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Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review

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Abstract

Classical psychedelics are a group of drugs characterized by their activation of the serotonin-2A (5-hydroxytryptamine-2A; 5-HT2A) receptor and the unique hallucinogenic and mystical-type experiences that result. After a substantial period of restrictions limiting investigations into the therapeutic potential of psychedelics, a relatively recent recommencement of interest has sparked the burgeoning possibility for these drugs to play a part in the treatment of a wide array of psychopathologies. One of the most promising is in the study of addiction. Evidence has emerged that psychedelic agents may provide a novel avenue for the clinical treatment of patients dealing with substance use disorders (SUD). These serotonergic hallucinogens have displayed remarkable and enduring positive outcomes in this area, even when administered as one or two doses. The neural targets for these psychedelics are varied and underlie a complex mechanism of action—modulating multiple neural networks. It is believed that these agents allow for the reorganization of disordered neural pathways in the default mode network and attenuate maladaptive signaling in mesolimbic reward circuitry. The aim of this review is to examine the current standing of evidence regarding psychedelic psychopharmacology and to provide an overview of the use and effectiveness of these drugs in the treatment of SUD, alcohol use disorder, and for smoking cessation.

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References

  1. Aixala M, Dos Santos RG, Hallak JEC, Bouso JC (2018) Psychedelics and personality. ACS Chem Neurosci 9(10):2304–2306

    CAS  PubMed  Google Scholar 

  2. Canal CE, Murnane KS (2017) The serotonin 5-HT2C receptor and the non-addictive nature of classic hallucinogens. J Psychopharmacol 31(1):127–143

    CAS  PubMed  Google Scholar 

  3. Noorani T, Garcia-Romeu A, Swift TC, Griffiths RR, Johnson MW (2018) Psychedelic therapy for smoking cessation: qualitative analysis of participant accounts. J Psychopharmacol 32(7):756–769

    PubMed  Google Scholar 

  4. Garcia-Romeu A, Davis AK, Erowid E, Erowid F, Griffiths RR, Johnson MW (2019a) Persisting reductions in cannabis, opioid, and stimulant misuse after naturalistic psychedelic use: an online survey. Front Psychiatry 10:955

    PubMed  Google Scholar 

  5. Garcia-Romeu A, Davis AK, Erowid F, Erowid E, Griffiths RR, Johnson MW (2019b) Cessation and reduction in alcohol consumption and misuse after psychedelic use. J Psychopharmacol 33(9):1088–1101

    PubMed  Google Scholar 

  6. Brierley DI, Davidson C (2013) Harmine augments electrically evoked dopamine efflux in the nucleus accumbens shell. J Psychopharmacol 27(1):98–108

    CAS  PubMed  Google Scholar 

  7. Daniel J, Haberman M (2017) Clinical potential of psilocybin as a treatment for mental health conditions. Ment Health Clin 7(1):24–28

    PubMed  Google Scholar 

  8. Dinis-Oliveira RJ, Pereira CL, da Silva DD (2019) Pharmacokinetic and pharmacodynamic aspects of peyote and mescaline: clinical and forensic repercussions. Curr Mol Pharmacol 12(3):184–194

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Garcia-Romeu A, Richards WA (2018) Current perspectives on psychedelic therapy: use of serotonergic hallucinogens in clinical interventions. Int Rev Psychiatry 30(4):291–316

    PubMed  Google Scholar 

  10. Hofmann A, Ott J (1980) LSD, my problem child. McGraw-Hill, New York

    Google Scholar 

  11. Comprehensive Drug Abuse Prevention and Control Act of 1970,  Pub. L. No. 91-513, § 801, 84 Stat. 1236 (1970)

  12. Belouin SJ, Henningfield JE (2018) Psychedelics: where we are now, why we got here, what we must do. Neuropharmacology 142:7–19

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  14. Calderon SN, Hunt J, Klein M (2018) A regulatory perspective on the evaluation of hallucinogen drugs for human use. Neuropharmacology 142:135–142

