Skip to main content
SpringerLink
Log in

Pharmacological Action of LSD

LSD Effect on the Neurotransmission and Animal Behavior

  • Living reference work entry
  • Latest version View entry history
  • First Online:
Handbook of Substance Misuse and Addictions

  • 154 Accesses

Abstract

Lysergic acid diethylamide (LSD) is one of the most well-known hallucinogens. Accidental discovery of psychedelic properties of the drug in the 1950s started the increasing importance of LSD usage in various therapies. Unfortunately, its intensified interest moved also to a recreational use that resulted in placing LSD in Schedule I of the Controlled Substances Act. Nowadays, a renewed interest in LSD-related therapies has been observed. Nevertheless, the mechanism of action underlying induced changes remains incomprehensible. LSD is characterized by the high safety profile with no deaths related to its overdose as well as practically lack of dependence liability. It has the highest binding affinity to serotonin receptors (5-HT1A and 5-HT2A) in the frontal cortex but also to other receptors located in various brain regions. Its pharmacological action involves different neuronal pathways like serotonin, dopamine, glutamate, and noradrenaline circuits. The chapter discusses the current knowledge of LSD research, especially pharmacological profile, neural mechanisms, metabolism, and the influence on animals’ behavior. The promising data related to LSD-associated therapy potential was also highlighted.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution

Institutional subscriptions

Abbreviations

5-HT:

Serotonin

Ca2+:

Calcium ion

Ca2+/CaMKII:

Calcium/calmodulin-dependent protein kinase II

CPP:

Conditioned place preference test

CSA:

Controlled Substances Act

DA:

Dopamine

DOI:

2,5-dimethoxy-4-iodoamphetamine

EPPTB:

Trace-amine associate receptor 1 antagonist

GABA:

γ-aminobutyric acid

mGluR2:

Metabotropic glutamate receptor 2

i.m. :

Intramuscular route of drug administration

i.p.:

Intraperitoneal route of drug administration

i.v.:

Intravenous route of drug administration

K+:

Potassium ion

KO mouse:

Knock-out mouse in which a specific gene has been inactivated

LC:

Locus coeruleus

LD50:

Median lethal dose

LSD:

Lysergic acid diethylamide

LY341495:

Glutamate mGlu2 receptor antagonist

M100907:

Serotonin 5-HT2A receptor antagonist (formerly MDL 100907)

MDL11939:

Serotonin 5-HT2A receptor antagonist

NAS:

Nucleus accumbens

NMDA:

N-methyl-D-aspartate receptor

p.o.:

Per os (oral) route of drug administration

PCPA:

p-chlorophenylalanine

PFC:

Prefrontal cortex

PLA2:

Phospholipase A2

PLC:

Phospholipase C

PLD:

Phospholipase D

PPI:

Prepulse inhibition

RN:

Raphe nuclei

s.c.:

Subcutaneous route of drug administration

SERT:

Sodium-dependent serotonin transporter

STR:

Striatum

TAAR1:

Trace-amine associate receptor 1

VTA:

Ventral tegmental area

WAY100635:

Serotonin 5-HT1A receptor antagonist

References

  • Abramson HA, Jarvik ME, Govin MH, Hirsch MW (1956) Lysergic acid diethylamide (LSD-25): XVII. Tolerance development and is relationship to a theory of psychosis. J Psychol 41:81–105

    Article  CAS  Google Scholar 

  • Adams LM, Geyer MA (1982) LSD-induced alterations of locomotor patterns and exploration in rats. Psychopharmacology 77:179–185

    Article  CAS  PubMed  Google Scholar 

  • Aghajanian GK, Marek GJ (2000) Serotonin model of schizophrenia: emerging role of glutamate mechanisms. Brain Res Rev 31:302–312

    Article  CAS  PubMed  Google Scholar 

  • Ahn HS, Makman MH (1979) Interaction of LSD and other hallucinogens with dopamine-sensitive adenylate cyclase in primate brain: regional differences. Brain Res 162:77–88

    Article  CAS  PubMed  Google Scholar 

  • Antkiewicz-Michaluk L, Romanska I, Vetulani J (1997) Ca2+ channel blockade prevents lysergic acid diethylamide-induced changes in dopamine and serotonin metabolism. Eur J Pharmacol 332:9–14

