antidepressive anxiolytic and antiaddictive effects of ayahuasca psilocybin and lysergic acid diethylamide (pdf)
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the serotonin 5-ht2c receptor and the non-addictive nature of classic hallucinogens


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: antidepressive effects of ayahuasca, psilocybin and LSD

by

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 1-21

DOI: 10.1177/2045125316638008

© The Author(s), 2016.

Correspondence to:
Rafael G. dos Santos, PhD Departamento de Neurociências e Ciências do Comportamento, Faculdade de Medicina de Ribeirão Preto, Universidade de São Paulo, Hospital das Clínicas, Terceiro Andar, Av. Bandeirantes, 3900, Ribeirão Preto, São Paulo, Brazil.
banisteria@gmail.com

Flávia L. Osório, PhD José Alexandre S. Crippa, MD, PhD Antônio W. Zuardi, MD, PhD Jaime E. C. Hallak, MD, PhD, Department of Neuroscience and Behavior, Ribeirão Preto Medical School, University of São Paulo, SP, Brazil National Institute for Translational Medicine (INCT-TM), CNPq, Brazil

Jordi Riba, PhD, Centre d'Investigació de Medicaments, Servei de Farmacologia Clínica, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Human Experimental Neuropsychopharmacology, Institut de Recerca, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain Departament de Farmacologia i Terapèutica, Universitat Autònoma de Barcelona, Spain Centro de Investigación Biomédica en Red de Salud Mental, CIBERSAM, Barcelona, Spain.

Table of Contents:
Abstract
Methods
 Data acquisition
 Search strategy
 Eligibility criteria
  Article type
  Study design
  Participants
  Interventions
  Comparisons
  Outcomes
 Data extraction
Results
 Study selection
 Drugs
  Psilocybin
   Obsessive-compulsive disorder
   Anxiety associated with advanced-stage cancer
   Tobacco dependence
   Alcohol dependence
  Lysergic acid diethylamide (LSD)
   Anxiety associated with life-threatening diseases
  Ayahuasca
   Major depressive disorder
Discussion
 Possible mechanisms of therapeutic action
 Safety
Limitations
Conclusion
References

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

Naturally occurring classical or serotonergic hallucinogens such as the tryptamines N,N-dimethyltryptamine (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 semisynthetic 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].

DMT, psilocybin and LSD are agonists of serotonin 5-HT1A/2A/2C receptors [Pierce and Peroutka, 1989; McKenna et al. 1990; Glennon et al. 2000; Passie et al. 2002, 2008; Nichols, 2004; Hintzen and Passie, 2010; Hanks and González-Maeso, 2013; Tylš et al. 2014; Halberstadt, 2015]. Although the 5-HT1A/2C receptors modulate the effects of serotonergic hallucinogens, activation of fronto-cortical glutamate receptors secondary to 5-HT2A receptor-related glutamate release appears to be the key mechanism of action of these drugs [Nichols, 2004; González-Maeso et al. 2008; Moreno et al. 2011, 2013; Hanks and GonzálezMaeso, 2013; Santini et al. 2014; Buchborn et al. 2015; Carbonaro et al. 2015; Halberstadt, 2015]. The 5-HT2A and the metabotropic glutamate 2/3 (mGluR2/3) receptors show an overlapping distribution in the brain cortex, and their interaction has a crucial role in the neuropsychopharmacology of classical hallucinogens [González-Maeso et al. 2008; Moreno et al. 2011].

In the last 25 years, the ritual and therapeutic use of ayahuasca has spread from small cities in the Amazonian jungle to the urban centers of South America, the United States, Europe, Asia and Africa [Labate et al. 2009; Labate and Jungaberle, 2011; Labate and Cavnar, 2014]. Animal research [Glick et al. 1994; Aricioglu-Kartal et al. 2003; Hilber and Chapillon, 2005; Farzin and Mansouri, 2006; Lima et al. 2006; Wu et al. 2009; Fortunato et al. 2009, 2010a, 2010b; Réus et al. 2010, 2012; Brierley and Davidson, 2012, 2013; Liester and Prickett, 2012; Owaisat et al. 2012; Abelaira et al. 2013; Oliveira-Lima et al. 2015; Pic-Taylor et al. 2015; dos Santos et al. 2016] and observational and preliminary experimental studies of ayahuasca consumers [Grob et al. 1996; Barbosa et al. 2005, 2012; da Silveira et al. 2005; Doering-Silveira et al. 2005; dos Santos et al. 2007, 2016; Halpern et al. 2008; Barbosa et al. 2009; Labate et al. 2009, 2014; Fábregas et al. 2010; Labate and Jungaberle, 2011; Bouso et al. 2012; dos Santos, 2013; Thomas et al. 2013; Bouso and Riba, 2014; Fernández and Fábregas, 2014; Fernández et al. 2014; Loizaga-Velder and Loizaga Pazzi, 2014; Loizaga-Velder and Verres, 2014; Palhano-Fontes et al. 2014; Winkelman, 2014] suggest that ayahuasca and its isolated alkaloids have antidepressive, anxiolytic, and antiaddictive effects.

Moreover, experimental studies of acute ayahuasca administration to healthy volunteers [Riba et al. 2001, 2003, 2006; dos Santos et al. 2011, 2012; de Araujo et al. 2012; Palhano-Fontes et al. 2015; McKenna and Riba, 2016] and mental health assessments of long-term ayahuasca consumers [Grob et al. 1996; Barbosa et al. 2005, 2009, 2012; da Silveira et al. 2005; Doering-Silveira et al. 2005; Halpern et al. 2008; Fábregas et al. 2010; Bouso et al. 2012, 2015; dos Santos, 2013] suggest that this preparation is quite safe.

In the case of psilocybin and LSD between the mid-1950s and mid-1970s, several studies investigated the potential therapeutic use of these drugs in the treatment of neurosis, obsessive-compulsive disorder (OCD), substance dependence, and as an adjunctive therapy in the terminally ill [Kurland et al. 1971; McGlothlin and Arnold, 1971; Grispoon and Bakalar, 1981; Riedlinger and Riedlinger, 1994; Abraham et al. 1996; Delgado and Moreno, 1998; Grob, 1998; Grof, 2001; Hofmann, 2005; Dyck, 2006; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Burdick and Adinoff, 2013; Baumeister et al. 2014; Liester, 2014; Oram, 2014; Smith et al. 2014; Bogenschutz and Johnson, 2016].