    CAS  PubMed  Google Scholar 

  15. Nichols CD, Ronesi J, Pratt W, Sanders-Bush E (2002) Hallucinogens and Drosophila: linking serotonin receptor activation to behavior. Neuroscience 115(3):979–984

    CAS  PubMed  Google Scholar 

  16. de Veen BTH, Schellekens AFA, Verheij MMM, Homberg JR (2017) Psilocybin for treating substance use disorders? Expert Rev Neurother 17(2):203–212

    PubMed  Google Scholar 

  17. Hedegaard H, Miniño AM, Warner M (2020) Drug overdose deaths in the United States, 1999–2018. NCHS Data Brief 356:1–8

    Google Scholar 

  18. Jerome L, Schuster S, Yazar-Klosinski BB (2013) Can MDMA play a role in the treatment of substance abuse? Curr Drug Abuse Rev 6(1):54–62

    CAS  PubMed  Google Scholar 

  19. Dos Santos RG, Bouso JC, Alcazar-Corcoles MA, Hallak JEC (2018) Efficacy, tolerability, and safety of serotonergic psychedelics for the management of mood, anxiety, and substance-use disorders: a systematic review of systematic reviews. Expert Rev Clin Pharmacol 11(9):889–902

    PubMed  Google Scholar 

  20. World Health Organization (2018) Global status report on alcohol and health 2018. World Health Organization, Geneva

    Google Scholar 

  21. World Health Organization (2020) Tobacco. www.who.int/news-room/fact-sheets/detail/tobacco.  Accessed 8 Nov 2020

  22. Lofwall MR, Walsh SL, Nunes EV, Bailey GL, Sigmon SC, Kampman KM et al (2018) Weekly and monthly subcutaneous buprenorphine depot formulations vs daily sublingual buprenorphine with naloxone for treatment of opioid use disorder: a randomized clinical trial. JAMA Intern Med 178(6):764–773

    PubMed  PubMed Central  Google Scholar 

  23. Gonzales D, Rennard SI, Nides M, Oncken C, Azoulay S, Billing CB et al (2006) Varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs sustained-release bupropion and placebo for smoking cessation: a randomized controlled trial. JAMA 296(1):47–55

    CAS  PubMed  Google Scholar 

  24. Flanagan TW, Nichols CD (2018) Psychedelics as anti-inflammatory agents. Int Rev Psychiatry 30(4):363–375

    PubMed  Google Scholar 

  25. Griffiths RR, Johnson MW, Richards WA, Richards BD, McCann U, Jesse R (2011) Psilocybin occasioned mystical-type experiences: immediate and persisting dose-related effects. Psychopharmacology 218(4):649–665

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Gasser P, Holstein D, Michel Y, Doblin R, Yazar-Klosinski B, Passie T et al (2014) Safety and efficacy of lysergic acid diethylamide-assisted psychotherapy for anxiety associated with life-threatening diseases. J Nerv Ment Dis 202(7):513–520

    PubMed  PubMed Central  Google Scholar 

  27. Johnson M, Richards W, Griffiths R (2008) Human hallucinogen research: guidelines for safety. J Psychopharmacol 22(6):603–620

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Cohen S (1960) Lysergic-acid diethylamide—side-effects and complications. J Nerv Ment Dis 130(1):30–40

    CAS  PubMed  Google Scholar 

  29. Auclair A, Drouin C, Cotecchia S, Glowinski J, Tassin JP (2004) 5-HT2A and alpha1b-adrenergic receptors entirely mediate dopamine release, locomotor response and behavioural sensitization to opiates and psychostimulants. Eur J Neurosci 20(11):3073–3084

    PubMed  Google Scholar 

  30. Kosten TR, Baxter LE (2019) Review article: effective management of opioid withdrawal symptoms: a gateway to opioid dependence treatment. Am J Addict 28(2):55–62

