OPEN Foundation

Day: 1 December 2016

The role of psychedelics in palliative care reconsidered: A case for psilocybin

Kelmendi, B., Corlett, P., Ranganathan, M., D’Souza, C., & Krystal, J. H. (2016). The role of psychedelics in palliative care reconsidered: A case for psilocybin. Journal of psychopharmacology (Oxford, England), 30(12), 1212. 10.1177/0269881116675781
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Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology

Abstract

Placebo response theory and set and setting theory are two fields which examine how non-biological factors shape the response to therapy. Both consider factors such as expectancy, preparation and beliefs to be crucial for understanding the extra-pharmacological processes which shape the response to drugs. Yet there are also fundamental differences between the two theories. Set and setting concerns itself with response to psychoactive drugs only; placebo theory relates to all therapeutic interventions. Placebo theory is aimed at medical professionals; set and setting theory is aimed at professionals and drug users alike. Placebo theory is primarily descriptive, describing how placebo acts; set and setting theory is primarily prescriptive, educating therapists and users on how to control and optimize the effects of drugs. This paper examines how placebo theory and set and setting theory can complement and benefit each other, broadening our understanding of how non-biological factors shape response to drugs and other treatment interventions.

Hartogsohn, I. (2016). Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology. Journal of Psychopharmacology, 0269881116677852.
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Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial

Abstract

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.

Griffiths, R. R., Johnson, M. W., Carducci, M. A., Umbricht, A., Richards, W. A., Richards, B. D., … & Klinedinst, M. A. (2016). Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial. Journal of Psychopharmacology, 30(12), 1181-1197. 10.1177/0269881116675513
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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

Abstract

Cancer patients often develop chronic, clinically significant symptoms of depression and anxiety. Previous studies suggest that psilocybin may decrease depression and anxiety in cancer patients. The effects of psilocybin were studied in 51 cancer patients with life-threatening diagnoses and symptoms of depression and/or anxiety. This randomized, double-blind, cross-over trial investigated the effects of a very low (placebo-like) dose (1 or 3 mg/70 kg) vs. a high dose (22 or 30 mg/70 kg) of psilocybin administered in counterbalanced sequence with 5 weeks between sessions and a 6-month follow-up. Instructions to participants and staff minimized expectancy effects. Participants, staff, and community observers rated participant moods, attitudes, and behaviors throughout the study. High-dose psilocybin produced large decreases in clinician- and self-rated measures of depressed mood and anxiety, along with increases in quality of life, life meaning, and optimism, and decreases in death anxiety. At 6-month follow-up, these changes were sustained, with about 80% of participants continuing to show clinically significant decreases in depressed mood and anxiety. Participants attributed improvements in attitudes about life/self, mood, relationships, and spirituality to the high-dose experience, with >80% endorsing moderately or greater increased well-being/life satisfaction. Community observer ratings showed corresponding changes. Mystical-type psilocybin experience on session day mediated the effect of psilocybin dose on therapeutic outcomes.

Ross, S., Bossis, A., Guss, J., Agin-Liebes, G., Malone, T., Cohen, B., … & Su, Z. (2016). Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: a randomized controlled trial. Journal of Psychopharmacology, 30(12), 1165-1180. 10.1177/0269881116675513
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Discriminative Stimulus Properties of MDMA: The Role of Serotonin and Dopamine

Abstract

Rationale: ±3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) produces unique and complex subjective effects which distinguish it from other recreationally used drugs. An understanding of the neurochemical mechanisms that underlie these effects is important in order to assess the potential for MDMA abuse and to inform researchers exploring of the drug’s therapeutic potential. The present thesis investigated the neurochemical mechanisms underlying the subjective effects of MDMA using drug discrimination procedures in laboratory animals. Despite evidence that training dose can markedly impact the results of drug discrimination studies, the impact of training dose on the discriminative stimulus properties of MDMA has been largely overlooked. The broad aims of these experiments were 1) to test the ability of two different doses of MDMA to support drug discrimination learning, and 2) to determine the role of serotonin (5-HT) and dopamine (DA) neurotransmitter systems in producing the discriminative stimulus effects of each MDMA training dose. 

