Psychedelic Therapeutics in Psychiatry: An Update

Learning Objectives:

1. Mechanism of action of psychedelic drugs;

2. Mechanism of action of psychedelic drugs; and

3. Main use and side-effects of psychedelic drugs.

Abstract:

Hallucinogens (from the Latin alucinari, “to wander in mind”) or psychedelics (from the Greek words psyche [mind] and delos [visible], thus “to see/manifest the mind”) are a group of substances that induce profound changes in thinking patterns, sensory perception, emotion and cognition without clouding the mind. The main examples of this group of drugs are lysergic acid diethylamide (LSD), mescaline, psilocybin, and dimethyltryptamine (DMT). These chemicals are also called serotonergic or classic hallucinogens/psychedelics and share a central pharmacological mechanism: 5-HT2A receptor agonism. Here we will discuss the therapeutic properties of these drugs, focusing on the advances from observational and randomized controlled trials that have found positive results for psilocybin, LSD, ayahuasca and ibogaine. We will also discuss the main risks of these drugs We will finally discuss that these compounds are not “magic bullets” or “miracle drugs,” but they indicate the possibility of a brave new world in psychiatric treatment, and we are cautiously optimistic about their potential.

Literature References:

1: Osório Fde L, Sanches RF, Macedo LR, Santos RG, Maia-de-Oliveira JP, WichertAna L, Araujo DB, Riba J, Crippa JA, Hallak JE. Antidepressant effects of a single dose of ayahuasca in patients with recurrent depression: a preliminary report. Braz J Psychiatry. 2015 Jan-Mar;37(1):13-20. doi: 10.1590/1516-4446-2014-1496. PMID: 25806551.

2: Sanches RF, de Lima Osório F, Dos Santos RG, Macedo LR, Maia-de-Oliveira JP, Wichert-Ana L, de Araujo DB, Riba J, Crippa JA, Hallak JE. Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. J Clin Psychopharmacol. 2016 Feb;36(1):77-81. doi: 10.1097/JCP.0000000000000436. PMID: 26650973.

3: Dos Santos RG, Osório FL, Crippa JA, Hallak JE. Antidepressive and anxiolytic effects of ayahuasca: a systematic literature review of animal and human studies. Braz J Psychiatry. 2016 Mar;38(1):65-72. doi: 10.1590/1516-4446-2015-1701. PMID: 27111702; PMCID: PMC7115465.

4: Dos Santos RG, Balthazar FM, Bouso JC, Hallak JE. The current state of research on ayahuasca: A systematic review of human studies assessing psychiatric symptoms, neuropsychological functioning, and neuroimaging. J Psychopharmacol. 2016 Dec;30(12):1230-1247. doi: 10.1177/0269881116652578. Epub 2016 Jun 10. PMID: 27287824.

5: Dos Santos RG, Osório FL, Crippa JA, Riba J, Zuardi AW, Hallak JE. Antidepressive, anxiolytic, and antiaddictive effects of ayahuasca, psilocybin and lysergic acid diethylamide (LSD): a systematic review of clinical trials published in the last 25 years. Ther Adv Psychopharmacol. 2016 Jun;6(3):193-213. doi: 10.1177/2045125316638008. Epub 2016 Mar 18. PMID: 27354908; PMCID: PMC4910400.

6: Dos Santos RG, Osório FL, Crippa JAS, Hallak JEC. Classical hallucinogens and neuroimaging: A systematic review of human studies: Hallucinogens and neuroimaging. Neurosci Biobehav Rev. 2016 Dec;71:715-728. doi: 10.1016/j.neubiorev.2016.10.026. Epub 2016 Oct 31. PMID: 27810345.

7: Bouso JC, Dos Santos RG, Alcázar-Córcoles MÁ, Hallak JEC. Serotonergic psychedelics and personality: A systematic review of contemporary research. Neurosci Biobehav Rev. 2018 Apr;87:118-132. doi: 10.1016/j.neubiorev.2018.02.004. Epub 2018 Feb 13. PMID: 29452127.

8: Palhano-Fontes F, Barreto D, Onias H, Andrade KC, Novaes MM, Pessoa JA, MotaRolim SA, Osório FL, Sanches R, Dos Santos RG, Tófoli LF, de Oliveira Silveira G, Yonamine M, Riba J, Santos FR, Silva-Junior AA, Alchieri JC, Galvão-Coelho NL, Lobão-Soares B, Hallak JEC, Arcoverde E, Maia-de-Oliveira JP, Araújo DB. Rapid antidepressant effects of the psychedelic ayahuasca in treatment-resistant depression: a randomized placebo-controlled trial. Psychol Med. 2019 Mar;49(4):655-663. doi: 10.1017/S0033291718001356. Epub 2018 Jun 15. PMID: 29903051; PMCID: PMC6378413.

9: Dos Santos RG, Bouso JC, Hallak JEC. Serotonergic hallucinogens/psychedelics could be promising treatments for depressive and anxiety disorders in end-stage cancer. BMC Psychiatry. 2019 Oct 28;19(1):321. doi: 10.1186/s12888-019-2288-z. PMID: 31660905; PMCID: PMC6816167.

10: Dos Santos RG, Hallak JEC. Therapeutic use of serotoninergic hallucinogens: A review of the evidence and of the biological and psychological mechanisms. Neurosci Biobehav Rev. 2020 Jan;108:423-434. doi: 10.1016/j.neubiorev.2019.12.001. Epub 2019 Dec 3. PMID: 31809772.

11: Dos Santos RG, Bouso JC, Hallak JE. Hallucinogens/psychedelics resurrected as new tools in psychiatric therapy. Braz J Psychiatry. 2020 Jun 1:S1516-44462020005015210. doi: 10.1590/1516-4446-2020-1035. Epub ahead of print. PMID: 32491039.