N,N-dimethyltryptamine and Amazonian ayahuasca plant medicine.

OBJECTIVE: Reports have indicated possible uses of ayahuasca for the treatment of conditions including depression, addictions, post-traumatic stress disorder, anxiety and specific psychoneuroendocrine immune system pathologies. The article assesses potential ayahuasca and N,N-dimethyltryptamine (DMT) integration with contemporary healthcare. The review also seeks to provide a summary of selected literature regarding the mechanisms of action of DMT and ayahuasca; and assess to what extent the state of research can explain reports of unusual phenomenology. DESIGN: A narrative review. RESULTS: Compounds in ayahuasca have been found to bind to serotonergic receptors, glutaminergic receptors, sigma-1 receptors, trace amine-associated receptors, and modulate BDNF expression and the dopaminergic system. Subjective effects are associated with increased delta and theta oscillations in amygdala and hippocampal regions, decreased alpha wave activity in the default mode network, and stimulations of vision-related brain regions particularly in the visual association cortex. Both biological processes and field of consciousness models have been proposed to explain subjective effects of DMT and ayahuasca, however, the evidence supporting the proposed models is not sufficient to make confident conclusions. Ayahuasca plant medicine and DMT represent potentially novel treatment modalities. CONCLUSIONS: Further research is required to clarify the mechanisms of action and develop treatments which can be made available to the general public. Integration between healthcare research institutions and reputable practitioners in the Amazon is recommended.

Psilocybin occasioned mystical-type experiences.

OBJECTIVE: Research into psychedelic therapy models has shown promise for the treatment of specific psychiatric conditions. Mystical-type experiences occasioned by psilocybin have been correlated with therapeutic benefits and long-term improvements in positive mental outlook and attitudes. This article aims to provide an overview of the topic, highlight strengths and weaknesses in current research, generate novel perspectives and discussion, and consider future avenues for research. DESIGN: This narrative review was designed to summarise and assess the state of research on psilocybin occasioned mystical-type experiences and applications for the treatment of specific psychiatric conditions. RESULTS: Contemporary methods on the quantification of mystical-type experiences and their acute subjective effects are discussed. Recent studies provide some understanding of the pharmacological actions of psychedelics although the neurological similarities and differences between spontaneous and psychedelic mystical-type experiences are not well described. Applicability to modern clinical settings is assessed. Potential novel therapeutic applications include use in positive psychology interventions in healthy individuals. CONCLUSIONS: Since 2006 significant advancements in understanding the therapeutic potential of psilocybin-assisted psychotherapy have been made; however, more work is required to understand the neuromechanistic processes and applicability in modern clinical settings. Despite promising results in recent studies, funding issues for clinical trials, legal concerns and socio-cultural resistance provide a counterpoint to experimental evidence.

Neural correlates of the LSD experience revealed by multimodal neuroimaging.

Lysergic acid diethylamide (LSD) is the prototypical psychedelic drug, but its effects on the human brain have never been studied before with modern neuroimaging. Here, three complementary neuroimaging techniques: arterial spin labeling (ASL), blood oxygen level-dependent (BOLD) measures, and magnetoencephalography (MEG), implemented during resting state conditions, revealed marked changes in brain activity after LSD that correlated strongly with its characteristic psychological effects. Increased visual cortex cerebral blood flow (CBF), decreased visual cortex alpha power, and a greatly expanded primary visual cortex (V1) functional connectivity profile correlated strongly with ratings of visual hallucinations, implying that intrinsic brain activity exerts greater influence on visual processing in the psychedelic state, thereby defining its hallucinatory quality. LSD's marked effects on the visual cortex did not significantly correlate with the drug's other characteristic effects on consciousness, however. Rather, decreased connectivity between the parahippocampus and retrosplenial cortex (RSC) correlated strongly with ratings of "ego-dissolution" and "altered meaning," implying the importance of this particular circuit for the maintenance of "self" or "ego" and its processing of "meaning." Strong relationships were also found between the different imaging metrics, enabling firmer inferences to be made about their functional significance. This uniquely comprehensive examination of the LSD state represents an important advance in scientific research with psychedelic drugs at a time of growing interest in their scientific and therapeutic value. The present results contribute important new insights into the characteristic hallucinatory and consciousness-altering properties of psychedelics that inform on how they can model certain pathological states and potentially treat others.

