Hallucinogenic Drugs

Abstract

Hallucinogens constitute one of the oldest classes of drugs used by humanity, often in the context of spiritual practices. Classic hallucinogens such as lysergic acid diethylamide (LSD), psilocybin, N,N‐dimethyltryptamine (DMT), mescaline and 2,5‐dimethoxy‐4‐methylamphetamine (DOM) produce complex psychological and physical effects, including perceptual changes, cognitive shifts in reality, and emotional alterations. These drugs primarily act on serotonin systems through 5‐hydroxytryptamine 2A (5HT2A) receptors, with additional activity through 5HT1A receptors, as well as dopamine and glutamate systems. Investigations into the neurochemical and behavioural effects of this class of drugs have provided important insights into pharmacology and psychiatric conditions. Given their popularity as recreational drugs, investigation of their actions and effects continues to be an important endeavour. In the past 30 years, there has been a renewed interest in conducting clinical studies with these drugs in healthy individuals and in patients with psychiatric conditions in laboratories around the world.

Key Concepts

  • Hallucinogens have been used for thousands of years by various societies, often in conjunction with spiritual practices.
  • In the present day, hallucinogens remain highly popular as recreational drugs.
  • The chemical structure of hallucinogens consists of tryptamines (LSD and psilocybin) and phenethylamines (mescaline and DOM).
  • The potency of hallucinogens is directly correlated to their ability to act as agonists at the serotonin receptor subtype, 5‐HT2A.
  • Drugs that act at sites other than 5‐HT2A receptors can also produce hallucinogen‐like effects (e.g. ketamine, MDMA, salvinorin A, nitrous oxide, GHB).
  • The signature effects of hallucinogens include perceptual changes, alterations in effect and shifts in cognitive ability.
  • Negative responses associated with hallucinogens include ‘bad trips’ (severe anxiety and a disconnection with reality) as well as rare instances of ‘flashbacks’ and psychotic breaks.
  • Human research with hallucinogens has recently been revitalised, augmenting the scientific advances made previously with animal and human studies.

Keywords: hallucinogen; psychedelic; LSD; serotonin; 5‐HT2; drugs of abuse; behavioural pharmacology

Figure 1. Tryptamine hallucinogens.
Figure 2. Phenethylamine hallucinogens.
Figure 3. Drugs with hallucinogenic‐like effects.
close

References

Agin‐Liebes GI, Malone T, Yalch MM, et al. (2020) Long‐term follow‐up of psilocybin‐assisted psychotherapy for psychiatric and existential distress in patients with life‐threatening cancer. Journal of Psychopharmacology 34 (2): 155–166.

Baker LE, Broadbent J, Michael EK, et al. (1995) Assessment of the discriminative stimulus effects of the optical isomers of ecstasy (3,4‐methylenedioxymethamphetamine; MDMA). Behavioural Pharmacology 6 (3): 263–275.

Barrett FS, Johnson MW and Griffiths RR (2015) Validation of the revised Mystical Experience Questionnaire in experimental sessions with psilocybin. Journal of Psychopharmacology 29 (11): 1182–1190.

Barsuglia J, Davis AK, Palmer R, et al. (2018) Intensity of Mystical Experiences Occasioned by 5‐MeO‐DMT and Comparison With a Prior Psilocybin Study. Frontiers in Psychology 9: 2459.

Bogenschutz MP, Forcehimes AA, Pommy JA, et al. (2015) Psilocybin‐assisted treatment for alcohol dependence: a proof‐of‐concept study. Journal of Psychopharmacology 29 (3): 289–299.

Bonson KR, Buckholtz JW and Murphy DL (1996) Chronic administration of serotonergic antidepressants attenuates the subjective effects of LSD in humans. Neuropsychopharmacology 14 (6): 425–436.

Bonson KR and Murphy DL (1996) Alterations in responses to LSD in humans associated with chronic administration of tricyclic antidepressants, monoamine oxidase inhibitors or lithium. Behavioural Brain Research 73 (1–2): 229–233.

Bonson KR (2018) Regulation of human research with LSD in the United States (1949‐1987). Psychopharmacology 235 (2): 591–604.

Buckholtz NS, Zhou DF, Freedman DX and Potter WZ (1990) Lysergic acid diethylamide (LSD) administration selectively downregulates serotonin 2 receptors in rat brain. Neuropsychopharmacology 3 (2): 137–148.

Burroughs WS and Ginsberg A (1963) The Yage Letters. City Lights Booksellers and Publishers: San Francisco, CA.

