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

Rafael G. dos Santos, Flávia L. Osório, José Alexandre S. Crippa, Jordi Riba, Antônio W. Zuardi and Jaime E. C. Hallak

Therapeutic Advances in Psychopharmacology, 2016, Vol. 6, (3) 193–213

Doi : 10.1177/2045125316638008

 

Abstract :

To date, pharmacological treatments for mood and anxiety disorders and for drug dependence show limited efficacy, leaving a large number of patients suffering severe and persistent symptoms. Preliminary studies in animals and humans suggest that ayahuasca, psilocybin and lysergic acid diethylamide (LSD) may have antidepressive, anxiolytic, and antiaddictive properties. Thus, we conducted a systematic review of clinical trials published from 1990 until 2015, assessing these therapeutic properties. Electronic searches were performed using the PubMed, LILACS, and SciELO databases. Only clinical trials published in peer-reviewed journals were included. Of these, 151 studies were identified, of which six met the established criteria. Reviewed studies suggest beneficial effects for treatment-resistant depression, anxiety and depression associated with life-threatening diseases, and tobacco and alcohol dependence. All drugs were well tolerated. In conclusion, ayahuasca, psilocybin and LSD may be useful pharmacological tools for the treatment of drug dependence, and anxiety and mood disorders, especially in treatment-resistant patients. These drugs may also be useful pharmacological tools to understand psychiatric disorders and to develop new therapeutic agents. However, all studies reviewed had small sample sizes, and half of them were open-label, proof-of-concept studies. Randomized, double-blind, placebo-controlled studies with more patients are needed to replicate these preliminary findings.

Keywords : ayahuasca, dimethyltryptamine, hallucinogens, LSD, psilocybin, tryptamines

 

Introduction

Naturally occurring classical or serotonergic hallucinogens such as the tryptamines N,N dimethyl-tryptamine (DMT) and psilocybin (4-phosphoryloxy-N,N-DMT) have a long history of ritual use in Latin America [Harner, 1976; Grispoon and Bakalar, 1981; Dobkin de Rios, 1984, 1990; Schultes, 1986, 1998; Wasson et al. 1986; Schultes and Hofmann, 1992; Furst, 1994; Ott, 1994, 2004; Guzmán, 2008; McKenna and Riba, 2016]. DMT was first synthesized in 1931 by the Canadian chemist Richard Manske and subsequently isolated by the Brazilian chemist Oswaldo Gonçalves de Lima in 1946 from
Mimosa hostilis, a hallucinogenic plant used by northeastern Brazilian indigenous groups for the preparation of a sacred beverage called jurema [Ott, 1994, 1999, 2004; McKenna and Riba, 2016]. DMT is also the main psychotropic compound of ayahuasca, a psychotropic brew used for magico-ritual and therapeutic purposes by indigenous and urban populations of Amazonian countries such as Brazil, Colombia, Peru and Ecuador [Harner, 1976; Dobkin de Rios, 1984, 1990; Schultes, 1986, 1998; Schultes and Hofmann, 1992; Furst, 1994; Ott, 1994, 2004; McKenna and Riba, 2016].

Ayahuasca is usually obtained by boiling the stems of the liana Banisteriopsis caapi with the leaves of the shrub Psychotria viridis [Harner, 1976; Dobkin de Rios, 1984, 1990; McKenna et al. 1984; Schultes, 1986, 1998; Schultes and Hofmann, 1992; Furst, 1994; Ott, 1994, 1999, 2004; Riba et al. 2001, 2003; McKenna and Riba, 2016]. P. viridis is rich in DMT, while B. caapi contains β-carboline compounds that reversibly inhibit monoamine oxidase A (MAO-A), such as harmine, tetrahydroharmine (THH) and harmaline [Buckholtz and Boggan, 1977; Dobkin de Rios, 1984; McKenna et al. 1984; Schultes, 1986; Schultes and Hofmann, 1992; Ott, 1994, 1999, 2004; Riba, et al. 2001, 2003; McKenna and Riba, 2016]. Due to peripheral (gastrointestinal and liver) MAO-A degradation, DMT is not orally active [Riba et al. 2001, 2003, 2015; McKenna and Riba, 2016]. Thus, MAO-A inhibition by the β-carbolines in ayahuasca allows DMT to reach systemic circulation and the central nervous system [Ott, 1999; Riba et al. 2001,
2003, 2015; McKenna and Riba, 2016].

Psilocybin and its active dephosphorylated metabolite psilocin (4-hydroxy-N,N-DMT) are the primary psychoactive compounds of several species of hallucinogenic mushrooms found throughout the world [Harner, 1976; Grispoon and Bakalar, 1981; Wasson et al. 1986; Dobkin de Rios, 1990; Schultes and Hofmann, 1992; Furst, 1994; Schultes 1998; Passie et al. 2002; Ott, 2004; Guzmán, 2008; Tylš et al. 2014; McKenna and Riba, 2016]. Some of these species, such as Psilocybe mexicana, have a crucial
role in the religious and medicinal systems of indigenous groups in Mexico [Harner, 1976; Grispoon and Bakalar, 1981; Wasson et al. 1986; Dobkin de Rios, 1990; Schultes and Hofmann, 1992; Furst, 1994; Schultes, 1998; Ott, 2004; Guzmán, 2008; McKenna and Riba, 2016]. The Swiss chemist Albert Hofmann first isolated psilocybin and psilocin from P. mexicana in 1958 after several self-experiments, and synthetized these compounds later in the same year [Passie et al. 2002; Ott, 2004; Hofmann, 2005; Guzmán, 2008; Tylš et al. 2014; McKenna and Riba, 2016]. Although psilocybin is usually referred to as being the main psychoactive compound in hallucinogenic mushrooms, it is in fact a so-called prodrug of psilocin. Thus, after ingestion, it is rapidly dephosphorylated in the gut and liver into the active metabolite psilocin [Passie et al. 2002; Tylš et al. 2014; McKenna and Riba, 2016]. DMT and psilocybin are pharmacologically related to the ergoline D-lysergic acid diethylamide (LSD or LSD-25), a semi-synthetic derivative of the naturally occurring lysergic acid moiety, present in several alkaloids found in the rye ergot fungus (Claviceps purpurea) [Hofmann, 2005; Passie et al. 2008; Hintzen and Passie, 2010; Smith et al. 2014; McKenna and Riba, 2016]. LSD was first synthetized by Albert Hofmann in 1938, and its psychoactive effects were discovered when the Swiss chemist accidentally ingested the drug in 1943 [Hofmann, 2005; Passie et al. 2008; Hintzen and Passie, 2010; Smith et al. 2014; McKenna and Riba, 2016].

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