Methods: Groups of rats were trained to discriminate MDMA (1.5 or 3.0 mg/kg) from saline or to discriminate MDMA (1.5 or 3.0 mg/kg) from amphetamine (0.5 mg/kg) and saline, using two- or three-lever, food-reinforced drug discrimination procedures. The first experiments determined the impact of training dose on the acquisition of the MDMA discrimination. Reliability of the discrimination was assessed by measuring the impact of changes in acquisition criteria. Once the discrimination had been acquired, generalisation tests were carried out in two-lever experiments with the SSRIs, fluoxetine and clomipramine, the 5-HT2 agonists, mCPP and DOI, and the 5-HT1 agonists, 8-OH-DPAT and RU-24969, to investigate the role of 5-HT in the discriminative stimulus effects of 1.5 mg/kg vs 3.0 mg/kg MDMA. Next, the role of DA was investigated in further generalisation test sessions with the DA releasing stimulant, AMPH, the non-selective D1/D2 agonist, apomorphine, the D1 agonist, SKF38393, and the D2 agonist, quinpirole. Finally, experiments were carried out in which the ability of the 5-HT2A antagonist, ketanserin, the 5-HT1B/1D antagonist, GR-127935, the 5-HT1A antagonist, WAY100635, the D1 antagonist, SCH23390, and the D2 antagonist, eticlopride, to attenuate the discriminative stimulus effects of 1.5 mg/kg vs 3.0 mg/kg MDMA was assessed.

Results: A higher training dose of MDMA was associated with a more rapid acquisition of drug discrimination in both the two- and three-lever tasks, and significant differences were observed with respect to the ability of each dose of MDMA to maintain consistently accurate discrimination across both tasks. All of the serotonin agonists that were tested generalised to the discriminative stimulus effects of 1.5 mg/kg MDMA in a two-lever discrimination task. In contrast, only agonists for 5-HT1A or 5-HT2A receptors generalised to the discriminative stimulus effects of 3.0 mg/kg MDMA. Non-selective dopamine agonists generalised to the discriminative stimulus effects of 3.0 mg/kg but not 1.5 mg/kg MDMA, whereas selective D1 and D2 agonists failed to generalise to the discriminative stimulus effects of either training dose. None of the DA or 5-HT antagonists tested had a marked impact of the discrimination of 1.5 mg/kg MDMA whereas administration of a D2 antagonist produced a small but significant attenuation on the discriminative stimulus effects of 3.0 mg/kg MDMA.

Conclusions: The results of the present thesis suggest that the discriminative stimulus effects of MDMA may change both quantitatively and qualitatively as a function of dose. The subjective effects produced by lower doses appear to be mediated primarily via serotonergic mechanisms, whereas higher doses may involve the additional recruitment of dopaminergic mechanisms. These findings have implications for our understanding of MDMA in terms of the drug’s potential for dependence and abuse.

Webster, J. (2016). Discriminative Stimulus Properties of MDMA: The Role of Serotonin and Dopamine. 10063/5622

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Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT

Abstract

3,4-Methylenedioxymethamphetamine (MDMA), a common recreational drug, is known to cause serotonergic neurotoxicity in the brain. Dextromethorphan (DM) is a widely used antitussive reported to exert anti-inflammatory effect in vivo. In this study, we examined the long-term effect of MDMA on the primate serotonergic system and the protective property of DM against MDMA-induced serotonergic abnormality using single photon emission computed tomography (SPECT). Nine monkeys (Macaca cyclopis) were divided into three groups, namely control, MDMA and co-treatment (MDMA/DM). [123I]-ADAM was used as the radioligand for serotonin transporters (SERT) in SPECT scans. SERT levels of the brain were evaluated and presented as the uptake ratios (URs) of [123I]-ADAM in several regions of interest of the brain including midbrain, thalamus and striatum. We found that the URs of [123I]-ADAM were significantly lower in the brains of MDMA than control group, indicating lower brain SERT levels in the MDMA-treated monkeys. This MDMA-induced decrease in brain SERT levels could persist for over four years. However, the loss of brain SERT levels was not observed in co-treatment group. These results suggest that DM may exert a protective effect against MDMA-induced serotonergic toxicity in the brains of the non-human primate.

Ma, K. H., Liu, T. T., Weng, S. J., Chen, C. F. F., Huang, Y. S., Chueh, S. H., … & Huang, W. S. (2016). Effects of dextromethorphan on MDMA-induced serotonergic aberration in the brains of non-human primates using [123I]-ADAM/SPECT. Scientific Reports, 6. 10.1038/srep38695
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