Carhart‐Harris RL, Bolstridge M, Rucker J, et al. (2016) Psilocybin with psychological support for treatment‐resistant depression: an open‐label feasibility study. Lancet Psychiatry 3 (7): 619–627.

Carhart‐Harris RL, Bolstridge M, Day CMJ, et al. (2018) Psilocybin with psychological support for treatment‐resistant depression: six‐month follow‐up. Psychopharmacology 235 (2): 399–408.

Dolder PC, Schmid Y, Steuer AE, et al. (2017) Pharmacokinetics and pharmacodynamics of lysergic acid diethylamide in healthy subjects. Clinical Pharmacokinetics 56 (10): 1219–1230.

Dos Santos RG, Osório FL, Crippa JAS and Hallak JEC (2016) Classical hallucinogens and neuroimaging: a systematic review of human studies: Hallucinogens and neuroimaging. Neuroscience and Biobehavioral Reviews 71: 715–728.

Fantegrossi WE, Woods JH and Winger G (2004) Transient reinforcing effects of phenylisopropylamine and indolealkylamine hallucinogens in rhesus monkeys. Behavioural Pharmacology 15 (2): 149–157.

Fiorella D, Helsley S, Rabin RA and Winter JC (1996) Potentiation of LSD‐induced stimulus control by fluoxetine in the rat. Life Sciences 59 (18): PL283–PL287.

Fiorella D, Rabin RA and Winter JC (1995) The role of the 5HT2A and 5‐HT2C receptors in the stimulus effects of hallucinogenic drugs. I: antagonist correlation analysis. Psychopharmacology 121 (3): 347–356.

Fontanilla D, Johannessen M, Hajipour AR, et al. (2009) The hallucinogen N,N‐dimethyltryptamine (DMT) is an endogenous sigma‐1 receptor regulator. Science 323 (5916): 934–937.

Gasser P, Holstein D, Michel Y, et al. (2014) Safety and efficacy of lysergic acid diethylamide‐assisted psychotherapy for anxiety associated with life‐threatening diseases. The Journal of Nervous and Mental Disease 202 (7): 513–520.

Gasser P, Kirchner K and Passie T (2015) LSD‐assisted psychotherapy for anxiety associated with a life‐threatening disease: a qualitative study of acute and sustained subjective effects. Journal of Psychopharmacology 29 (1): 57–68.

Glennon RA, Titeler M and McKenney JD (1984) Evidence for 5HT2 involvement in the mechanism of action of hallucinogenic agents. Life Sciences 35 (25): 2505–2511.

Glennon RA, Titeler M and Young R (1986) Structure‐activity relationships and mechanism of action of hallucinogenic agents based on drug discrimination and radioligand binding studies. Psychopharmacology Bulletin 22: 953–958.

Griffiths RR, Richards WA, McCann U and Jesse R (2006) Psilocybin can occasion mystical‐type experiences having substantial and sustained personal meaning and spiritual significance. Psychopharmacology (Berlin) 187 (3): 268–283.

Griffiths R, Richards W, Johnson M, McCann U and Jesse R (2008) Mystical‐type experiences occasioned by psilocybin mediate the attribution of personal meaning and spiritual significance 14 months later. Journal of Psychopharmacology 22 (6): 621–632.

Griffiths RR, Johnson MW, Richards WA, et al. (2011) Psilocybin occasioned mystical‐type experiences: immediate and persisting dose‐related effects. Psychopharmacology 218 (4): 649–665.

Griffiths RR, Johnson MW, Carducci MA, et al. (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life‐threatening cancer: a randomized double‐blind trial. Journal of Psychopharmacology 30 (12): 1181–1197.

Grob CS, Danforth AL, Chopra GS, et al. (2011) Pilot study of psilocybin treatment for anxiety in patients with advanced‐stage cancer. Archives of General Psychiatry 68 (1): 71–78.

Halberstadt AL and Geyer MA (2011) Multiple receptors contribute to the behavioral effects of indoleamine hallucinogens. Neuropharmacology 61 (3): 364–381.

Halpern JH and Pope HG Jr (1999) Do hallucinogens cause residual neuropsychological toxicity? Drug and Alcohol Dependence 53 (3): 247–256.

Halpern JH and Pope HG Jr (2003) Hallucinogen persisting perception disorder: what do we know after 50 years? Drug and Alcohol Dependence 69 (2): 109–119.

Hintzen A and Passie T (2010) The Pharmacology of LSD. Oxford University Press: New York, NY.