    Google Scholar 

  • Arvanov VL, Liang X, Russo A, Wang RY (1999) LSD and DOB: interaction with 5-HT2A receptors to inhibit NMDA receptor-mediated transmission in the rat prefrontal cortex. Eur J Neurosci 11:3064–3072

    Article  CAS  PubMed  Google Scholar 

  • Axelrod J, Brady RO, Witkop B, Evarts EV (1957) The distribution and metabolism of LSD. Ann N Y Acad Sci 66:435–444

    Article  CAS  PubMed  Google Scholar 

  • Boyd E (1956) Preliminary studies on the metabolism of LSD. In: Cholden L (ed) Lysergic acid diethylamide and mescaline in experimental psychiatry. Grune and Stratton, London/New York, p 57

    Google Scholar 

  • Cumming P, Scheidegger M, Dornbierer D et al (2021) Molecular and functional imaging studies of psychedelic drug action in animals and humans. Molecules 26:2451

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • De Gregorio D, Posa L, Ochoa-Sanchez R et al (2016) The hallucinogen D-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT1A, D2 and TAAR1 receptors. Pharmacol Res 113:81–91

    Google Scholar 

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

    Google Scholar 

  • Essman WB (1967) Changes in locomotor activity and brain chemistry following LSD-25 administration in mice. Psychol Rep 20:124–126

    Article  CAS  PubMed  Google Scholar 

  • 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. J Nerv Ment Dis 202:513–520

    Article  PubMed  PubMed Central  Google Scholar 

  • Gonzalez-Maeso J, Weisstaub NV, Zhou M et al (2007) Hallucinogens recruit specific cortical 5-HT(2A) receptor-mediated signaling pathways to affect behaviour. Neuron 53:439–452

    Google Scholar 

  • Halberstadt AL, Geyer MA (2010) LSD but not lisuride disrupts prepulse inhibition in rats by activating the 5-HT(2A) receptor. Psychopharmacology 208:179–189

    Google Scholar 

  • Herian M, Wojtas A, Kaminska K et al (2019) Hallucinogen-like action of the novel designer drug 25I-NBOMe and its effect on cortical neurotransmitters in rats. Neurotox Res 36:91–100

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hetey L, Schwitzkowsky R, Oelssner W (1983) Influence of psychotomimetics and lisuride on synaptosomal dopamine release in the nucleus accumbens of rats. Eur J Pharmacol 93:213–220

    Article  CAS  PubMed  Google Scholar 

  • Hoffmeister F (1975) Negative reinforcing properties of some psychotropic drugs in drug-naive rhesus monkeys. J Pharmacol Exp Ther 192:468–477

    CAS  PubMed  Google Scholar 

  • Hofmann A (2009) LSD my problem child, 4th edn. Multidisciplinary Association for Psychedelic Studies, Santa Cruz

    Google Scholar 

  • Isbell H, Belleville RE, Fraser HF et al (1956) Studies on lysergic acid diethylamide: effects in former morphine addicts and development of tolerance during chronic intoxication. AMA Arch Neurol Psychiatry 76:468–478

    Article  PubMed  Google Scholar 

  • Jackson DD (1962) LSD and the new beginning. J Nerv Ment Dis 135:435–439

    CAS  PubMed  Google Scholar 

  • Krall C, Richards J, Rabin R, Winter J (2008) Marked decrease of LSD-induced stimulus control in serotonin transporter knockout mice. Pharmacol Biochem Behav 88:349–357

    Article  CAS  PubMed  Google Scholar 

  • Krebs TS, Johansen PO (2012) Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol 26:994–1002

    Article  PubMed  CAS  Google Scholar 

  • Kyzar EJ, Stewart AM, Kalueff AV (2016) Effects of LSD on grooming behavior in serotonin transporter heterozygous (Sert+/−) mice. Behav Brain Res 296:47–52

    Article  CAS  PubMed  Google Scholar 

  • Lambe EK, Aghajanian GK (2005) Hallucinogen-induced UP states in the brain slice of rat prefrontal cortex: role of glutamate spillover and NR2B-NMDA receptors. Neuropsychopharmacology 31:1682–1689

