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Objectives Classic psychedelics (serotonin 2A receptor agonists) and dissociative hallucinogens (NMDA receptor antagonists), though differing in pharmacology, may share neuropsychological effects. These drugs, however, have undergone limited direct comparison. This report presents data from a double-blind, placebo-controlled within-subjects study comparing the neuropsychological effects of multiple doses of the classic psychedelic psilocybin with the effects of a single high dose of the dissociative hallucinogen dextromethorphan (DXM). Methods Twenty hallucinogen users (11 females) completed neurocognitive assessments during five blinded drug administration sessions (10, 20, and 30 mg/70 kg psilocybin; 400 mg/70 kg DXM; and placebo) in which participants and study staff were informed that a large range of possible drug conditions may have been administered. Results Global cognitive impairment, assessed using the Mini-Mental State Examination during peak drug effects, was not observed with psilocybin or DXM. Orderly and dose-dependent effects of psilocybin were observed on psychomotor performance, working memory, episodic memory, associative learning, and visual perception. Effects of DXM on psychomotor performance, visual perception, and associative learning were in the range of effects of a moderate to high dose (20 to 30 mg/70 kg) of psilocybin. Conclusions This was the first study of the dose effects of psilocybin on a large battery of neurocognitive assessments. Evidence of delirium or global cognitive impairment was not observed with either psilocybin or DXM. Psilocybin had greater effects than DXM on working memory. DXM had greater effects than all psilocybin doses on balance, episodic memory, response inhibition, and executive control.

Interest in possible clinical uses for psychedelic drugs has grown steadily over the past decade. Although impressive findings from small studies stimulated considerable speculation and provided a strong justification for further study of psychedelic treatments, until very recently there was a dearth of high-quality evidence for their efficacy, mechanisms of action, and appropriate treatment models for clinical use. However, during the past 2-3 years, there have been dramatic advances in the field. This presentation will focus on 5 publications in the field of psychedelic medicine that exemplify three important aspects of the recent progress in psychedelic research. (1) There has been a rapid increase in the number and size of controlled clinical trials of various psychedelic treatments. (2) Conceptual models for studying and potentially understanding the therapeutic effect of psychedelics have increased in sophistication and comprehensiveness. And (3) progress has been made toward developing models of treatment that would facilitate access to safe and effective psychedelic treatments, if and when they are approved by regulatory bodies. Although progress has been rapid, the field of psychedelic medicine is still in its infancy. Much more work on these and many other fronts will be necessary to discover what the study of psychedelics can contribute to healthcare and neuroscience.Disclosure of InterestNone Declared

The last decade has seen a remarkable resurgence of interest in psychedelic drugs such as psilocybin (from magic mushrooms) LSD and DMT (dimethyl tryptamine – the active ingredient of ayahuasca). This has been driven by the discovery that these psychedelics all act agonists of 5-HT2A receptors. Human imaging studies have revealed this action leads to profound alterations in brain measures of activity particularly in terms of increased entropy of EEG MEG and fMRI signals and reduced within-network, but increased between-network, connectivity. In addition they all can increase synaptic growth and brain plasticity. These findings not only explain the subjective nature of the psychedelic experience but also have implications for the treatment of internalising disorders such as depression addiction anorexia and OCD that are characterised by increased within network connectivity especially of the default mode network. Subsequent trials, particularly of psilocybin, in these disorders has revealed significant clinical benefits from even just a single administration. A number of companies have now been set up to extend these discoveries with regulatory-level trials that could result in market authorisations within a few years. My talk will explore these brain mechanisms and clinical data and discuss the potential place of psychedelic medicine in the future of psychiatry.

Background/ObjectivesWe present case histories of severe adverse effects associated with Hallucinogen Persisting Perception Disorder (HPPD), a disorder of neuroperception involving visual and other senses that is due to the treatment of various neuropsychiatric disorders with hallucinogens. This includes the case of a young woman who developed visual hallucinations of distorted shapes and colours after participating in a clinical trial of psilocybin for treatment-resistant depression. She continued to have ongoing perceptual abnormalities, and other neuropsychiatric phenomena with severe effects on her quality of life.ObjectiveTo discuss the ramifications of HPPD stemming from treatment with psychedelics for neuropsychiatric disorders and the importance this holds for clinical practice and research trials.MethodsWe present case histories of people with HPPD, with a focus on a case occurring during a research trial as well as a systematic review of HPPD occurring with therapeutic use of hallucinogens.ResultsHPPD affects approximately 1 in 25 people taking psychedelics whether recreationally or therapeutically. HPPD occurs irrespective of dosing or frequency of use and may occur in those who have microdosed. HPPD may have serious long-term consequences often associated with other perceptual and neuropsychiatric symptoms.ConclusionHPPD is a potentially devastating adverse effect of hallucinogens irrespective whether the use occurs recreationally, therapeutically or even in a controlled trial. It is important that HPPD be screened for and that informed consent is obtained from patients with reference to this adverse effect. Patient education prior to being offered therapeutic hallucinogens is essential for clinical and research practice.