Johnson MW, Garcia‐Romeu A, Cosimano MP and Griffiths RR (2014) Pilot study of the 5‐HT2AR agonist psilocybin in the treatment of tobacco addiction. Journal of Psychopharmacology 28 (11): 983–992.

Johnson MW, Garcia‐Romeu A and Griffiths RR (2017) Long‐term follow‐up of psilocybin‐facilitated smoking cessation. The American Journal of Drug and Alcohol Abuse 43 (1): 55–60.

Johnson MW, Hendricks PS, Barrett FS and Griffiths RR (2019) Classic psychedelics: an integrative review of epidemiology, therapeutics, mystical experience, and brain network function. Pharmacology & Therapeutics 197: 83–102.

Killinger BA, Peet MM and Baker LE (2010) Salvinorin A fails to substitute for the discriminative stimulus effects of LSD or ketamine in Sprague‐Dawley rats. Pharmacology, Biochemistry, and Behavior 96 (3): 260–265.

Kuypers KP, Ng L, Erritzoe D, et al. (2019) Microdosing psychedelics: more questions than answers? An overview and suggestions for future research. Journal of Psychopharmacology 33 (9): 1039–1057.

Liechti ME (2017) Modern clinical research on LSD. Neuropsychopharmacology 42 (11): 2114–2127.

Liechti ME, Dolder PC and Schmid Y (2017) Alterations of consciousness and mystical‐type experiences after acute LSD in humans. Psychopharmacology 234 (9‐10): 1499–1510.

Madsen MK, Fisher PM, Burmester D, et al. (2019) Psychedelic effects of psilocybin correlate with serotonin 2A receptor occupancy and plasma psilocin levels. Neuropsychopharmacology 44 (7): 1328–1334.

Marona‐Lewicka D and Nichols DE (2007) Further evidence that the delayed temporal dopaminergic effects of LSD are mediated by a mechanism different than the first temporal phase of action. Pharmacology, Biochemistry, and Behavior 87 (4): 453–461.

McKenna DJ, Towers GH and Abbott F (1984) Monoamine oxidase inhibitors in South American hallucinogenic plants: tryptamine and beta‐carboline constituents of ayahuasca. Journal of Ethnopharmacology 10 (2): 195–223.

Moreno FA, Wiegand CB, Taitano EK and Delgado PL (2006) Safety, tolerability, and efficacy of psilocybin in 9 patients with obsessive‐compulsive disorder. Journal of Clinical Psychiatry 67 (11): 1735–1740.

Müller F, Liechti ME, Lang UE and Borgwardt S (2018) Advances and challenges in neuroimaging studies on the effects of serotonergic hallucinogens: Contributions of the resting brain. Progress in Brain Research 242: 159–177.

Nicholas CR, Henriquez KM, Gassman MC, et al. (2018) High dose psilocybin is associated with positive subjective effects in healthy volunteers. Journal of Psychopharmacology 32 (7): 770–778.

Nichols DE (2004) Hallucinogens. Pharmacology & Therapeutics 101 (2): 131–181.

Nichols DE (2018) Dark classics in chemical neuroscience: lysergic acid diethylamide (LSD). ACS Chemical Neuroscience 9 (10): 2331–2343.

Palhano‐Fontes F, Barreto D, Onias H, et al. (2019) Rapid antidepressant effects of the psychedelic ayahuasca in treatment‐resistant depression: a randomized placebo‐controlled trial. Psychological Medicine 49 (4): 655–663.

Panhke W (1963) Drugs and Mysticism: An Analysis of the Relationship between Psychedelic Drugs and the Mystical Consciousness. PhD dissertation, Harvard University.

Pollan, M. (2015) The Trip Treatment. New Yorker (February 2, 2015).

Poling A and Bryceland J (1979) Voluntary drug self‐administration by nonhumans: a review. Journal of Psychedelic Drugs 11: 185–190.

Quednow BB, Treyer V, Hasler F, et al. (2012) Assessment of serotonin release capacity in the human brain using dexfenfluramine challenge and [18F] altanserin positron emission tomography. NeuroImage 59 (4): 3922–3932.

Reissig CJ, Eckler JR, Rabin RA and Winter JC (2005) The 5‐HT1A receptor and the stimulus effects of LSD in the rat. Psychopharmacology (Berlin) 182 (2): 197–204.

Ross S, Bossis A, Guss J, et al. (2016) Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life‐threatening cancer: a randomized controlled trial. Journal of Psychopharmacology 30 (12): 1165–1180.