    PubMed  PubMed Central  Google Scholar 

  31. Koob GF, Volkow ND (2010) Neurocircuitry of addiction. Neuropsychopharmacology 35(1):217–238

    PubMed  Google Scholar 

  32. Baumann MH, Becketts KM, Rothman RB (1995) Evidence for alterations in presynaptic serotonergic function during withdrawal from chronic cocaine in rats. Eur J Pharmacol 282(1–3):87–93

    CAS  PubMed  Google Scholar 

  33. Rossetti ZL, Gessa GL (1995) Central dopaminergic mechanisms of alcohol and opiate withdrawal syndromes. Drug addiction and related clinical problems. Springer, Vienna, pp 19–26

    Google Scholar 

  34. Yan Q, Reith ME, Yan S (2000) Enhanced accumbal dopamine release following 5-HT(2A) receptor stimulation in rats pretreated with intermittent cocaine. Brain Res 863(1–2):254–258

    CAS  PubMed  Google Scholar 

  35. Watts VJ, Lawler CP, Fox DR, Neve KA, Nichols DE, Mailman RB (1995) LSD and structural analogs: pharmacological evaluation at D1 dopamine receptors. Psychopharmacology 118(4):401–409

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  37. Cornea-Hébert V, Riad M, Wu C, Singh SK, Descarries L (1999) Cellular and subcellular distribution of the serotonin 5-HT2A receptor in the central nervous system of adult rat. J Comp Neurol 409(2):187–209

    PubMed  Google Scholar 

  38. Pessia M, Jiang ZG, North RA, Johnson SW (1994) Actions of 5-hydroxytryptamine on ventral tegmental area neurons of the rat in vitro. Brain Res 654(2):324–330

    CAS  PubMed  Google Scholar 

  39. You IJ, Wright SR, Garcia-Garcia AL, Tapper AR, Gardner PD, Koob GF et al (2016) 5-HT1A autoreceptors in the dorsal raphe nucleus convey vulnerability to compulsive cocaine seeking. Neuropsychopharmacology 41(5):1210–1222

    CAS  PubMed  Google Scholar 

  40. Vargas-Perez H, Grieder TE, Ting AKR, Maal-Bared G, Chwalek M, van der Kooy D (2017) A single administration of the hallucinogen, 4-acetoxy-dimethyltryptamine, prevents the shift to a drug-dependent state and the expression of withdrawal aversions in rodents. Eur J Neurosci 45(11):1410–1417

    PubMed  Google Scholar 

  41. Nichols DE (2016) Psychedelics. Pharmacol Rev 68(2):264–355

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Wallach MB, Hine B, Gershon S (1974) Cross tolerance or tachyphylaxis among various psychotomimetic agents on cats. Eur J Pharmacol 29(1):89–92

    CAS  PubMed  Google Scholar 

  43. Buchborn T, Lyons T, Knöpfel T (2018) Tolerance and tachyphylaxis to head twitches induced by the 5-HT2A agonist 25CN-NBOH in mice. Front Pharmacol 9:17

    PubMed  PubMed Central  Google Scholar 

  44. Nutt D, Erritzoe D, Carhart-Harris R (2020) Psychedelic psychiatry’s brave new world. Cell 181(1):24–28

    CAS  PubMed  Google Scholar 

  45. Martin DA, Nichols CD (2016) Psychedelics recruit multiple cellular types and produce complex transcriptional responses within the brain. EBioMedicine 11:262–277

    PubMed  PubMed Central  Google Scholar 

  46. Nichols DE, Johnson MW, Nichols CD (2017) Psychedelics as medicines: an emerging new paradigm. Clin Pharmacol Ther 101(2):209–219

    CAS  PubMed  Google Scholar 

  47. Martin DA, Nichols CD (2018) The effects of hallucinogens on gene expression. Curr Top Behav Neurosci 36:137–158

    CAS  PubMed  Google Scholar 

  48. Hamor PU, Sirova J, Palenicek T, Zaniewska M, Bubenikova-Valesova V, Schwendt M (2018) Chronic methamphetamine self-administration dysregulates 5-HT2A and mGlu2 receptor expression in the rat prefrontal and perirhinal cortex: comparison to chronic phencyclidine and MK-801. Pharmacol Biochem Behav 175:89–100