Making a medicine out of MDMA.

From its first use 3,4,-methylenedioxymethamphetamine (MDMA) has been recognised as a drug with therapeutic potential. Research on its clinical utility stopped when it entered the recreational drug scene but has slowly resurrected in the past decade. Currently there is enough evidence for MDMA to be removed from its Schedule 1 status of 'no medical use' and moved into Schedule 2 (alongside other misused but useful medicines such as heroin and amphetamine). Such a regulatory move would liberate its use as a medicine for patients experiencing severe mental illnesses such as treatment-resistant post-traumatic stress disorder.

Can psychedelic compounds play a part in drug dependence therapy?

After a 40-year hiatus there is now a revisiting of psychedelic drug therapy throughout psychiatry, with studies examining the drugs psilocybin, ketamine, ibogaine and ayahuasca in the treatment of drug dependence. Limitations to these therapies are both clinical and legal, but the possibility of improving outcomes for patients with substance dependency imposes an obligation to research this area.

Broadband cortical desynchronization underlies the human psychedelic state.

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin--prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

A reconsideration and response to Parrott AC (2013) "Human psychobiology of MDMA or 'Ecstasy': an overview of 25 years of empirical research".

Parrott recently published a review of literature on MDMA/ecstasy. This commentary is a response to the content and tenor of his review, which mischaracterizes the literature through misstatement and omission of contrary findings, and fails to address the central controversies in the literature. The review makes several erroneous statements concerning MDMA-assisted psychotherapy, such as incorrect statements about research design and other statements that are baseless or contradicted by the literature. Though it critiques an attempt by other authors to characterize the risks of MDMA, the review fails to produce a competing model of risk assessment, and does not discuss potential benefits. Parrott does not represent an even-handed review of the literature, but instead recites dated misconceptions about neurotoxicity concerns involving the recreational drug ecstasy, which do not relate directly to the use of pure MDMA in a therapeutic setting. Unchallenged, Parrott's report may deter researchers from further investigating an innovative treatment that in early clinical trials has demonstrated lasting benefits for people with chronic, treatment-resistant post-traumatic stress disorder.

Why psychiatry needs psychedelics and psychedelics need psychiatry.

Without researching psychedelic drugs for medical therapy, psychiatry is turning its back on a group of compounds that could have great potential. Without the validation of the medical profession, the psychedelic drugs, and those who take them off-license, remain archaic sentiments of the past, with the users maligned as recreational drug abusers and subject to continued negative opinion. These two disparate groups--psychiatrists and recreational psychedelic drug users--are united by their shared recognition of the healing potential of these compounds. A resolution of this conflict is essential for the future of psychiatric medicine and psychedelic culture alike. Progression will come from professionals working in the field adapting to fit a conservative paradigm. In this way, they can provide the public with important treatments and also raise the profile of expanded consciousness in mainstream society.

The Psychedelic Renaissance in Clinical Research: A Bibliometric Analysis of Three Decades of Human Studies with Psychedelics.

Psychedelics were used in the treatment of psychiatric conditions prior to their prohibition in the late 1960s. In the past three decades, there is a revived research interest in the therapeutic potential of psychedelic drugs with expected FDA approvals for treatment of various conditions. Given the exponential scientific growth of this field, we sought to characterize, analyze, and visualize trends in its top-cited articles. Bibliometric analyses are quantitative approaches to characterize a scientific field, including evaluation of the impact of academic literature. The bibliometric analysis and visualizations were conducted with R-tools for comprehensive science mapping. The top-cited 100 articles were cited between 82 and 668 times (median 125; mean 158). Fifty-four percent of the T100 articles were produced in the past decade (2010-2020). Network and author impact analysis highlighted key figures and primary collaboration networks within the top 100 publications. UK, USA, Switzerland, Spain, and Brazil lead the field. Results are discussed in terms of research growth, access, diversity, and the distribution of knowledge and experience in the field. These aggregated data and insights on the second wave of psychedelic research facilitate research evaluation, data-driven funding policies, and a practical map for researchers and clinicians entering the field.