Substance Abuse and Mental Health Services Administration (2019) 2018 National Survey on Drug Use and Health: Methodological summary and definitions. Rockville, MD: Center for Behavioral Health Statistics and Quality, Substance Abuse and Mental Health Services Administration. Retrieved from https://www.samhsa.gov/data/

Schechter MD and Rosecrans JA (1972) Lysergic acid diethylamide (LSD) as a discriminative cue: drugs with similar stimulus properties. Psychopharmacology 26 (3): 313–316.

Schultes RE and Hofmann A (1980) The Botany and Chemistry of Hallucinogens. Thomas Publisher: Springfield, IL.

Schmid Y, Enzler F, Gasser P, et al. (2015) Acute effects of lysergic acid diethylamide in healthy subjects. Biological Psychiatry 78 (8): 544–553.

Schmid Y and Liechti ME (2018) Long‐lasting subjective effects of LSD in normal subjects. Psychopharmacology 235 (2): 535–545.

Shulgin A and Shulgin A (1991a) PIHKAL (Phenethylamines I Have Known and Loved). Transform Press: Berkeley, CA.

Shulgin A and Shulgin A (1991b) TIHKAL (Tryptamines I Have Known and Loved). Transform Press: Berkeley, CA.

Strassman RJ (1996) Human psychopharmacology of N,N‐dimethyltryptamine. Behavioural Brain Research 73 (1–2): 121–124.

Strassman RJ and Qualls CR (1994) Dose‐response study of N,N‐dimethyltryptamine in humans. I. Neuroendocrine, autonomic, and cardiovascular effects. Archives of General Psychiatry 51 (2): 85–97.

Strassman RJ, Qualls CR, Uhlenhuth EH and Kellner R (1994) 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.

Studerus E, Kometer M, Hasler F and Vollenweider FX (2011) Acute, subacute and long‐term subjective effects of psilocybin in healthy humans: a pooled analysis of experimental studies. Journal of Psychopharmacology 25 (11): 1434–1452.

Vollenweider FX, Vollenweider‐Scherpenhuyzen MF, Babler A, Vogel H and Hell D (1998) Psilocybin induces schizophrenialike psychosis in humans via a serotonin‐2 agonist action. Neuroreport 9 (17): 3897–3902.

Vollenweider FX, Vontobel P, Hell D and Leenders KL (1999) 5HT modulation of dopamine release in basal ganglia in psilocybin‐induced psychosis in man – a PET study with [11C]raclopride. Neuropsychopharmacology 20 (5): 424–433.

Wacker D, Wang S, McCorvy JD, et al. (2017) Crystal structure of an LSD‐bound human serotonin receptor. Cell 168 (3): 377–389.

Winter JC (1971) Tolerance to a behavioral effect of lysergic acid diethylamide and cross‐tolerance to mescaline in the rat: absence of a metabolic component. Journal of Pharmacology and Experimental Therapeutics 178 (3): 625–630.

Winter JC (2009) Hallucinogens as discriminative stimuli in animals: LSD, phenethylamines, and tryptamines. Psychopharmacology (Berlin) 203 (2): 251–263.

Winter JC, Eckler JR and Rabin RA (2004) Serotonergic/glutamatergic interactions: the effects of mGlu2/3 receptor ligands in rats trained with LSD and PCP as discriminative stimuli. Psychopharmacology (Berlin) 172 (2): 233–240.

Further Reading

Fantegrossi WE, Murnane KS and Reissig CJ (2008) The behavioral pharmacology of hallucinogens. Biochemical Pharmacology 75 (1): 17–33.

Pellerin C (1998) Trips: How Hallucinogens Work in Your Brain. Seven Stories Press: New York, NY.

Roberts TB and Winkelman M (2007) Psychedelic Medicine: New Evidence for Hallucinogenic Substances as Treatments. Praeger: Santa Barbara, CA.

Schultes RE and Hofmann A (1980) The Botany and Chemistry of Hallucinogens. Charles C. Thomas: New York.

Schultes RE, Hofmann A and Ratsch C (2001) Plants of the Gods: Their Sacred, Healing, and Hallucinogenic Powers. Healing Arts Press: Rochester, VA.

Stamets P and Weil A (1996) Psilocybin Mushrooms of the World: An Identification Guide. Ten Speed Press: Ithaca, NY.

Contact Editor close
Submit a note to the editor about this article by filling in the form below.

* Required Field

How to Cite close
Bonson, Katherine R(Sep 2020) Hallucinogenic Drugs. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0029200]