Bogenschutz, M. P. (2016). It’s time to take psilocybin seriously as a possible treatment for substance use disorders. The American Journal of Drug and Alcohol Abuse, 1-3. http://dx.doi.org/10.1080/00952990.2016.1200060
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We write with reference to the study on psilocybin for treatment-resistant depression, reported by Robin L Carhart-Harris and colleagues in The Lancet Psychiatry. Although we are relieved that attention is once again being given to basic research into depression—after the hiatus created the effective abandonment of this area of research by Big Pharma from 2010 onwards—we are nonetheless deeply concerned that the mistakes that led to this withdrawal are in danger of being repeated. Carhart-Harris and colleagues’ study included 12 patients, and although the investigators reported that eight patients achieved complete remission at 1 week, only five of these patients were still in complete remission after 3 months of follow-up.
Hendrie, C., & Pickles, A. (2016). Psilocybin: panacea or placebo?. The Lancet Psychiatry, 3(9), 805-806. http://dx.doi.org/10.1016/S2215-0366(16)30103-1
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In The Lancet Psychiatry, Robin Carhart-Harris and colleagues conclude that there is preliminary support for the safety and efficacy of psilocybin for treatment-resistant unipolar depression. This finding is important because more effective pharmacological treatments with acceptable side-effects are urgently needed for patients suffering from depression. We support the limitations the authors have pointed out about the study population and trial design. We also recognise the paucity of well-designed trials in psychiatry that are based on the principles of clinical pharmacology.
Dijkstra, F. M., Jacobs, G. E., & Cohen, A. F. (2016). Question-based Drug Development for psilocybin. The Lancet Psychiatry, 3(9), 806-807. http://dx.doi.org/10.1016/S2215-0366(16)30214-0
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Psilocybin, the clinically most researched classic psychedelic has recently been tested for its safety and efficacy in a clinical population of treatment resistant depression. The efficacy of psilocybin in clinical depression previously demonstrated in the elecrophysiologic and neuroimaging findings as also in neuropsychological assessments is further validated by the findings of this rigorously conducted randomized trial. Mechanism of action of psilocybin and efficacy in treatment resistant depression are discussed in this paper. Ethical issues of conducting clinical trials with psychedelics are also discussed with particular emphasis on their relative safety and absence of addiction potential. Implications of these issues for conduct of larger trials for establishing risk benefit ratio in treatment resistant depression are further suggested.
Patra, S. (2016). Return of the psychedelics: Psilocybin for treatment resistant depression. Asian Journal of Psychiatry, 24, 51-52. http://dx.doi.org/10.1016/j.ajp.2016.08.010
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Inta, D., Sprengel, R., Borgwardt, S., Lang, U. E., & Gass, P. (2016). The antidepressant effect of ketamine: Mediated by AMPA receptors?. European Neuropsychopharmacology. http://dx.doi.org/10.1016/j.euroneuro.2016.08.002
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d-lysergic diethylamide (LSD) is a hallucinogenic drug that interacts with the serotonin (5-HT) system binding to 5-HT1 and 5-HT2 receptors. Little is known about its potential interactions with the dopamine (DA) neurons of the ventral tegmental area (VTA). Using in-vivo electrophysiology in male adult rats, we evaluated the effects of cumulative doses of LSD on VTA DA neuronal activity, compared these effects to those produced on 5-HT neurons in the dorsal raphe nucleus (DRN), and attempted to identify the mechanism of action mediating the effects of LSD on VTA DA neurons. LSD, at low doses (5–20 μg/kg, i.v.) induced a significant decrease of DRN 5-HT firing activity through 5-HT2A and D2 receptors. At these low doses, LSD did not alter VTA DA neuronal activity. On the contrary, at higher doses (30–120 μg/kg, i.v.), LSD dose-dependently decreased VTA DA firing activity. The depletion of 5-HT with p-chlorophenylalanine did not modulate the effects of LSD on DA firing activity. The inhibitory effects of LSD on VTA DA firing activity were prevented by the D2 receptor antagonist haloperidol (50 μg/kg, i.v.) and by the 5-HT1A receptor antagonist WAY-100,635 (500 μg/kg, i.v.). Notably, pretreatment with the trace amine-associate receptor 1 (TAAR1) antagonist EPPTB (5 mg/kg, i.v.) blocked the inhibitory effect of LSD on VTA DA neurons. These results suggest that LSD at high doses strongly affects DA mesolimbic neuronal activity in a 5-HT independent manner and with a pleiotropic mechanism of action involving 5-HT1A, D2 and TAAR1 receptors.
De Gregorio, D., Posa, L., Ochoa-Sanchez, R., McLaughlin, R., Maione, S., Comai, S., & Gobbi, G. (2016). The hallucinogen d-lysergic diethylamide (LSD) decreases dopamine firing activity through 5-HT 1A, D 2 and TAAR 1 receptors. Pharmacological Research, 113, 81-91. http://dx.doi.org/10.1016/j.phrs.2016.08.022
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INTRODUCTION: Evidence based treatment for Substance use disorders (SUD) includes psychotherapy and pharmacotherapy. However, these are only partially effective. Hallucinogens, such as psilocybin, may represent potential new treatment options for SUD. This review provides a summary of (human) studies on the putative therapeutic effects of psilocybin, and discusses the receptor systems, brain regions and cognitive and emotional processes mediating psilocybin’s effects. Psilocybin’s chemical structure is similar to that of serotonin. Dysregulations in the serotonin system are associated with alterations in stress hormones, such as cortisol, and mood disorders. After psilocybin administration cortisol levels spike and activate the executive control network, with subsequent increased control over emotional processes, and relief of negative thinking and persistent negative emotions. Preliminary data of ongoing alcohol and smoking addiction studies in humans shows promising effects of psilocybin administration on substance use. Importantly, psilocybin has a low risk of toxicity and dependence and can be used safely under controlled clinical conditions.
AREAS COVERED: This paper is a narrative review based on the search terms: psilocybin, substance use disorder, addiction, depression, serotonin. Literature on potential efficacy and mechanisms of action of psilocybin in SUD is discussed. Expert commentary: Recent positive findings with psilocybin need confirmation in well-designed placebo controlled randomized trials employing a large sample size.
de Veen, B. T., Schellekens, A. F., Verheij, M. M., & Homberg, J. R. (2016). Psilocybin for treating substance use disorders?. Expert Review of Neurotherapeutics, 1-10. 10.1080/14737175.2016.1220834
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