    Article  PubMed  CAS  Google Scholar 

  • Liester MB (2014) A review of lysergic acid diethylamide (LSD) in the treatment of addictions: historical perspectives and future prospects. Curr Drug Abuse Rev 7:146–156

    Article  CAS  PubMed  Google Scholar 

  • Marek GJ, Aghajanian GK (1996) LSD and the phenethylamine hallucinogen DOI are potent partial agonists at 5-HT2Areceptors on interneurons in rat piriform cortex. J Pharmacol Exp Ther 278:1373 –1382

    Google Scholar 

  • Marona-Lewicka D, Nichols DE (1995) Complex stimulus properties of LSD: a drug discrimination study with alpha 2-adrenoceptor agonists and antagonists. Psychopharmacology (Berl) 120:384–391

    Article  CAS  Google Scholar 

  • Marona-Lewicka D, Thisted RA, Nichols DE (2005) Distinct temporal phases in the behavioral pharmacology of LSD: dopamine D2 receptor-mediated effects in the rat and implications for psychosis. Psychopharmacology 180:427–435

    Google Scholar 

  • Martin-Ruiz R, Puig MV, Celada P et al (2001) Control of serotonergic function in medial prefrontal cortex by serotonin2A receptors through a glutamate-dependent mechanism. J Neurosci 21:9856–9866

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Meehan SM, Schechter MD (1998) LSD produces conditioned place preference in male but not female fawn hooded rats. Pharmacol Biochem Behav 59:105–108

    Article  CAS  PubMed  Google Scholar 

  • Meert T, de Haes P, Janssen P (1989) Risperidone (R 64 766), a potent and complete LSD antagonist in drugdiscrimination by rats. Psychopharmacology 97:206–212

    Article  CAS  PubMed  Google Scholar 

  • Miner LAH, Backstrom JR, Sanders-Bush E, Sesack SR (2003) Ultrastructural localization of serotonin2A receptors in the middle layers of the rat prelimbic prefrontal cortex. Neuroscience 116:107–117

    Article  CAS  PubMed  Google Scholar 

  • Moreno JL, Holloway T, Albizu L et al (2011) Metabotropic glutamate mGlu2 receptor is necessary for the pharmacological and behavioral effects induced by hallucinogenic 5-HT2A receptor agonists. Neurosci Lett 493:76–79

    Google Scholar 

  • Moreno JL, Holloway T, Rayannavar V, at al. (2013) Chronic treatment with LY341495 decreases 5-HT 2A receptor binding and hallucinogenic effects of LSD in mice. Neurosci Lett 536:69–73

    Google Scholar 

  • Muschamp JW, Regina MJ, Hull EM et al (2004) Lysergic acid diethylamide and [−]-2,5-dimethoxy-4-methylamphetamine increase extracellular glutamate in rat prefrontal cortex. Brain Res 1023:134–140

    Article  CAS  PubMed  Google Scholar 

  • Nichols DE (2001) LSD and its lysergamide cousins. In: The Heffter review of psychedelic research, vol 2. Heffter Research Institute, Santa Fe, pp 80–87

    Google Scholar 

  • Nichols DE (2004) Hallucinogens. Pharmacol Ther 101:131–181

    Article  CAS  PubMed  Google Scholar 

  • Nichols DE (2016) Psychedelics. Pharmacol Rev 68:264–355

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nichols DE (2018) Dark classics in chemical neuroscience: lysergic acid diethylamide (LSD). ACS Chem Neurosci 17:2331–2343

    Article  CAS  Google Scholar 

  • Nichols DE, Grob CS (2018) Is LSD toxic? Forensic Sci Int 284:141–145

    Article  CAS  PubMed  Google Scholar 

  • Nichols CD, Sanders-Bush E (2001) Serotonin receptor signaling and hallucinogenic drug action. In: The Heffter review of psychedelic research, vol 2. Heffter Research Institute, Santa Fe, pp 73–79

    Google Scholar 

  • Nichols DE, Frescas S, Marona-Lewicka D, Kurrasch-Orbaugh DM (2002) Lysergamides of isomeric 2,4-dimethylazetidines map the binding orientation of the diethylamide moiety in the potent hallucinogenic agent N,N-diethyllysergamide (LSD). J Med Chem 45:4344–4349

