Top Academic Articles

LSD: a new treatment emerging from the past

Psychedelics fell from medical grace nearly half a century ago, but recent activity suggests that some researchers have “high hopes” for their return.1,2 Over 60 years ago, Albert Hofmann at Sandoz Pharmaceutical Laboratories in Switzerland first synthesized lysergic acid diethylamide (LSD) and personally experienced its effects (later described as a voyage into madness or a chemically induced psychosis) in 1943. Hofmann’s drug opened up a new era of hallucinogenic research. Over the next 15 years, more than a thousand articles on the use of LSD appeared in medical and scientific publications. In 1957, that work gave rise to the term “psychedelic” to describe a mind-manifesting response, described by some as an experience that brought to light matters that had previously been part of the unconscious.

Ayahuasca: Pharmacology, neuroscience and therapeutic potential

Ayahuasca is the Quechua name for a tea obtained from the vine Banisteriopsis caapi, and used for ritual purposes by the indigenous populations of the Amazon. The use of a variation of the tea that combines B. caapi with the leaves of the shrub Psychotria viridis has experienced unprecedented expansion worldwide for its psychotropic properties. This preparation contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT) from P. viridis, plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties from B. caapi. Acute administration induces a transient modified state of consciousness characterized by introspection, visions, enhanced emotions and recollection of personal memories. A growing body of evidence suggests that ayahuasca may be useful to treat substance use disorders, anxiety and depression. Here we review the pharmacology and neuroscience of ayahuasca, and the potential psychological mechanisms underlying its therapeutic potential. We discuss recent findings indicating that ayahuasca intake increases certain mindfulness facets related to acceptance and to the ability to take a detached view of one’s own thoughts and emotions. Based on the available evidence, we conclude that ayahuasca shows promise as a therapeutic tool by enhancing self-acceptance and allowing safe exposure to emotional events. We postulate that ayahuasca could be of use in the treatment of impulse-related, personality and substance use disorders and also in the handling of trauma. More research is needed to assess the full potential of ayahuasca in the treatment of these disorders.

MDMA-assisted therapy for severe PTSD: a randomized, double-blind, placebo-controlled phase 3 study

Post-traumatic stress disorder (PTSD) presents a major public health problem for which currently available treatments are modestly effective. We report the findings of a randomized, double-blind, placebo-controlled, multi-site phase 3 clinical trial (NCT03537014) to test the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted therapy for the treatment of patients with severe PTSD, including those with common comorbidities such as dissociation, depression, a history of alcohol and substance use disorders, and childhood trauma. After psychiatric medication washout, participants (n = 90) were randomized 1:1 to receive manualized therapy with MDMA or with placebo, combined with three preparatory and nine integrative therapy sessions. PTSD symptoms, measured with the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5, the primary endpoint), and functional impairment, measured with the Sheehan Disability Scale (SDS, the secondary endpoint) were assessed at baseline and at 2 months after the last experimental session. Adverse events and suicidality were tracked throughout the study. MDMA was found to induce significant and robust attenuation in CAPS-5 score compared with placebo (P < 0.0001, d = 0.91) and to significantly decrease the SDS total score (P = 0.0116, d = 0.43). The mean change in CAPS-5 scores in participants completing treatment was −24.4 (s.d. 11.6) in the MDMA group and −13.9 (s.d. 11.5) in the placebo group. MDMA did not induce adverse events of abuse potential, suicidality or QT prolongation. These data indicate that, compared with manualized therapy with inactive placebo, MDMA-assisted therapy is highly efficacious in individuals with severe PTSD, and treatment is safe and well-tolerated, even in those with comorbidities. We conclude that MDMA-assisted therapy represents a potential breakthrough treatment that merits expedited clinical evaluation.