However, clinical research with hallucinogens was interrupted in the late 1960s mid-1970s due to an increase in the recreational use of these substances and their association with the countercultural movements [Grispoon and Bakalar, 1981; Riedlinger and Riedlinger, 1994; Grob, 1998; Grof, 2001; Hofmann, 2005; Dyck, 2006; Hintzen and Passie, 2010; Liester, 2014; Oram, 2014; Smith et al. 2014; Bogenschutz and Johnson, 2016]. Moreover, new rules for investigating novel pharmacological agents were introduced in the 1960-1970s [Liester, 2014; Oram, 2014], creating many difficulties for human hallucinogen research since most of these studies had important methodological limitations, such as absence of adequate control groups and follow-up measurements; substantial variation of dose and dosing duration among studies; lack of control for confounding factors such as pre-existing mental health problems or participant sex and age; non-standardized criteria for therapeutic outcome; and use of diverse theoretical approaches for assessing beneficial effects (ranging from psychoanalysis or transpersonal psychology to hypnosis and sensorial isolation or overload) [Grispoon and Bakalar, 1981; Kurland et al. 1971; McGlothlin and Arnold, 1971; Riedlinger and Riedlinger, 1994; Grob, 1998; Grof, 2001; Dyck, 2006; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Burdick and Adinoff, 2013; Baumeister et al. 2014; Liester, 2014; Oram, 2014; Bogenschutz and Johnson, 2016].

Therefore, although the early clinical studies with hallucinogens showed promising results, their methodological limitations suggest caution when interpreting their results. After a halt of almost 20 years, controlled laboratory studies in humans involving the administration of hallucinogens resumed in the 1990s with the investigations in healthy volunteers of Leo Hermle and collaborators in Germany, using orally administered mescaline [Hermle et al. 1992], and of Rick Strassman and coworkers in the United States, administering intravenous DMT [Strassman and Qualls, 1994; Strassman et al. 1994].

More recent preclinical research [Delgado and Moreno, 1998; Zghoul and Blier, 2003; Matsushima et al. 2009; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Bogenschutz, 2013; Burdick and Adinoff, 2013; Baumeister et al. 2014; Buchborn et al. 2014; Bogenschutz and Johnson, 2016], case reports [Leonard and Rapoport, 1987; Riedlinger and Riedlinger, 1994; Hanes, 1996; Delgado and Moreno, 1998; Perrine, 1999; Wilcox, 2014] and observational [Krebs and Johansen, 2013; Hendricks et al. 2014, 2015; Johansen and Krebs, 2015] and preliminary experimental studies in healthy volunteers [Griffiths et al. 2006, 2011; Vollenweider and Kometer, 2010; Studerus et al. 2011; Kometer et al. 2012; Kraehenmann et al. 2016; Schmid et al. 2016] suggest that classical hallucinogens such as psilocybin and LSD have anxiolytic, antidepressive, and antiaddictive properties.

Moreover, early clinical research [Kurland et al. 1971; McGlothlin and Arnold, 1971; Grispoon and Bakalar, 1981; Strassman, 1984; Riedlinger and Riedlinger, 1994; Grob, 1998; Grof, 2001; Passie et al. 2002, 2008; Hofmann, 2005; Dyck, 2006; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Liester, 2014; Smith et al. 2014; Tylš et al. 2014; Bogenschutz and Johnson, 2016], and more recent observational studies [Krebs and Johansen, 2013; Hendricks et al. 2014, 2015; Johansen and Krebs, 2015], drug harm or risk assessments [Nutt et al. 2010; van Amsterdam et al. 2011, 2013, 2015; Morgan et al. 2013], and pharmacological studies of acute drug administration to healthy volunteers [Griffiths et al. 2006, 2011; Vollenweider and Kometer, 2010; Studerus et al. 2011; Kometer et al. 2012; Carhart-Harris et al. 2012a, 2012b, 2013; Kraehenmann et al. 2016; Schmid et al. 2016] suggest that these compounds have low toxicity and are reasonably safe when administered in supervised or controlled settings. Indeed, classic hallucinogens such as psilocybin and LSD are considered less toxic and harmful than most licit and illicit drugs [Nutt et al. 2010; van Amsterdam et al. 2011, 2013, 2015; Morgan et al. 2013].

Thus, considering this context, this study aimed to conduct a systematic literature review of clinical trials published in the last 25 years (1990- 2015) that investigated anxiolytic, antidepressive, and antiaddictive effects of ayahuasca, psilocybin and LSD.

Methods

Data for this systematic review were collected in accordance with the Systematic Reviews and Meta-Analyses guidelines (PRISMA) [Moher et al. 2009].

Data acquisition

We intended to identify all clinical trials available for review from 1 January 1990 to 1 July 2015, in which the anxiolytic, antidepressive, or antiaddictive effects of ayahuasca, psilocybin or LSD were analyzed.

Search strategy

Electronic searches were performed using the PubMed (1 January 1990 - 1 July 2015), LILACS (1 January 1990 - 1 July 2015) and SciELO (1 January 1990 - 1 July 2015) databases. The following key words were used: ayahuasca OR psilocybin OR lysergic acid diethylamide AND anxiety OR depression OR dependence. References were retrieved through searching electronic databases and manual searches through reference lists of identified literature. All studies published in English, Spanish, and Portuguese up to 1 July 2015 were included.

Eligibility criteria

The following inclusion and exclusion criteria were established prior to the literature search:

Article type

For purposes of this review, only clinical trials (open-label pilot studies, single-blind trials, or double-blind placebo-controlled trials) published in peer-reviewed journals were included. Animal studies, experimental studies in healthy volunteers, observational studies, review papers, qualitative studies, opinion pieces or comments, letters or editorials, conference abstracts or posters, books or book chapters, case reports, and published abstracts were excluded.

Study design

The review included only clinical trials involving patients with a diagnosis of an anxiety, depressive, or dependence disorder based on a structured diagnostic interview [Diagnostic and Statistical Manual of Mental Disorders (DSM)].

Participants

Only studies that included patients with a diagnosis of an anxiety, depressive, or dependence disorder based on a structured diagnostic interview (DSM) were included.

Interventions

All clinical trials evaluating the effects of ayahuasca, psilocybin, or LSD on anxiety, depressive, or dependence symptoms were included.

Comparisons

The main comparators considered were placebo and active placebo.