    Article  CAS  PubMed  Google Scholar 

  • Nocjar C, Alex KD, Sonneborn A et al (2015) Serotonin-2c and -2a receptor co-expression on cells in the rat medial prefrontal cortex. Neuroscience 297:22–37

    Article  CAS  PubMed  Google Scholar 

  • Noworyta-Sokolowska K, Kaminska K, Kreiner G et al (2016) Neurotoxic effects of 5-MeO-DIPT: a psychoactive tryptamine derivative in rats. Neurotox Res 30:606–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Pahnke WN, Kurland AA, Goodman LE, Richards WA (1969) LSD-assisted psychotherapy with terminal cancer patients. Curr Psychiatr Ther 9:144–152

    CAS  PubMed  Google Scholar 

  • Parker LA (1996) LSD produces place preference and flavor avoidance but does not produce flavor aversion in rats. Behav Neurosci 110:503–508

    Article  CAS  PubMed  Google Scholar 

  • Passie T, Halpern JH, Stichtenoth DO et al (2008) The pharmacology of lysergic acid diethylamide: a review. CNS Neurosci Ther 14:295–314

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rickli A, Luethi D, Reinisch J et al (2015) Receptor interaction profiles of novel N-2-methoxybenzyl (NBOMe) derivatives of 2,5-dimethoxy-substituted phenethylamines (2C drugs). Neuropharmacology 99:546–553

    Article  CAS  PubMed  Google Scholar 

  • Sandison RA, Spencer AM, Whitelaw JDA (1954) The therapeutic value of lysergic acid diethylamide in mental illness. J Ment Sci 100:491–507

    Article  CAS  PubMed  Google Scholar 

  • Santana N, Artigas F (2017) Expression of serotonin 2C receptors in pyramidal and GABAergic neurons of rat prefrontal cortex: a comparison with striatum. Cereb Cortex 27:3125–3139

    PubMed  Google Scholar 

  • Sewell RA, Halpern JH, Pope HG Jr (2006) Response of cluster headache to psilocybin and LSD. Neurology 66:1920–1922

    Article  PubMed  Google Scholar 

  • von Hungen K, Roberts S, Hill DF (1974) LSD as an agonist and antagonist at central dopamine receptors. Nature 252:588–589

    Article  Google Scholar 

  • Weber ET, Andrade R (2010) Htr2a gene and 5-HT2A receptor expression in the cerebral cortex studied using genetically modified mice. Front Neurosci 4:1–12

    Google Scholar 

  • Willins DL, Deutch AY, Roth BL (1997) Serotonin 5-HT(2A) receptors are expressed on pyramidal cells and interneurons in the rat cortex. Synapse 27:79–82

    Article  CAS  PubMed  Google Scholar 

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

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Maj Institute of Pharmacology, Polish Academy of Sciences, Cracow, Poland

    Monika Herian

Authors
  1. Monika Herian
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monika Herian .

Editor information

Editors and Affiliations

  1. Department of Biomedical Sciences, University of Westminster, London, UK

    Vinood B. Patel

  2. Dept of Nutrition & Dietetics, King's College London, London, UK

    Victor R. Preedy

Rights and permissions

Reprints and permissions

Copyright information

© 2022 Springer Nature Switzerland AG

About this entry

Check for updates. Verify currency and authenticity via CrossMark

Cite this entry

Herian, M. (2022). Pharmacological Action of LSD. In: Patel, V.B., Preedy, V.R. (eds) Handbook of Substance Misuse and Addictions. Springer, Cham. https://doi.org/10.1007/978-3-030-67928-6_131-2

Download citation

  • DOI: https://doi.org/10.1007/978-3-030-67928-6_131-2

  • Received:

  • Accepted:

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-67928-6

  • Online ISBN: 978-3-030-67928-6

  • eBook Packages: Springer Reference MedicineReference Module Medicine

Publish with us

Policies and ethics

Chapter history

  1. Latest

    Pharmacological Action of LSD
    Published:
    02 June 2022

    DOI: https://doi.org/10.1007/978-3-030-67928-6_131-2

  2. Original

    Pharmacological Action of LSD
    Published:
    29 March 2022

    DOI: https://doi.org/10.1007/978-3-030-67928-6_131-1

Search

Navigation