Treating drug dependence with the aid of ibogaine: a retrospective study

Ibogaine is an alkaloid purported to be an effective drug dependence treatment. However, its efficacy has been hard to evaluate, partly because it is illegal in some countries. In such places, treatments are conducted in underground settings where fatalities have occurred. In Brazil ibogaine is unregulated and a combined approach of psychotherapy and ibogaine is being practiced to treat addiction. To evaluate the safety and efficacy of ibogaine, we conducted a retrospective analysis of data from 75 previous alcohol, cannabis, cocaine and crack users (72% poly-drug users). We observed no serious adverse reactions or fatalities, and found 61% of participants abstinent. Participants treated with ibogaine only once reported abstinence for a median of 5.5 months and those treated multiple times for a median of 8.4 months. This increase was statistically significant (p < 0.001), and both single or multiple treatments led to longer abstinence periods than before the first ibogaine session (p < 0.001). These results suggest that the use of ibogaine supervised by a physician and accompanied by psychotherapy can facilitate prolonged periods of abstinence, without the occurrence of fatalities or complications. These results suggest that ibogaine can be a safe and effective treatment for dependence on stimulant and other non-opiate drugs

Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance

Rationale: Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. Objectives: This double-blind study evaluated the acute and longer-term psychological effects of a high dose of psilocybin relative to a comparison compound administered under comfortable, supportive conditions. Materials and methods: The participants were hallucinogen-naïve adults reporting regular participation in religious or spiritual activities. Two or three sessions were conducted at 2-month intervals. Thirty volunteers received orally administered psilocybin (30 mg/70 kg) and methylphenidate hydrochloride (40 mg/70 kg) in counterbalanced order. To obscure the study design, six additional volunteers received methylphenidate in the first two sessions and unblinded psilocybin in a third session. The 8-h sessions were conducted individually. Volunteers were encouraged to close their eyes and direct their attention inward. Study monitors rated volunteers’ behavior during sessions. Volunteers completed questionnaires assessing drug effects and mystical experience immediately after and 2 months after sessions. Community observers rated changes in the volunteer’s attitudes and behavior. Results: Psilocybin produced a range of acute perceptual changes, subjective experiences, and labile moods including anxiety. Psilocybin also increased measures of mystical experience. At 2 months, the volunteers rated the psilocybin experience as having substantial personal meaning and spiritual significance and attributed to the experience sustained positive changes in attitudes and behavior consistent with changes rated by community observers. Conclusions: When administered under supportive conditions, psilocybin occasioned experiences similar to spontaneously occurring mystical experiences. The ability to occasion such experiences prospectively will allow rigorous scientific investigations of their causes and consequences.

The epidemiology of mescaline use: Pattern of use, motivations for consumption, and perceived consequences, benefits, and acute and enduring subjective effects

Background: Mescaline is a naturally occurring psychoactive phenethylamine found in several cacti and historically used ceremonially by Indigenous and Latin American populations. Broader recognition of its possible therapeutic value in Western science began in the 1950s; however, knowledge of the safety profile of mescaline and the extent of its use remains limited. The primary aim of this study is to examine the epidemiology of mescaline use among English-speaking adults. Methods: About 452 respondents completed a web-based survey designed to assess their previous experience with mescaline (subjective effects, outcome measures, and mescaline type used). Results: Most respondents reported that they had consumed mescaline infrequently (⩽once/year), for spiritual exploration or to connect with nature (74%). A small number of respondents reported drug craving/desire (9%), whereas very few reported legal (1%), or psychological problems (1%) related to its use, and none reported seeking any medical attention. Overall, respondents rated the acute mystical-type effects as “moderate,” ego-dissolution and psychological insight effects as “slight,” and challenging effects as “very slight.” Most respondents reported that they used Peyote and San Pedro in their most memorable mescaline experience. Overall, the intensity of acute mescaline effects did not differ between mescaline types. About 50% of the sample reported having a psychiatric condition (i.e. depression, anxiety, etc.), and most (>67%) reported improvements in these conditions following their most memorable experience with mescaline. Conclusion: Findings indicate that the mescaline in any form may produce a psychedelic experience that is associated with the spiritual significance and improvements in the mental health with low potential for abuse. Keywords: 3,4,5-trimethoxyphenethylamine; Mescaline; epidemiology; survey.