Outcomes

Reductions in anxiety, depressive, or dependence symptoms measured with validated scales.

Data extraction

All studies were screened by two independent reviewers, with discrepancies resolved by a third reviewer. From the articles included we recorded names of authors, year of publication, study design (open label, single or double blind), characteristics of the participants (anxiety, depressive, or dependence symptoms, and sample size), response criteria (anxiolytic, antidepressive, or antiaddictive effect), type of intervention (drug, dose, and form of administration), and type of outcome measure (anxiety, depression, or dependence symptoms and scales).

Results

Study selection

A flow diagram illustrating the different phases of the systematic review is presented in Figure 1.

150 records identified through database searching6 duplicated records excluded
144 records screened according to eligibility criteria139 records excluded according to exclusion criteria
Five full-text articles assessed for eligibility + one additional citation found through hand searchNo full-text articles were excluded after detailed examination of reports
Six studies included in the systematic review

Figure 1. Flow diagram illustrating the different phases of the systematic review.

The search of the literature yielded 150 separate references. Owing to the overlap of coverage between the databases, six of the references were found to be duplicates. Thus, a total of 144 citations were reviewed for abstract screening (first pass). Following the first pass, five potentially relevant references were identified [Moreno et al. 2006; Grob et al. 2011; Gasser et al. 2014; Bogenschutz et al. 2015; Osório et al. 2015]. The remaining 139 studies were excluded according to the exclusion criteria. Full-text reports of the five selected citations were obtained for more detailed evaluation (second pass). Following detailed examination of the reports, all five citations were included. Another citation was found after hand search of the bibliography of the selected reports [Johnson et al. 2014]. Thus, six citations were included in the systematic review.

Studies were classified according to drug (ayahuasca, psilocybin, or LSD) and symptom (anxiety, depression, or dependence symptoms). The included studies comprised four studies with psilocybin (one study of OCD: Moreno et al. 2006; one study of anxiety associated with advanced-stage cancer: Grob et al. 2011; one study of tobacco dependence: Johnson et al. 2014; and one study of alcohol dependence: Bogenschutz et al. 2015), one study with LSD (anxiety associated with life-threatening diseases: Gasser et al. 2014), and one study with ayahuasca [Osório et al. 2015]. The details of the selected studies are summarized in Table 1.

Despite the small number of studies, the small sample sizes (6-15 volunteers), the high degree of heterogeneity among studies, and the lack of placebo and control groups in three of the selected citations (open-label, proof-of-concept studies), the reported results consistently show that ayahuasca, psilocybin, and LSD have anxiolytic, antidepressive, and antiaddictive properties. These findings will be further discussed in detail below.

Table 1. Clinical trials assessing the anxiolytic, antidepressive, and antiaddictive effects of ayahuasca, psilocybin, and lysergic acid diethylamide (LSD).
ReferenceNo. of Patients/DiagnosticStudy DesignDrug (mg/kg)Main Findings
Moreno et al. [2006]9
OCD
Double blind, randomized, dose escalationPsilocybin 0.25-0.3Reduction in YBOCS scores in all subjects during one or more sessions
Reduction in VAS scores for overall OCD symptom severity
Grob et al. [2011]12
Anxiety associated with advanced-stage cancer
Double blind, randomized, active placebo (niacin 250 mg)Psilocybin 0.2Reduction in STAI trait anxiety scores at 1 and 3-month follow up, and in BDI scores at 6-month follow up
Gasser et al. [2014]12
Anxiety associated with life-threatening diseases
Double blind, randomized, active placebo (LSD 20 µg)LSD 2.9 x 10-3Reduction in STAI state anxiety scores at 2-month follow up
Johnson et al. [2014]15
Tobacco dependence
Open labelPsilocybin
0.29-0.43
Reduction in breath CO levels, urine cotinine, daily smoking (TLFB), withdrawal (WSWS), craving (QSU), and temptation to smoke (SASE), and increase in confidence to abstain (SASE) through the 6-month follow up
Bogenschutz et al. [2015]10
Alcohol dependence
Open labelPsilocybin 0.3-0.4Reduction in percent-drinking days (TLFB) at all follow up points (weeks 5-36)
Reduction in drinking consequences (SIP) and craving (PACS), and improves in self-efficacy (AASE), motivation (SOCRATES 8A), and mood (POMS) at multiple time points (weeks 5-36)
Osório et al. [2015]6
MDD
Open labelAyahuasca 2.2 ml/kg1Reduction in HAM-D, MADRS, and BPRS-AD scores between baseline and 1, 7 and 21 days after drug intake
AASE, Alcohol Abstinence Self-Efficacy Confidence score; BPRS-AD, Anxious-Depression subscale of the Brief Psychiatric Rating Scale; BDI, Beck Depression Inventory; CO, carbon monoxide; DSM, Diagnostic and Statistical Manual of Mental Disorders; HAM-D, Hamilton Rating Scale for Depression; LSD, lysergic acid diethylamide; MADRS, Montgomery-Åsberg Depression Rating Scale; MDD, major depressive disorder; OCD, obsessive-compulsive disorder; PACS, Penn Alcohol Craving Scale; POMS, Profile of Mood States; QSU, Questionnaire on Smoking Urges; SASE, Smoking Abstinence Self-Efficacy scale; SIP, Short Inventory of Problems; SOCRATES 8A, Stages of Change Readiness and Treatment Eagerness Scale; STAI, State-Trait Anxiety Inventory; TLFB, Time-Line Follow-Back; VAS, Visual Analog Scales; WSWS, Wisconsin Smoking Withdrawal Scale; YBOCS, Yale-Brown Obsessive-Compulsive Scale.
1 Orally administered as a decoction; alkaloid content 0.8 mg/ml DMT, 0.21 mg/ml harmine (no harmaline was detected).

Drugs

Psilocybin

Obsessive-compulsive disorder

In a double-blind study, nine subjects (seven men, two women) with obsessive-compulsive disorder (OCD) and at least one treatment failure with a serotonin reuptake inhibitor (mean 3.4 ± 1.9 treatment failures) received up to four different doses of orally administered psilocybin (one dose for test session) in a dose-escalation blinded design [Moreno et al. 2006]. Low (100 µg/kg), medium (200 µg/kg), and high (300 µg/kg) doses of psilocybin were administered in that order, and a very low dose (25 µg/kg) was inserted randomly and in double-blind design at any time after the first dose (100 µg/kg). Subjects met DSM-IV criteria for OCD and had a mean baseline Yale-Brown Obsessive-Compulsive Scale (YBOCS) score of 24.1 ± 5.9. YBOCS and Visual Analog Scales (VAS) scores for overall OCD symptom severity were measured immediately before drug ingestion and at 4, 8, and 24 hours after ingestion.