Debunking the myth of 'Blue Mondays': No evidence of affect drop after taking clinical MDMA.

BACKGROUND: Incorporating 3,4-methylenedioxymethamphetamine (MDMA) as an adjunct to psychotherapy has shown promise in recent years for treating various mental health conditions, particularly those involving trauma. However, concerns about declines in mood and cognition during the days following dosing, also known as 'Blue Mondays', have been raised as limitations to its clinical use. Although these changes have been well-documented among recreational users, there are critical confounds to these reports that limit generalizability to clinically administered MDMA. AIMS: Here, we aimed to evaluate the evidence basis for the negative side effects associated with MDMA as well as inform our understanding of the drug's post-acute effects in a clinical context with an open-label study. METHODS: The current open-label study examined MDMA therapy for alcohol use disorder (AUD; N = 14) and measured mood, sleep quality, illicit MDMA consumption and anecdotal reports after the acute drug effects had worn off. RESULTS: Participants maintained a positive mood during the week following drug administration in a clinical context. Relative to baseline, self-reported sleep quality improved at the 3- and 6-month follow-ups. Finally, no participants reported using or desiring to use illicit MDMA, and the anecdotal reports indicated that they perceived the treatment favourably. CONCLUSION: The results support the overall safety and tolerability of clinically administered MDMA and, importantly, suggest that the 'come downs' previously associated with the substance may be explained by confounds in research relating to the illicit sourcing of the drug and specific environmental setting for recreational consumption.

First study of safety and tolerability of 3,4-methylenedioxymethamphetamine-assisted psychotherapy in patients with alcohol use disorder.

BACKGROUND: 3,4-methylenedioxymethamphetamine (MDMA) therapy has qualities that make it potentially well suited for patients with addictions, but this has never been explored in a research study. We present data from the Bristol Imperial MDMA in Alcoholism (BIMA) study. This is the first MDMA addiction study, an open-label safety and tolerability proof-of-concept study investigating the potential role for MDMA therapy in treating patients with alcohol use disorder (AUD). AIMS: This study aimed to assess if MDMA-assisted psychotherapy can be delivered safely and can be tolerated by patients with AUD post detoxification. Outcomes regarding drinking behaviour, quality of life and psychosocial functioning were evaluated. METHODS: Fourteen patients with AUD completed a community alcohol detoxification and received an eight-week course of recovery-based therapy. Participants received two sessions with MDMA (187.5 mg each session). Psychological support was provided before, during and after each session. Safety and tolerability were assessed alongside psychological and physiological outcome measures. Alcohol use behaviour, mental well-being and functioning data were collected for nine months after alcohol detoxification. RESULTS: MDMA treatment was well tolerated by all participants. No unexpected adverse events were observed. Psychosocial functioning improved across the cohort. Regarding alcohol use, at nine months post detox, the average units of alcohol consumption by participants was 18.7 units per week compared to 130.6 units per week before the detox. This compares favourably to a previous observational study (the 'Outcomes' study) by the same team with a similar population of people with AUD. CONCLUSIONS: This study provides preliminary support for the safety and tolerability of a novel intervention for AUD post detox. Further trials to examine better the therapeutic potential of this approach are now indicated.

A Review of 3,4-methylenedioxymethamphetamine (MDMA)-Assisted Psychotherapy.

This paper provides a brief review of the history, proposed pharmacological mechanisms, safety issues, and clinical applications of the medicine 3,4-methylenedioxymethamphetamine (MDMA). Most clinical MDMA research in patients to date has focused on MDMA-assisted psychotherapy to treat posttraumatic stress disorder (PTSD). In this review paper other potential therapeutic applications for MDMA therapy are described, including contemporary studies treating anxiety associated with autism and the authors' ongoing study exploring the potential role for MDMA-assisted psychotherapy to treat alcohol use disorder. MDMA therapy for PTSD is now entering the final Phase 3 stage of drug development, with a target set for licensing by the FDA and EMA in 2021. This means that if clinical efficacy criteria are achieved, MDMA would become a medicine.