RationalePsychedelic research continues to garner significant public and scientific interest with a growing number of clinical studies examining a wide range of conditions and disorders. However, expectancy effects and effective condition masking have been raised as critical limitations to the interpretability of the research.ObjectiveIn this article, we review the many methodological challenges of conducting psychedelic clinical trials and provide recommendations for improving the rigor of future research.ResultsAlthough some challenges are shared with psychotherapy and pharmacology trials more broadly, psychedelic clinical trials have to contend with several unique sources of potential bias. The subjective effects of a high-dose psychedelic are often so pronounced that it is difficult to mask participants to their treatment condition; the significant hype from positive media coverage on the clinical potential of psychedelics influences participants’ expectations for treatment benefit; and participant unmasking and treatment expectations can interact in such a way that makes psychedelic therapy highly susceptible to large placebo and nocebo effects. Specific recommendations to increase the success of masking procedures and reduce the influence of participant expectancies are discussed in the context of study development, participant recruitment and selection, incomplete disclosure of the study design, choice of active placebo condition, as well as the measurement of participant expectations and masking efficacy.ConclusionIncorporating the recommended design elements is intended to reduce the risk of bias in psychedelic clinical trials and thereby increases the ability to discern treatment-specific effects of psychedelic therapy.

Mike Jay has written widely on the history of science and medicine, and particularly on the discovery of psychoactive drugs during the 18th and 19th centuries. His books on the subject include Emperors of Dreams: drugs in the nineteenth century (2000, revised edition 2011) and most recently High Society: mind-altering drugs in history and culture (2010), which accompanied the exhibition he curated at Wellcome Collection in London. The Atmosphere of Heaven is also the third book in his series of biographical narratives of political reformers in 1790s Britain. It follows The Air Loom Gang (2003, revised edition forthcoming 2012) and The Unfortunate Colonel Despard (2004).The history of psychedelics in psychiatry is longer than usually recognised. The potential of psychedelic drugs to effect mental cures, and the difficulty of managing their powerful effects, were both recognised over a century ago. Since 1962 the research protocols for demonstrating drug efficacy have posed particular problems for psychedelic-assisted therapy.

Psychoactive substances with chemical structures or pharmacological profiles that are similar to traditional drugs of abuse continue to emerge on the recreational drug market. Internet vendors may at least temporarily sell these so-called designer drugs without adhering to legal statutes or facing legal consequences. Overall, the mechanism of action and adverse effects of designer drugs are similar to traditional drugs of abuse. Stimulants, such as amphetamines and cathinones, primarily interact with monoamine transporters and mostly induce sympathomimetic adverse effects. Agonism at μ-opioid receptors and γ-aminobutyric acid-A (GABAA) or GABAB receptors mediates the pharmacological effects of sedatives, which may induce cardiorespiratory depression. Dissociative designer drugs primarily act as N-methyl-d-aspartate receptor antagonists and pose similar health risks as the medically approved dissociative anesthetic ketamine. The cannabinoid type 1 (CB1) receptor is thought to drive the psychoactive effects of synthetic cannabinoids, which are associated with a less desirable effect profile and more severe adverse effects compared with cannabis. Serotonergic 5-hydroxytryptamine-2A (5-HT2A) receptors mediate alterations of perception and cognition that are induced by serotonergic psychedelics. Because of their novelty, designer drugs may remain undetected by routine drug screening, thus hampering evaluations of adverse effects. Intoxication reports suggest that several designer drugs are used concurrently, posing a high risk for severe adverse effects and even death.

Psilocybin is being studied for use in treatment-resistant depression. In this phase 2 double-blind trial, we randomly assigned adults with treatment-resistant depression to receive a single dose of a proprietary, synthetic formulation of psilocybin at a dose of 25 mg, 10 mg, or 1 mg (control), along with psychological support. The primary end point was the change from baseline to week 3 in the total score on the Montgomery-Åsberg Depression Rating Scale (MADRS; range, 0 to 60, with higher scores indicating more severe depression). Secondary end points included response at week 3 (≥50% decrease from baseline in the MADRS total score), remission at week 3 (MADRS total score ≤10), and sustained response at 12 weeks (meeting response criteria at week 3 and all subsequent visits). A total of 79 participants were in the 25-mg group, 75 in the 10-mg group, and 79 in the 1-mg group. The mean MADRS total score at baseline was 32 or 33 in each group. Least-squares mean changes from baseline to week 3 in the score were -12.0 for 25 mg, -7.9 for 10 mg, and -5.4 for 1 mg; the difference between the 25-mg group and 1-mg group was -6.6 (95% confidence interval [CI], -10.2 to -2.9; P<0.001) and between the 10-mg group and 1-mg group was -2.5 (95% CI, -6.2 to 1.2; P = 0.18). In the 25-mg group, the incidences of response and remission at 3 weeks, but not sustained response at 12 weeks, were generally supportive of the primary results. Adverse events occurred in 179 of 233 participants (77%) and included headache, nausea, and dizziness. Suicidal ideation or behavior or self-injury occurred in all dose groups. In this phase 2 trial involving participants with treatment-resistant depression, psilocybin at a single dose of 25 mg, but not 10 mg, reduced depression scores significantly more than a 1-mg dose over a period of 3 weeks but was associated with adverse effects. Larger and longer trials, including comparison with existing treatments, are required to determine the efficacy and safety of psilocybin for this disorder. (Funded by COMPASS Pathfinder; EudraCT number, 2017-003288-36; ClinicalTrials.gov number, NCT03775200.).