All subjects received the low dose, seven received the very low and medium doses, and six received all doses. Reductions in YBOCS scores ranging from 23% to 100% were observed in all subjects during one or more sessions. Moreover, 88.9% of subjects maintained no less than a 25% decrease and 66.7% maintained no less than a 50% decrease in YBOCS scores at 24 hours with at least one psilocybin dose. Symptom improvement during the following week was reported by two subjects, and one volunteer reported improvement at the 6-month follow up. VAS scores were also reduced throughout the study period, and psilocybin was well tolerated by all volunteers.

Anxiety associated with advanced-stage cancer

A double blind, randomized, placebo-controlled study assessed the safety and potential therapeutic effects of psilocybin in the treatment of psychological distress associated with the existential crisis of terminal disease [Grob et al. 2011]. Twelve subjects (11 women) with advanced-stage cancer and a DSM-IV diagnosis of acute stress disorder, generalized anxiety disorder, anxiety disorder due to cancer, or adjustment disorder with anxiety, received oral psilocybin (0.2 mg/kg) or the active placebo niacin (250 mg) in a double-blind fashion. The Beck Depression Inventory (BDI), the Profile of Mood States (POMS), and the State-Trait Anxiety Inventory (STAI) were administered the day before, at the conclusion, the day after, and 2 weeks after each experimental session. The BDI, POMS, and STAI were administered again at monthly intervals for 6 months after the final session.

All 12 participants completed the 3 months of follow up, 11 completed the 4-month follow up, and eight completed the 6-month follow up. During the study, two subjects died of their cancer and two became too ill to continue the study. Significant decreases were observed in STAI scores at the 1- and 3-month follow ups, and in BDI scores at the 6-month follow up. No significant changes were observed in POMS scores, and psilocybin was well tolerated by all patients. By the time of the paper's submission in 2010, 10 of the 12 subjects had died of their cancer.

Tobacco dependence

An open-label study assessed the effects of moderate (20 mg/70 kg) and high (30 mg/70 kg) doses of psilocybin in 15 (ten men, five women; mean age of 51 years) nicotine-dependent smokers [Johnson et al. 2014]. Participants had a mean of six previous lifetime quit attempts, and smoked a mean of 19 cigarettes per day for a mean of 31 years. Volunteers participated in a 15-week smoking cessation treatment (cognitive behavioral therapy), with psilocybin administration occurring in weeks 5 (moderate dose), 7 (high dose), and 13 (high dose) (participants were permitted to repeat the moderate dose on sessions two and three). Changes in mean cigarettes per day were compared between the 30 days prior to study intake and the 6 months after the first psilocybin session (at week 5 of treatment). Exhaled carbon monoxide (CO) and urinary cotinine level were assessed at intake, weekly throughout the intervention, and at 6-month follow up to measure recent smoking.

All participants completed the study. According to the Time-Line Follow-Back (TLFB) and biomarker data (breath CO, urine cotinine), 80% (12 of 15) of participants were abstinent at 6-month follow up. Among the entire sample, significant reductions from intake to the 6-month follow up were observed in breath CO levels, urine cotinine, and self-reported daily smoking. Moreover, craving [Questionnaire on Smoking Urges (QSU)] and temptation to smoke [Smoking Abstinence Self-Efficacy scale (SASE)] were significantly reduced across all time points.

Significant increases were reported for confidence to abstain (SASE) from intake to the 6-month follow up, and withdrawal scores [Wisconsin Smoking Withdrawal Scale (WSWS)] peaked at 1-week post-psilocybin and decreased significantly through the 6-month follow up. No significant adverse events were reported during psilocybin sessions.

Alcohol dependence

Ten volunteers (four women, six men) with DSM-IV alcohol dependence (mean duration of dependence 15.1 ± 11.5 years, range 4-32) participated in an open-label trial that included a 12-session psychosocial intervention and two oral doses of psilocybin [Bogenschutz et al. 2015]. Eight of the 10 volunteers had evidence of physical dependence (tolerance or withdrawal). The psychosocial intervention included seven sessions of Motivational Enhancement Therapy (MET); three preparation sessions; two debriefing sessions; four sessions before the first psilocybin dose (0.3 mg/kg); four sessions between the first and second psilocybin dose (0.4 mg/kg); and four sessions after the second psilocybin dose. Outcome measures were collected for 36 weeks.

Nine volunteers completed all follow-up assessments; 10 completed the first psilocybin session, and seven the second session. However, only six patients were included in the analysis of the second session since one volunteer did not receive the 0.4 mg/kg psilocybin dose, receiving the 0.3 mg/kg due to meeting criteria for 'complete mystical experience' [Mystical Experience Questionnaire (MEQ)] in the first session. One patient discontinued participation and was excluded from the analysis.

According to the TLFB, percent-drinking days (consumption of any amount of an alcoholic beverage) and heavy-drinking days (consumption of four or more drinks of 14 g of alcohol) decreased significantly relative to weeks 1-4 prior to psilocybin, and also during weeks 5-12 relative to baseline. Following the first psilocybin session, percent-drinking days and heavy-drinking days were significantly lower than baseline at all follow-up points.

Significant correlations were observed between the overall intensity (Hallucinogen Rating Scale Intensity score; Altered States of Consciousness Scale summary score) and mystical quality (MEQ) of the psilocybin session and changes in percent-drinking days (TLFB), craving [Penn Alcohol Craving Scale (PACS)], self-efficacy to abstain from drinking [Alcohol Abstinence Self-Efficacy Confidence score (AASE)], and motivation [Stages of Change Readiness and Treatment Eagerness Scale (SOCRATES 8A)].

Improvements were largely maintained throughout the 36 weeks follow up. At multiple time points relative to baseline and (or) week 4, psilocybin reduced drinking consequences [Short Inventory of Problems, (SIP); weeks 8 to 36] and craving (PACS), and improved self-efficacy (AASE; weeks 5, 9, 24 and 36), motivation (SOCRATES 8A; weeks 5 to 36), and mood [Profile of Mood States, (POMS); weeks 4 and 24]. No significant adverse effects were reported after psilocybin administration.

