychedelics reveals multiple targets for potential therapeutics"(PDF).Neuron.113 (19): 3129–3142.e9.doi:10.1016/j.neuron.2025.06.012.PMID40683247.Recent studies have suggested that psychedelics such as LSD directly interact with TrkB with high affinity, promoting BDNF-mediated neuroplasticity and antidepressant-like effects via allosteric potentiation of BDNF signaling in active synapses.8 To investigate this, we screened LSD across 450 human kinases, including TrkB, but found no significant interactions between LSD and any tested human kinases. Further experiments in transfected cells revealed no effect of LSD or psilocin on BDNF-mediated activation of a TrkB reporter. We note that similar negative preliminary results, which have not yet been published in a peer-reviewed journal, were recently reported by Boltaev et al.63
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^Smith S, Timmis GM (1936). "311. The alkaloids of ergot. Part VII. isoErgine and isolysergic acids".Journal of the Chemical Society (Resumed): 1440.doi:10.1039/jr9360001440.ISSN0368-1769.
^Gach J (2008). "Biological Psychiatry in the Nineteenth and Twentieth Centuries".History of Psychiatry and Medical Psychology(PDF). Boston, MA: Springer US. pp. 381–418.doi:10.1007/978-0-387-34708-0_12.ISBN978-0-387-34707-3. Archived fromthe original(PDF) on 19 March 2025.In 1938 the Swiss chemist Albert Hofmann produced lysergic acid diethylamide (LSD)—the first, and most prominent, of these chemically synthesized agents—in the course of a systematic investigation of partially synthetic amides of lysergic acid in the Sandoz Pharmaceutical Laboratories in Basel (Hofmann 1970). [Taking] LSD by accident in 1943, Hofmann discovered its psychoactivity. He then experimented with it on himself and found that it produced a peculiar restlessness, extreme activity of the imagination, and an uninterrupted stream of images. Hofmann did not publish the results of his experiment, though he became quite famous later. Hofmann and Arthur Stoll, the head of the Sandoz pharmaceutical laboratory in Basle, published the first paper on the synthesis of LSD in 1943, while Stoll went on to publish the first paper on the effects of lysergic diethylamide acid in 1947. [...] Stoll, Arthur and Hofmann, Albert. 1943. Partialsynthese von Alkaloiden vom Typus des Ergobasins. Helv. Chim. Acta 26:944. Stoll, Arthur. 1947. Lysergsäure-diäthylamid, ein Phantastikum aus der Mutterkorngruppe. Schweiz. Arch. Neurol. Psychiat. 60:279. [The first paper on the hallucinogenic effect of LSD.]
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^Passie T, Guss J, Krähenmann R (2022)."Lower-dose psycholytic therapy - A neglected approach".Front Psychiatry.13 1020505.doi:10.3389/fpsyt.2022.1020505.PMC9755513.PMID36532196.Around 1960, Sandoz developed two short-acting derivatives of psilocybin, codenamed CZ-74 (4-HO-DET, 4-hydroxy-N,N-diethyltryptamine) and CEY-19 (ethocybin, 4-phosphoryloxy-N,N-diethyltryptamine) (37), which were used in psycholytic therapy [e.g. (34, 38, 39)].
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^Barceloux DG (9 March 2012). "Tryptamine Designer Drugs".Medical Toxicology of Drug Abuse: Synthesized Chemicals and Psychoactive Plants. Wiley. pp. 193–199.doi:10.1002/9781118105955.ch11.ISBN978-0-471-72760-6.During the early 1960s, α-ethyltryptamine [(AET)] (Monase®, Upjohn Company) was marketed in the United States as an antidepressant and stimulant, but the drug was removed shortly after introduction because of the occurrence of serious blood disorders. [...] [α-Methyltryptamine (AMT)] (Indopan) was marketed in the Soviet Union during the 1960s as an antidepressant.
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^Hamilton Morris (8 February 2021)."Ultra LSD".Hamilton's Pharmacopeia. Season 3. Episode 6.Vice Media. Event occurs at 19:41–22:17.Viceland.[Morris:] David Nichols has synthesized more psychedelic compounds than almost any other chemist in history. Maybe the most. He's made enormous contributions to the pharmacological understanding of how psychedelics act in the brain. And he's a real legend among anyone who cares about the science surrounding psychedelics.
^Passie T, Brandt SD (2018)."Self-Experiments with Psychoactive Substances: A Historical Perspective"(PDF).Handb Exp Pharmacol. Handbook of Experimental Pharmacology.252:69–110.doi:10.1007/164_2018_177.ISBN978-3-030-10560-0.PMID30478735.One follower of Shulgin's research can be seen in the Swiss chemist Daniel Trachsel, who published various contributions on many new psychoactive substances and their effects (Trachsel 2011, 2012; Trachsel et al. 2013). Experimental results about their psychoactive effects are included, but the author distanced himself from any [self-experiments (SEs)] (Trachsel 2011, p. 12).
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