    CAS  PubMed  PubMed Central  Google Scholar 

  49. Tagliazucchi E, Roseman L, Kaelen M, Orban C, Muthukumaraswamy SD, Murphy K et al (2016) Increased global functional connectivity correlates with LSD-induced ego dissolution. Curr Biol 26(8):1043–1050

    CAS  PubMed  Google Scholar 

  50. Zhang R, Volkow ND (2019) Brain default-mode network dysfunction in addiction. NeuroImage 200:313–331

    CAS  PubMed  Google Scholar 

  51. Buckner RL, Andrews-Hanna JR, Schacter DL (2008) The brain’s default network—anatomy, function, and relevance to disease. Year Cognit Neurosci 2008(1124):1–38

    Google Scholar 

  52. Smigielski L, Scheidegger M, Kometer M, Vollenweider FX (2019) Psilocybin-assisted mindfulness training modulates self-consciousness and brain default mode network connectivity with lasting effects. NeuroImage 196:207–215

    CAS  PubMed  Google Scholar 

  53. Carhart-Harris RL, Roseman L, Bolstridge M, Demetriou L, Pannekoek JN, Wall MB et al (2017) Psilocybin for treatment-resistant depression: fMRI-measured brain mechanisms. Sci Rep 7(1):13187

    PubMed  PubMed Central  Google Scholar 

  54. Sampedro F, de la Fuente RM, Valle M, Roberto N, Domínguez-Clavé E, Elices M et al (2017) Assessing the psychedelic “after-glow” in ayahuasca users: post-acute neurometabolic and functional connectivity changes are associated with enhanced mindfulness capacities. Int J Neuropsychopharmacol 20(9):698–711

    PubMed  PubMed Central  Google Scholar 

  55. Strajhar P, Schmid Y, Liakoni E, Dolder PC, Rentsch KM, Kratschmar DV et al (2016) Acute effects of lysergic acid diethylamide on circulating steroid levels in healthy subjects. J Neuroendocrinol 28(3):12374

    CAS  PubMed  Google Scholar 

  56. Schmid Y, Enzler F, Gasser P, Grouzmann E, Preller KH, Vollenweider FX et al (2015) Acute effects of lysergic acid diethylamide in healthy subjects. Biol Psychiatry 78(8):544–553

    CAS  PubMed  Google Scholar 

  57. Dos Santos RG, Grasa E, Valle M, Ballester MR, Bouso JC, Nomdedéu JF et al (2012) Pharmacology of ayahuasca administered in two repeated doses. Psychopharmacology 219(4):1039–1053

    PubMed  Google Scholar 

  58. Hasler F, Grimberg U, Benz MA, Huber T, Vollenweider FX (2004) Acute psychological and physiological effects of psilocybin in healthy humans: a double-blind, placebo-controlled dose-effect study. Psychopharmacology 172(2):145–156

    CAS  PubMed  Google Scholar 

  59. Owens MJ, Knight DL, Ritchie JC, Nemeroff CB (1991) The 5-hydroxytryptamine2 agonist, (+-)-1-(2,5-dimethoxy-4-bromophenyl)-2-aminopropane stimulates the hypothalamic-pituitary-adrenal (HPA) axis. I. Acute effects on HPA axis activity and corticotropin-releasing factor-containing neurons in the rat brain. J Pharmacol Exp Ther 256(2):787–794

    CAS  PubMed  Google Scholar 

  60. Van de Kar LD, Javed A, Zhang Y, Serres F, Raap DK, Gray TS (2001) 5-HT2A receptors stimulate ACTH, corticosterone, oxytocin, renin, and prolactin release and activate hypothalamic CRF and oxytocin-expressing cells. J Neurosci 21(10):3572–3579

    PubMed  PubMed Central  Google Scholar 

  61. Griffiths RR, Johnson MW, Carducci MA, Umbricht A, Richards WA, Richards BD et al (2016) Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol 30(12):1181–1197