Lysergic acid diethylamide (LSD)

Anxiety associated with life-threatening diseases

A double blind, randomized, active placebo-controlled study assessed the effects of lysergic acid diethylamide (LSD) in 12 patients (seven men, four women) with anxiety associated with life-threatening diseases (cancer, or chronic motor or inflammatory diseases) [Gasser et al. 2014]. Volunteers had a score of no less than 40 on the state or trait scales of the STAI and a DSM-IV diagnosis of major depressive disorder (MDD), reactive depression, dysthymia, posttraumatic stress disorder (PTSD), panic disorder, or social phobia. The study included drug-free psychotherapy sessions and two LSD-assisted psychotherapy sessions. Volunteers received either an experimental dose (200 µg, n = 8) or an active placebo (20 µg, n = 3) of LSD 2 to 3 weeks apart, with an open-label crossover to 200 µg of LSD after the initial blinded treatment (n = 4). Outcome data were collected at baseline, 1 week after LSD sessions, and at 2- and 12-month follow ups.

At the 2-month point, STAI state anxiety was significantly reduced, and a trend was found for reductions in STAI trait anxiety. STAI reductions were sustained for 12 months. Beneficial results were also observed in secondary outcome measures, including the European Cancer Quality of Life Questionnaire 30-item version 1.0 (EORTCQLQ-30), the Symptom Checklist-90-Revised (SCL-90-R), and the Hospital Anxiety and Depression Scale (HADS). However, due to concerns about multiplicity, changes in secondary outcome measures were not analyzed for statistical significance. No adverse effects or treatment-related serious adverse events were reported.

Ayahuasca

Major depressive disorder

An open-label trial assessed the antidepressive potential of ayahuasca in patients with diagnosis of recurrent major depressive disorder (MDD) [Osório et al. 2015]. A single dose of orally administered ayahuasca (2.2 ml/kg body weight) was administered to six volunteers (two men, four women) suffering a mild (n = 2), moderate (n = 3) or severe (n = 1) depressive episode. Ayahuasca administration produced statistically significant reductions of up to 82% in depressive scores between baseline and 1, 7 and 21 days after drug intake, according to the Hamilton Rating Scale for Depression (HAMD), the Montgomery-Åsberg Depression Rating Scale (MADRS), and the Anxious-Depression subscale of the Brief Psychiatric Rating Scale (BPRS). Ayahuasca did not produce significant effects in the Young Mania Rating Scale (YMRS) scores or in the other subscales of the BPRS. Ayahuasca was well tolerated by all patients and vomiting was the only adverse effect recorded, being reported by 50% of the volunteers. Patients did not consider this emetic effect as causing severe discomfort.

Discussion

Possible mechanisms of therapeutic action

The mechanisms of action responsible for the beneficial effects produced by ayahuasca, psilocybin and LSD are not completely understood. Preclinical evidence show that ayahuasca [Lima et al. 2006; Pic-Taylor et al. 2015] and its β-carbolines harmine [Aricioglu-Kartal et al. 2003; Farzin and Mansouri, 2006; Fortunato et al. 2009, 2010a, 2010b; Réus et al. 2010, 2012; Brierley and Davidson, 2012; Owaisat et al. 2012] and harmaline [Glick et al. 1994; Hilber and Chapillon, 2005; Wu et al. 2009], as well as psilocybin [Matsushima et al. 2009] and LSD [Zghoul and Blier, 2003; Buchborn et al. 2014], have antidepressive, anxiolytic, and antiaddictive properties. Experimental studies with healthy volunteers report that acute administration of DMT [Gillin et al. 1976; Strassman et al. 1994; Riba et al. 2015], psilocybin [Griffiths et al. 2006, 2011; Studerus et al. 2011; Kometer et al. 2012; Kraehenmann et al. 2016], and LSD [Schmid et al. 2016] increase positive mood. Furthermore, observational and preliminary experimental studies of ayahuasca consumers [Grob et al. 1996; Barbosa et al. 2005, 2009, 2012; da Silveira et al. 2005; Doering-Silveira et al. 2005; dos Santos et al. 2007, 2016; Halpern et al. 2008; Labate et al. 2009, 2014; Fábregas et al. 2010; Labate and Jungaberle, 2011; Bouso et al. 2012; dos Santos, 2013; Thomas et al. 2013; Bouso and Riba, 2014; Fernández and Fábregas, 2014; Fernández et al. 2014; Loizaga-Velder and Loizaga Pazzi, 2014; Loizaga-Velder and Verres, 2014; Palhano-Fontes et al. 2014; Winkelman, 2014], as well as case reports [Leonard and Rapoport, 1987; Riedlinger and Riedlinger, 1994; Hanes, 1996; Delgado and Moreno, 1998; Perrine, 1999; Wilcox, 2014] and observational studies [Krebs and Johansen, 2013; Hendricks et al. 2014, 2015; Johansen and Krebs, 2015] involving psilocybin and LSD, also suggest that these drugs have therapeutic potentials.

Since DMT, psilocybin and LSD are agonists of serotonin 5-HT1A/2A/2C receptors [Pierce and Peroutka, 1989; McKenna et al. 1990; Glennon et al. 2000; Passie et al. 2002, 2008; Nichols, 2004; Hintzen and Passie, 2010; Hanks and González-Maeso, 2013; Tylš et al. 2014; Halberstadt, 2015], these receptors may be involved in the therapeutic effects of these tryptamines. In fact, cortical expression of 5-HT1A/2A/2C receptor is altered in postmortem samples of depressed patients, suggesting that these receptors are involved in emotional processing [Vollenweider and Kometer, 2010; Baumeister et al. 2014]. Furthermore, animal models and clinical studies show that 5-HT1A receptor agonists have anxiolytic and antidepressive properties [Nutt, 2005; Katzman, 2009; Baumeister et al. 2014], and 5-HT2A/2C receptor agonists reduce anxiety- and depression-related behavior in animals [Masuda and Sugiyama, 2000; Nic Dhonnchadha et al. 2003a, 2003b; Baumeister et al. 2014].