First study of safety and tolerability of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in patients with alcohol use disorder: preliminary data on the first four participants.

We present the preliminary data in an ongoing open-label safety and tolerability proof of concept study exploring the potential role for 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy in treating patients with alcohol use disorder. At this stage, seven participants have completed the full 8-week MDMA-assisted psychotherapy course, including two therapy sessions each with MDMA. This paper focuses on the safety and tolerability of the therapeutic course for the first four participants to complete treatment. Longer-term outcomes of drinking behaviour will be presented later when the full project data are published. Results show all four participants have successfully tolerated the treatment. There have been no serious adverse events related to MDMA, no unexpected physiological responses to the MDMA sessions or changes to blood results or electrocardiograms, measured before and after the 8-week course. We conclude that the treatment is well- tolerated and are making plans to expand the project into a randomised placebo-controlled study.

The 21st century psychedelic renaissance: heroic steps forward on the back of an elephant.

Given the plethora of new studies and published papers in the scientific press and the increasingly emerging presence of articles about positive psychedelic experiences appearing in the popular media, there is little doubt that we are in the midst of a Psychedelic Renaissance. The classical psychedelic drugs LSD and psilocybin and the entactogen MDMA are showing promise as tools to assist psychotherapy for a wide range of mental disorders, with multiple pilot studies demonstrating their safety and efficacy. In this article, the author describes how MDMA in particular has inherent characteristics that make it well suited for assisting trauma-focused psychotherapy in a population of patients who have experienced child abuse. But despite these advances, there remain many obstacles ahead of the widespread mainstream acceptance of psychedelic medicines. The author argues that the Misuse of Drugs Act 1971 is one such obstacle. Other impediments include a prevailing attitude of pseudoscience and rigidity from within the non-scientific psychedelic community itself. Resolution of these conflicts must be sought if medicine and society are to see psychedelics gaining a place in mainstream culture and science.

Why MDMA therapy for alcohol use disorder? And why now?

Alcohol use disorder represents a serious clinical, social and personal burden on its sufferers and a significant financial strain on society. Current treatments, both psychological and pharmacological are poor, with high rates of relapse after medical detoxification and dedicated treatment programs. The earliest historical roots of psychedelic drug-assisted psychotherapy in the 1950s were associated with Lysergic acid diethylamide (LSD)-assisted psychotherapy to treat what was then called, alcoholism. But results were varied and psychedelic therapy with LSD and other 'classical' psychedelics fell out of favour in the wake of socio-political pressures and cultural changes. A current revisiting of psychedelic clinical research is now targeting substance use disorders - and particularly alcohol use disorder - again. 3,4-Methylenedioxymethamphetamine (MDMA)-assisted psychotherapy has never been formally explored as a treatment for any form of substance use disorder. But in recent years MDMA has risen in prominence as an agent to treat posttraumatic stress disorder (PTSD). With its unique receptor profile and a relatively well-tolerated subjective experience of drug effects when used clinically, MDMA Therapy is ideally suited to allow a patient to explore and address painful memories without being overwhelmed by negative affect. Given that alcohol use disorder is so often associated with early traumatic experiences, the author is proposing in a current on-going UK-based study that patients with alcohol use disorder who have undergone a medical detoxification from alcohol might benefit from a course of MDMA-assisted psychotherapy. This article is part of the Special Issue entitled 'Psychedelics: New Doors, Altered Perceptions'.

Is there a case for MDMA-assisted psychotherapy in the UK?

Much has been written in scientific and popular literature in recent years about the dangers surrounding the recreational use of the drug MDMA/ecstasy. What is little known and understood however is the history of the apparently safe and effective use of MDMA as a therapeutic tool for psychotherapy. In this paper the author explores this history and describes the recent re-emergence of scientific interest in MDMA and other psychedelic drugs. There are currently several new double-blind randomised controlled trials underway re-visiting the subject. By acknowledging the limitations of this new research and emphasising the importance of exercising appropriate but realistic caution, the author asks that the medical profession consider a dispassionate and open-minded debate to examine whether MDMA might have a legitimate place as an adjunct to psychotherapy in modern psychiatric practice.