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Polito V, Stevenson RJ (2019) A systematic study of microdosing psychedelics. PLoS ONE 14(2):e0211023

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Hutten N, Mason NL, Dolder PC, Kuypers KPC (2019) Self-rated effectiveness of microdosing with psychedelics for mental and physical health problems among microdosers. Front Psychiatry 10:672

    PubMed  PubMed Central  Google Scholar 

  64. Lea T, Amada N, Jungaberle H, Schecke H, Scherbaum N, Klein M (2020) Perceived outcomes of psychedelic microdosing as self-managed therapies for mental and substance use disorders. Psychopharmacology. https://doi.org/10.1007/s00213-020-05477-0

    Article  PubMed  Google Scholar 

  65. Bershad AK, Preller KH, Lee R, Keedy S, Wren-Jarvis J, Bremmer MP et al (2020) Preliminary report on the effects of a low dose of LSD on resting-state amygdala functional connectivity. Biol Psychiatry Cognit Neurosci Neuroimaging 5(4):461–467

    Google Scholar 

  66. Barrett FS, Doss MK, Sepeda ND, Pekar JJ, Griffiths RR (2020) Emotions and brain function are altered up to one month after a single high dose of psilocybin. Sci Rep 10(1):1–14

    Google Scholar 

  67. Johnson FG (1969) LSD in the treatment of alcoholism. Am J Psychiatry 126(4):481–487

    CAS  PubMed  Google Scholar 

  68. Smart RG, Storm T, Baker EF, Solursh L (1966) A controlled study of lysergide in the treatment of alcoholism. I. The effects on drinking behavior. Q J Stud Alcohol 27(3):469–482

    CAS  PubMed  Google Scholar 

  69. Krebs TS, Johansen P (2012) Lysergic acid diethylamide (LSD) for alcoholism: meta-analysis of randomized controlled trials. J Psychopharmacol 26(7):994–1002

    PubMed  Google Scholar 

  70. Johnson MW, Griffiths RR (2017) Potential therapeutic effects of psilocybin. Neurotherapeutics 14(3):734–740

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Bogenschutz MP, Forcehimes AA, Pommy JA, Wilcox CE, Barbosa PC, Strassman RJ (2015) Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study. J Psychopharmacol 29(3):289–299

    CAS  PubMed  Google Scholar 

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

    PubMed  PubMed Central  Google Scholar 

  73. Johnson MW, Griffiths RR, Hendricks PS, Henningfield JE (2018) The abuse potential of medical psilocybin according to the 8 factors of the controlled substances act. Neuropharmacology 142:143–166

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Johnson MW, Garcia-Romeu A, Griffiths RR (2017) Long-term follow-up of psilocybin-facilitated smoking cessation. Am J Drug Alcohol Abuse 43(1):55–60

    PubMed  Google Scholar 

  75. Johnson MW, Garcia-Romeu A, Johnson PS, Griffiths RR (2017) An online survey of tobacco smoking cessation associated with naturalistic psychedelic use. J Psychopharmacol 31(7):841–850

    PubMed  PubMed Central  Google Scholar 

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Acknowledgements

Ellen Unterwald, PhD provided valuable consultation with pathways discussed in this review and assisted in proofreading of this publication.

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  1. Lewis Katz School of Medicine at Temple University, 1505 South Juniper St., Philadelphia, PA, 19147, USA

    Alec J. DiVito

  2. Lewis Katz School of Medicine at Temple University, 42 South 15th St., No 501, Philadelphia, PA, 19102, USA

    Robert F. Leger

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AJD and RFL contributed equally to the research and composition involved with this publication.

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Correspondence to Robert F. Leger.

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DiVito, A.J., Leger, R.F. Psychedelics as an emerging novel intervention in the treatment of substance use disorder: a review. Mol Biol Rep 47, 9791–9799 (2020). https://doi.org/10.1007/s11033-020-06009-x

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