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      Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial

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          Abstract

          Background:

          Clinically significant anxiety and depression are common in patients with cancer, and are associated with poor psychiatric and medical outcomes. Historical and recent research suggests a role for psilocybin to treat cancer-related anxiety and depression.

          Methods:

          In this double-blind, placebo-controlled, crossover trial, 29 patients with cancer-related anxiety and depression were randomly assigned and received treatment with single-dose psilocybin (0.3 mg/kg) or niacin, both in conjunction with psychotherapy. The primary outcomes were anxiety and depression assessed between groups prior to the crossover at 7 weeks.

          Results:

          Prior to the crossover, psilocybin produced immediate, substantial, and sustained improvements in anxiety and depression and led to decreases in cancer-related demoralization and hopelessness, improved spiritual wellbeing, and increased quality of life. At the 6.5-month follow-up, psilocybin was associated with enduring anxiolytic and anti-depressant effects (approximately 60–80% of participants continued with clinically significant reductions in depression or anxiety), sustained benefits in existential distress and quality of life, as well as improved attitudes towards death. The psilocybin-induced mystical experience mediated the therapeutic effect of psilocybin on anxiety and depression.

          Conclusions:

          In conjunction with psychotherapy, single moderate-dose psilocybin produced rapid, robust and enduring anxiolytic and anti-depressant effects in patients with cancer-related psychological distress.

          Trial Registration: ClinicalTrials.gov Identifier: NCT00957359

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          Most cited references65

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          NMDAR inhibition-independent antidepressant actions of ketamine metabolites

          Major depressive disorder afflicts ~16 percent of the world population at some point in their lives. Despite a number of available monoaminergic-based antidepressants, most patients require many weeks, if not months, to respond to these treatments, and many patients never attain sustained remission of their symptoms. The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), exerts rapid and sustained antidepressant effects following a single dose in depressed patients. Here we show that the metabolism of ketamine to (2S,6S;2R,6R)-hydroxynorketamine (HNK) is essential for its antidepressant effects, and that the (2R,6R)-HNK enantiomer exerts behavioural, electroencephalographic, electrophysiological and cellular antidepressant actions in vivo. Notably, we demonstrate that these antidepressant actions are NMDAR inhibition-independent but they involve early and sustained α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor activation. We also establish that (2R,6R)-HNK lacks ketamine-related side-effects. Our results indicate a novel mechanism underlying ketamine’s unique antidepressant properties, which involves the required activity of a distinct metabolite and is independent of NMDAR inhibition. These findings have relevance for the development of next generation, rapid-acting antidepressants.
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            Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance.

            Although psilocybin has been used for centuries for religious purposes, little is known scientifically about its acute and persisting effects. 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. 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. 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. 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.
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              Psilocybin-assisted treatment for alcohol dependence: a proof-of-concept study.

              Several lines of evidence suggest that classic (5HT2A agonist) hallucinogens have clinically relevant effects in alcohol and drug addiction. Although recent studies have investigated the effects of psilocybin in various populations, there have been no studies on the efficacy of psilocybin for alcohol dependence. We conducted a single-group proof-of-concept study to quantify acute effects of psilocybin in alcohol-dependent participants and to provide preliminary outcome and safety data. Ten volunteers with DSM-IV alcohol dependence received orally administered psilocybin in one or two supervised sessions in addition to Motivational Enhancement Therapy and therapy sessions devoted to preparation for and debriefing from the psilocybin sessions. Participants' responses to psilocybin were qualitatively similar to those described in other populations. Abstinence did not increase significantly in the first 4 weeks of treatment (when participants had not yet received psilocybin), but increased significantly following psilocybin administration (p < 0.05). Gains were largely maintained at follow-up to 36 weeks. The intensity of effects in the first psilocybin session (at week 4) strongly predicted change in drinking during weeks 5-8 (r = 0.76 to r = 0.89) and also predicted decreases in craving and increases in abstinence self-efficacy during week 5. There were no significant treatment-related adverse events. These preliminary findings provide a strong rationale for controlled trials with larger samples to investigate efficacy and mechanisms.
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                Author and article information

                Journal
                J Psychopharmacol
                J. Psychopharmacol. (Oxford)
                JOP
                spjop
                Journal of Psychopharmacology (Oxford, England)
                SAGE Publications (Sage UK: London, England )
                0269-8811
                1461-7285
                30 November 2016
                December 2016
                : 30
                : 12
                : 1165-1180
                Affiliations
                [1 ]Department of Psychiatry, New York University School of Medicine, New York, NY, USA
                [2 ]New York University College of Dentistry, Bluestone Center for Clinical Research, New York, NY, USA
                [3 ]Department of Child and Adolescent Psychiatry, New York University School of Medicine, New York, NY, USA
                [4 ]Department of Psychiatry, Bellevue Hospital Center, New York, USA
                [5 ]NYU Langone Medical Center, New York, NY, USA
                [6 ]New York University-Health and Hospitals Corporation (NYU-HHC) Clinical and Translational Science Institute, New York, NY, USA
                [7 ]Department of Psychology, New York University, New York, NY, USA
                [8 ]Department of Applied Psychology, New York University Steinhardt School of Culture, Education, and Human Development, New York, NY, USA
                [9 ]Department of Radiology, New York University School of Medicine, New York, NY, USA
                [10 ]Palo Alto University, Palo Alto, CA, USA
                Author notes
                [*]Stephen Ross, NYU School of Medicine/Bellevue Hospital, 462 First Avenue, NBV 20E7, New York, NY 10016, USA. Email: stephen.ross@ 123456nyumc.org
                Article
                10.1177_0269881116675512
                10.1177/0269881116675512
                5367551
                27909164
                c0cd9ee6-2bb8-46f8-a833-a3fd12f1c979
                © The Author(s) 2016

                This article is distributed under the terms of the Creative Commons Attribution 3.0 License ( http://www.creativecommons.org/licenses/by/3.0/) which permits any use, reproduction and distribution of the work without further permission provided the original work is attributed as specified on the SAGE and Open Access page ( https://us.sagepub.com/en-us/nam/open-access-at-sage).

                History
                Categories
                Original Papers

                Pharmacology & Pharmaceutical medicine
                psilocybin,psychedelic,cancer,depression,anxiety,mystical experience

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