Another possible mechanism of therapeutic action is the modulation of glutamatergic neurotransmission induced by 5-HT2A-receptor agonism [Nichols, 2004; González-Maeso et al. 2008; Vollenweider and Kometer, 2010; Moreno et al. 2011, 2013; Hanks and González-Maeso, 2013; Santini et al. 2014; Buchborn et al. 2015; Carbonaro et al. 2015; Halberstadt, 2015]. Activation of frontocortical glutamate networks by 5-HT2A receptor agonists could lead to increases in the expression of neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) and in the size of dendritic spines on cortical neurons, thus enhancing neuroplasticity and neurogenesis [Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Ross, 2012; Baumeister et al. 2014; Bogenschutz and Johnson, 2016]. For instance, depression is associated with deficient neurogenesis and neurotrophic activity, and BDNF levels are decreased in depressed patients and normalized after antidepressant treatment [Baumeister et al. 2014]. Furthermore, alcohol self-administration and conditioned place preference are inversely related to BDNF or GDNF expression in animal models [Bogenschutz and Pommy, 2012; Bogenschutz and Johnson, 2016]. Interestingly, a low dose (0.1 mg/kg) of psilocybin produced a trend toward increased neurogenesis in the mouse hippocampus 2 weeks after its administration, while a high dose (1 mg/kg) significantly decreased neurogenesis [Catlow et al. 2013]. These results suggest that the effects of psilocybin on neurogenesis are dose- and time-related.

Agonism at the 5-HT2A receptor could also produce beneficial effects due to an anti-inflammatory action [Nau et al. 2013; Baumeister et al. 2014; dos Santos, 2014; Szabo et al. 2014]. Increased levels of pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), interleukin-6 (IL-6), IL-8, and IL-1β are associated with depressive illness, while normalization of these levels are related to antidepressant effects [Baumeister et al. 2014; Réus et al. 2015]. The 5-HT2A receptor is expressed in central and peripheral immune-related cells [Stefulj et al. 2000; Nau et al. 2013], and 5-HT2A agonists may modulate the immune system [Forrer and Goldner, 1951; Feld et al. 1958; Sackler et al. 1963, 1966; Hollister and Sjoberg, 1964; House et al. 1994, 1997; Stefulj et al. 2000; Passie et al. 2002; Davydova et al. 2010; Hintzen and Passie, 2010; dos Santos et al. 2011, 2012; Frecska et al. 2013; Nau et al. 2013; Baumeister et al. 2014; dos Santos, 2014; Szabo et al. 2014]. Indeed, in vitro studies show that LSD inhibits the production of IL-6 [House et al. 1994, 1997], and the serotonergic hallucinogen 4-iodo-2,5-dimethoxyphenylisopropylamine (DOI, a 5-HT2A receptor agonist) produces anti-inflammatory effects in mice by blocking TNF-α-induced expression of pro-inflammatory cell adhesion (Icam-1, Vcam-1), cytokine (IL-6, IL-1β), and chemokine (Mcp-1, Cx3cl1) genes, and expression of VCAM-1 protein [Nau et al. 2013]. These effects were blocked by a 5-HT2A selective antagonist, implicating this receptor in the anti-inflammatory effects of DOI. Moreover, DMT and the related tryptamine 5-methoxy-DMT (5-MeO-DMT) reduced the mRNA expression and the levels of IL-6, IL-8, IL-1β, and TNF-α, increased the levels of the anti-inflammatory cytokine IL-10, and inhibited the immune responses of inflammatory T helper 1/17 (Th1/Th17) cells [Szabo et al. 2014]. Interestingly, gene knock-down experiments showed that the effects of both tryptamines on TNFα, IL-10, and Th1/Th17 responses were mediated by the sigma-1 receptor, and recent studies show that DMT is an endogenous agonist for the sigma-1 receptor [Fontanilla et al. 2009; Su et al. 2009; Frecska et al. 2013; Szabo et al. 2014].

The possible modulation of the sigma-1 receptor by DMT shows that other mechanisms of action that are not dependent of the 5-HT1A/2A/2C receptors may also be involved in the therapeutic action of classic hallucinogens. For instance, harmine, THH and harmaline reversibly inhibit MAO-A [Buckholtz and Boggan, 1977; McKenna et al. 1984; Ott, 1994, 1999, 2004; Riba et al. 2001, 2003; McKenna and Riba, 2016], and reversible inhibitors of MAO-A (RIMAs) are clinically used as anxiolytic and antidepressant drugs [Yamada and Yasuhara, 2004; Nutt, 2005]. Moreover, rodent studies show that the antidepressive effects of harmine are associated with increases in BDNF levels [Fortunato et al. 2009; 2010a; 2010b].

Neural oxidative stress and subsequent neuroinflammation are associated with psychiatric disorders such as depression [Réus et al. 2015], and several preclinical studies show that harmine and harmaline have antioxidant and neuroprotective effects that seem to be mediated by MAO inhibition [Maher and Davis, 1996; Biradar et al. 2013], regulation of the dual specificity tyrosine-phosphorylation-regulated kinase DYRK1A [Frost et al. 2011], modulation of dopaminergic [Lee et al. 2000; Schwarz et al. 2003], cholinergic [Biradar et al. 2013], and glutamatergic [Maher and Davis, 1996; Li et al. 2011; Sun et al. 2014] pathways, interaction with voltage-gated membrane channels [Splettstoesser et al. 2005], and regulation of cell-energy homeostasis, mitochondrial functions, and oxygen free radical scavenging [Moura et al. 2007; Réus et al. 2010, 2012; Abelaira et al. 2013]. Furthermore, harmine also has anti-inflammatory properties that seem to be mediated at least in part by DYRK1A [Khor et al. 2015].

The antiaddictive effects of ayahuasca, psilocybin and LSD could also be related to the activation of the dopaminergic system. For instance, preclinical studies show that LSD [Nichols, 2004; Passie et al. 2008; Hintzen and Passie, 2010], psilocybin [Tylš et al. 2014; Sakashita et al. 2015], and ayahuasca [de Castro-Neto et al. 2013] may indirectly stimulate dopaminergic pathways, probably through 5-HT2A-receptor activation (LSD, psilocybin, and DMT) or MAO inhibition (β-carbolines). Moreover, acute psilocybin administration indirectly increased (through 5-HT1A/2A receptors) the release of dopamine in the ventral striatum in humans [Vollenweider et al. 1999]. Animal studies suggest that the antiaddictive potentials of harmine and harmaline appear to involve imidazoline, glutamate, and dopamine pathways [Glick et al. 1994; Iurlo et al. 2001; Aricioglu-Kartal et al. 2003; Schwarz et al. 2003; Brierley and Davidson, 2012, 2013; Owaisat et al. 2012].