Ketamine: 50 Years of Modulating the Mind

Ketamine was introduced into clinical practice in the 1960s and continues to be both clinically useful and scientifically fascinating. With considerably diverse molecular targets and neurophysiological properties, ketamine’s effects on the central nervous system remain incompletely understood. Investigators have leveraged the unique characteristics of ketamine to explore the invariant, fundamental mechanisms of anesthetic action. Emerging evidence indicates that ketamine-mediated anesthesia may occur via disruption of corticocortical information transfer in a frontal-to-parietal (“top down”) distribution. This proposed mechanism of general anesthesia has since been demonstrated with anesthetics in other pharmacological classes as well. Ketamine remains invaluable to the fields of anesthesiology and critical care medicine, in large part due to its ability to maintain cardiorespiratory stability while providing effective sedation and analgesia. Furthermore, there may be an emerging role for ketamine in treatment of refractory depression and Post-Traumatic Stress Disorder. In this article, we review the history of ketamine, its pharmacology, putative mechanisms of action and current clinical applications.

N, N-Dimethyltryptamine (DMT), an Endogenous Hallucinogen: Past, Present, and Future Research to Determine Its Role and Function

This report provides a historical overview of research concerning the endogenous hallucinogen N, N-dimethyltryptamine (DMT), focusing on data regarding its biosynthesis and metabolism in the brain and peripheral tissues, methods and results for DMT detection in body fluids and brain, new sites of action for DMT, and new data regarding its possible physiological and therapeutic roles. Research that further elaborates its consideration as a putative neurotransmitter is also addressed. Taking these studies together, the report proposes several new directions and experiments to ascertain the role of DMT in the brain, including brain mapping of enzymes responsible for the biosynthesis of DMT, further studies to elaborate its presence and role in the pineal gland, a reconsideration of binding site data, and new administration and imaging studies. The need to resolve the “natural” role of an endogenous hallucinogen from the effects observed from peripheral administration are also emphasized.

Intensity of Mystical Experiences Occasioned by 5-MeO-DMT and Comparison With a Prior Psilocybin Study

5-MeO-DMT is a psychoactive substance found in high concentrations in the bufotoxin of the Colorado River Toad (Bufo alvarius). Emerging evidence suggests that vaporized 5-MeO-DMT may occasion mystical experiences of comparable intensity to those occasioned by more widely studied psychedelics such as psilocybin, but no empirical study has tested this hypothesis. Data was obtained from 20 individuals (Mage = 38.9, ± 10.7; male = 55%, Caucasian = 85%) who were administered 5-MeO-DMT as part of a psychospiritual retreat program in Mexico. All participants received 50 mg of inhaled vaporized toad bufotoxin which contains 5-MeO-DMT and completed the Mystical Experience Questionnaire (MEQ30) approximately 4–6 h after their session. Administration of 5-MeO-DMT occasioned strong mystical experiences (MEQ30 Overall Mintensity = 4.17, ± 0.64, range 0–5) and the majority (n = 15, 75%) had “a complete mystical experience” (≥60% on all MEQ30 subscales). Compared to a prior laboratory-based psilocybin study, there were no differences in the intensity of mystical effects between 5-MeO-DMT and a high dose (30 mg/70 kg) of psilocybin, but the intensity of mystical effects was significantly higher in the 5-MeO-DMT sample compared to moderate/high dose (20 mg/70 kg) of psilocybin (MEQ30 Total Score: p = 0.02, d = 0.81). Administration of vaporized 5-MeO-DMT reliably occasioned complete mystical experiences in 75% of individuals and was similar in intensity to high dose psilocybin administered in a laboratory setting. The short duration of action may be advantageous for clinical interventions and for studying mystical-type experiences.

Psychedelic crossings: American mental health and LSD in the 1970s

This article places a spotlight on lysergic acid diethylamide (LSD) and American mental health in the 1970s, an era in which psychedelic science was far from settled and researchers continued to push the limits of regulation, resist change and attempt to revolutionise the mental health market-place. The following pages reveal some of the connections between mental health, LSD and the wider setting, avoiding both ascension and declension narratives. We offer a renewed approach to a substance, LSD, which bridged the gap between biomedical understandings of ‘health’ and ‘cure’ and the subjective needs of the individual. Garnering much attention, much like today, LSD created a cross-over point that brought together the humanities and arts, social sciences, health policy, medical education, patient experience and the public at large. It also divided opinion. This study draws on archival materials, medical literature and popular culture to understand the dynamics of psychedelic crossings as a means of engendering a fresh approach to cultural and countercultural-based healthcare during the 1970s.