Recent neuroimaging studies in humans suggest that the mood-enhancing properties of ayahuasca and psilocybin could be related to modifications in the activity of brain regions such as the amygdala and the anterior cingulate cortex (ACC), involved in emotional processing, and the default mode network (DMN), a group of brain regions associated with introspection and other internally focused functions [Riba et al. 2006; Araujo et al. 2012; Carhart-Harris et al. 2012a, 2014; Tagliazucchi et al. 2014; Bouso et al. 2015; Palhano-Fontes et al. 2015; Alonso et al. 2015; Kraehenmann et al. 2016; McKenna and Riba, 2016]. Psilocybin reduced amygdala reactivity, which correlated with increases in positive mood [Kraehenmann et al. 2016]. Increased activity of the DMN is associated with intensification of the self-reference process of rumination, which is an important depressive symptom, and acute administration of ayahuasca [Palhano-Fontes et al. 2015] and psilocybin [Carhart-Harris et al. 2012a] reduces brain activity in key regions of the DMN, such as the posterior cingulate cortex (PCC). Moreover, regular ayahuasca use is associated with cortical thinning in the PCC [Bouso et al. 2015].

Early human research with classical hallucinogens suggests that the therapeutic properties of these compounds are related at least in part to their effects on perceptions, emotions, and thoughts [Kurland et al. 1971; McGlothlin and Arnold, 1971; Grispoon and Bakalar, 1981; Riedlinger and Riedlinger, 1994; Abraham et al. 1996; Delgado and Moreno, 1998; Grob, 1998; Grof, 2001; Hofmann, 2005; Dyck, 2006; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Burdick and Adinoff, 2013; Baumeister et al. 2014; Liester, 2014; Oram, 2014; Majiæ et al. 2015; Bogenschutz and Johnson, 2016]. The subjective experience produced by these drugs would create a 'window of opportunity' in which changes in unhealthy thoughts, emotions, and behaviors could take place in a psychotherapeutic context [Kurland et al. 1971; McGlothlin and Arnold, 1971; Grispoon and Bakalar, 1981; Riedlinger and Riedlinger, 1994; Abraham et al. 1996; Delgado and Moreno, 1998; Grob, 1998; Grof, 2001; Hofmann, 2005; Dyck, 2006; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Burdick and Adinoff, 2013; Baumeister et al. 2014; Liester, 2014; Oram, 2014; Majiæ et al. 2015; Bogenschutz and Johnson, 2016]. Recent neuroimaging studies with ayahuasca and psilocybin seem to corroborate these early ideas by suggesting that the altered state of consciousness produced by these drugs would create a disruption or interruption of the repetitive, rigid, and pathological pattern of negative and compulsive thoughts present in anxiety and mood disorders and in drug dependence, contributing to mental flexibility and changes in perspective, values, and behavior [Carhart-Harris et al. 2012a, 2014; Tagliazucchi et al. 2014; Palhano-Fontes et al. 2015; McKenna and Riba, 2016].

Furthermore, the ability of classical hallucinogens to elicit religious, mystical, transcendent, or peak experiences has also been proposed as a possible psychological mechanism associated with the beneficial effects of these drugs [Kurland et al. 1971; McGlothlin and Arnold, 1971; Grispoon and Bakalar, 1981; Riedlinger and Riedlinger, 1994; Abraham et al. 1996; Delgado and Moreno, 1998; Grob, 1998; Grof, 2001; Hofmann, 2005; Dyck, 2006; Griffiths et al. 2006, 2008, 2011; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; MacLean et al. 2011; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Burdick and Adinoff, 2013; Baumeister et al. 2014; Liester, 2014; Oram, 2014; Majiæ et al. 2015; Bogenschutz and Johnson, 2016]. Indeed, recent studies in healthy individuals show that acute psilocybin administration induces highly meaningful and spiritually significant experiences with sustained positive changes in attitudes, mood, personality, and behavior [Griffiths et al. 2006, 2008, 2011; MacLean et al. 2011]. Moreover, a secondary analysis of the data from the study of psilocybin and tobacco dependence reported that the mystical-type effects of psilocybin and their personal meaning, spiritual significance, and impact on well-being were correlated with improvements in smoking cessation [Garcia-Romeu et al. 2014; Johnson et al. 2014]. A qualitative follow-up assessment of the patients enrolled in the study of LSD-assisted psychotherapy for anxiety associated with a life-threatening disease also suggested that the intense emotional experiences with mystic-like features produced by LSD could mediate the observed long-term beneficial changes in perspectives, attitudes, values, and quality of life [Gasser et al. 2014, 2015].

Interestingly, these findings are consistent with studies that suggest that the dissociative, psychotomimetic, and mystical-type effects produced by the N-methyl-D-aspartate (NMDA) antagonist ketamine may mediate the anxiolytic [Kolp et al. 2007], antidepressive [Sos et al. 2013; Luckenbaugh et al. 2014], and antiaddictive [Krupitsky et al. 1992, 2002, 2007; Krupitsky and Grinenko, 1997; Jansen, 2001; Kolp et al. 2006; Krupitsky and Kolp, 2007; Dakwar et al. 2014a, 2014b] properties of this non-classic hallucinogen. Moreover, some authors suggested that the temporary mental state produced by classic hallucinogens might induce profound long-term effects by producing an 'inverse post-traumatic stress disorder (PTSD)-like effect' in which a highly significant and positive experience would cause lasting beneficial changes, as opposed to chronic negative mood and other detrimental symptoms caused by a single traumatic event, which characterizes PTSD [MacLean et al. 2011; Young 2013; Garcia-Romeu et al. 2014].

Human hallucinogenic research performed in the 1960s and 1970s also suggests that the context and the psychotherapeutic approach used in combination with classic hallucinogens are also important components of the beneficial effects produced by these drugs [Kurland et al. 1971; McGlothlin and Arnold, 1971; Grispoon and Bakalar, 1981; Riedlinger and Riedlinger, 1994; Abraham et al. 1996; Delgado and Moreno, 1998; Grob, 1998; Grof, 2001; Hofmann, 2005; Dyck, 2006; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Burdick and Adinoff, 2013; Baumeister et al. 2014; Liester, 2014; Oram, 2014; Majiæ et al. 2015; Bogenschutz and Johnson, 2016]. The methodology of the clinical trials included in the present systematic review are very diverse regarding this topic: three studies assessed the effects of single-dose exposures without psychotherapeutic approaches [Moreno et al. 2006; Grob et al. 2011; Osório et al. 2015] and three trials included some form of psychological intervention over a few weeks [Gasser et al. 2014; Johnson et al. 2014; Bogenschutz et al. 2015]. The studies without psychotherapy suggest that biochemical mechanisms may be involved in the beneficial effects observed. On the other hand, the inclusion of psychological interventions in the other studies suggests that at least some part of the therapeutic results is related to nondrug factors. Placebo effects and enhanced suggestibility may also play a role as adjuncts in hallucinogen-assisted psychotherapy [Young, 2013; Carhart-Harris et al. 2015].

Future research should investigate the possible influence of different psychotherapeutic approaches or other nondrug factors - such as patient preparation before drug administration and integration of the drug session afterwards - in mediating the therapeutic properties of classic hallucinogens.

Safety

No serious adverse reactions were reported in any of the clinical trials reviewed in the present systematic review, suggesting that classic hallucinogens can be safely administered to patients suffering anxiety, depression, or drug dependence. Previous experimental studies of acute ayahuasca administration to healthy volunteers [Riba et al. 2001, 2003, 2006; dos Santos et al. 2011, 2012; de Araujo et al. 2012; Palhano-Fontes et al. 2015; McKenna and Riba, 2016] also suggest that this drug can be safely administered in controlled experimental settings. Observational studies of long-term ayahuasca consumers [Grob et al. 1996; Barbosa et al. 2005, 2009, 2012; da Silveira et al. 2005; Doering-Silveira et al. 2005; Halpern et al. 2008; Fábregas et al. 2010; Bouso et al. 2012, 2015; dos Santos, 2013] also suggest that this brew has a low toxicity profile when consumed in ritual contexts. Previous clinical research [Kurland et al. 1971; McGlothlin and Arnold, 1971; Grispoon and Bakalar, 1981; Strassman, 1984; Riedlinger and Riedlinger, 1994; Grob, 1998; Grof, 2001; Passie et al. 2002, 2008; Hofmann, 2005; Dyck, 2006; Hintzen and Passie, 2010; Vollenweider and Kometer, 2010; Bogenschutz and Pommy, 2012; Krebs and Johansen, 2012; Bogenschutz, 2013; Liester, 2014; Smith et al. 2014; Tylš et al. 2014; Bogenschutz and Johnson, 2016] and recent observational studies [Krebs and Johansen, 2013; Hendricks et al. 2014, 2015; Johansen and Krebs, 2015], drug harm or risk assessments [Nutt et al. 2010; van Amsterdam et al. 2011, 2013, 2015; Morgan et al. 2013], and experimental studies with healthy volunteers [Vollenweider and Kometer, 2010; Carhart-Harris et al. 2012a, 2012b, 2013] also suggest that psilocybin and LSD can be safely administered in controlled settings.

Limitations

A main limitation of the present systematic review is the inclusion of a small number of studies (six) with small sample sizes (6-15 volunteers), which limits the generalization of the reported results. Included studies also show a high degree of heterogeneity, and three of the selected citations did not include placebo or a control group (open-label, proof-of-concept studies). Another important limitation is the difficulty in disentangling placebo effects, drug effects, and the influence of the psychological intervention included in the clinical trial.

However, despite these important limitations, results consistently showed that ayahuasca, psilocybin, and LSD produced anxiolytic, antidepressive, and antiaddictive effects in patients, and these results were also observed in animal studies and with healthy volunteers. Given the low success rates of current pharmacological and nonpharmacological treatments for drug dependence and anxiety and mood disorders, and considering the high morbidity and mortality associated with these disorders, it is necessary to perform more studies with these drugs, even if only a small portion of patients may reduce their suffering with these drugs. Future studies should include more patients, placebo or active placebo, randomized and double-blind designs, and multiple doses during treatment. Moreover, the influence of psychological interventions and the possible increases in therapeutic efficacy proportionated by these psychotherapeutic approaches should be better explored.

Conclusion

Currently available pharmacological treatments for drug dependence and anxiety and mood disorders have limited efficacy and often produce important adverse reactions that may limit treatment continuation. Classic tryptamine hallucinogens such as ayahuasca/DMT, psilocybin, and LSD are safely administered in controlled settings and several basic, experimental, and clinical studies suggest that these drugs have anxiolytic, antidepressive, and antiaddictive effects. Such beneficial properties seem to be mediated by an agonist action of these compounds on 5-HT1A/2A/2C receptors, which are involved in emotional processing, regulation of neurotrophic factors, anti-inflammatory actions, and modulation of frontal and medial brain structures. Other mechanisms of action not related to serotonergic receptors, such as regulation of cell energy homeostasis, mitochondrial functions, and oxidative stress, also appear to mediate these therapeutic effects.

The reviewed studies suggest that the therapeutic use of classic hallucinogens may offer to some patients fast-acting and prolonged beneficial effects after a single dose, producing few adverse effects. Indeed, interest in the medicinal uses of this class of drugs is increasing: new clinical trials investigating the effects of psilocybin in the treatment of alcoholism, cocaine dependence, tobacco dependence, and anxiety and depression associated with cancer are currently underway [ClinicalTrials.gov identifiers: NCT02061293, NCT02037126, NCT01943994, NCT00957359, NCT00465595]. Moreover, our group recently replicated the results of the original open-label, proof-of-concept study [Osório et al. 2015] but including an increased sample size (n =17) and single-photon emission computed tomography (SPECT), showing that ayahuasca antidepressive properties may be associated with increased blood perfusion in brain areas related to depressive symptoms (Sanches et al. 2016 "This reference was not included in the review because it was not published at the time of the electronic search"). Our group is currently performing randomized, double blind, placebo-controlled studies assessing the antidepressive and anxiolytic potentials of ayahuasca [Frood, 2015].

Further studies are urgently needed to better understand the effects of classical tryptamine hallucinogens in psychiatric disorders.

Acknowledgements
Rafael dos Santos is a fellow of the 'National Post-Doctorate' Program, Brazil (PNPD/CAPES).

Funding
This research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors.

Conflict of interest statement
The authors declare that there is no conflict of interest.

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