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Regulation of human research with LSD in the United States (1949-1987)

November 17, 2017 / History, LSD, Other disciplines, Other subjects, Papers, Publications, Safety / By /

Abstract

Human research with hallucinogens such as lysergic acid diethylamide (LSD) has been ongoing in the USA since 1949. During the 1960s, LSD was investigated for a variety of psychiatric indications, including the following: as an aid in treatment of schizophrenia; as a means of creating a “model psychosis”; as a direct antidepressant; and as an adjunct to psychotherapy. Studies with all drugs, including LSD, have always been conducted under federal regulatory controls, including the 1938 Food Drug and Cosmetic Act (FDCA; which ensured the safety of drugs) and the 1962 Kefauver-Harris Amendments to the FDCA (which described appropriate scientific methodology and ensured drug efficacy). This paper details how the 1962 Amendments introduced numerous safety and efficacy requirements that must be in satisfied during clinical drug research-and how human studies conducted with LSD in the 1960s struggled with their fulfillment. Information is provided from Senate hearings, case law, and interviews with key investigators. Examples are also drawn from scientific papers and symposia published during and since that period, with a focus on information from clinical studies conducted with LSD by psychiatrist Albert Kurland at the Spring Grove State Hospital, near Baltimore, MD. While Kurland largely conformed with these new regulations, other investigators often fell short of complying with scientific standards and federal requirements. Thus, the human hallucinogen studies of the 1960s are best understood as providing pilot data on safety and efficacy, as well as testable hypotheses for current hallucinogen studies conducted under modern scientific and regulatory standards.
Bonson, K. R. (2017). Regulation of human research with LSD in the United States (1949-1987). Psychopharmacology, 1-14. 10.1007/s00213-017-4777-4
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Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system

November 17, 2017 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the ‘oxidative phosphorylation’ (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response.
Weckmann, K., Deery, M. J., Howard, J. A., Feret, R., Asara, J. M., Dethloff, F., … & Webhofer, C. (2017). Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system. Scientific reports, 7(1), 15788. 10.1038/s41598-017-16183-x
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Ketamine's antidepressant effect is mediated by energy metabolism and antioxidant defense system

November 17, 2017 / Depression, Ketamine, Neuroscience, Papers, Psychiatry, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Fewer than 50% of all patients with major depressive disorder (MDD) treated with currently available antidepressants (ADs) show full remission. Moreover, about one third of the patients suffering from MDD does not respond to conventional ADs and develop treatment-resistant depression (TRD). Ketamine, a non-competitive, voltage-dependent N-Methyl-D-aspartate receptor (NMDAR) antagonist, has been shown to have a rapid antidepressant effect, especially in patients suffering from TRD. Hippocampi of ketamine-treated mice were analysed by metabolome and proteome profiling to delineate ketamine treatment-affected molecular pathways and biosignatures. Our data implicate mitochondrial energy metabolism and the antioxidant defense system as downstream effectors of the ketamine response. Specifically, ketamine tended to downregulate the adenosine triphosphate (ATP)/adenosine diphosphate (ADP) metabolite ratio which strongly correlated with forced swim test (FST) floating time. Furthermore, we found increased levels of enzymes that are part of the ‘oxidative phosphorylation’ (OXPHOS) pathway. Our study also suggests that ketamine causes less protein damage by rapidly decreasing reactive oxygen species (ROS) production and lend further support to the hypothesis that mitochondria have a critical role for mediating antidepressant action including the rapid ketamine response.
Weckmann, K., Deery, M. J., Howard, J. A., Feret, R., Asara, J. M., Dethloff, F., … & Webhofer, C. (2017). Ketamine’s antidepressant effect is mediated by energy metabolism and antioxidant defense system. Scientific reports, 7(1), 15788. 10.1038/s41598-017-16183-x
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Well-being, problematic alcohol consumption and acute subjective drug effects in past-year ayahuasca users: a large, international, self-selecting online survey

November 9, 2017 / Ayahuasca, Papers, Psychology, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Ayahuasca is a natural psychedelic brew, which contains dimethyltryptamine (DMT). Its potential as a psychiatric medicine has recently been demonstrated and its non-medical use around the world appears to be growing. We aimed to investigate well-being and problematic alcohol use in ayahuasca users, and ayahuasca’s subjective effects. An online, self-selecting, global survey examining patterns of drug use was conducted in 2015 and 2016 (n = 96,901). Questions were asked about: use of ayahuasca, lysergic acid diethylamide (LSD) and magic mushrooms; demographics, current well-being and past-year problematic alcohol use of past-year ayahuasca users and comparison drug users; and subjective effects of ayahuasca and comparison drugs. Ayahuasca users (n = 527) reported greater well-being than both classic psychedelic users (n = 18,138) and non-psychedelic drug-using respondents (n = 78,236). Ayahuasca users reported less problematic drinking than classic psychedelic users, although both groups reported greater problematic drinking than the other respondents. Ayahuasca’s acute subjective effects usually lasted for six hours and were most strongly felt one hour after consumption. Within our online, self-selecting survey, ayahuasca users reported better well-being than comparison groups and less problematic drinking than classic psychedelic users. Future longitudinal studies of international samples and randomised controlled trials are needed to dissect the effects of ayahuasca on these outcomes.
Lawn, W., Hallak, J. E., Crippa, J. A., Santos, R., Porffy, L., Barratt, M. J., … & Morgan, C. J. (2017). Well-being, problematic alcohol consumption and acute subjective drug effects in past-year ayahuasca users: a large, international, self-selecting online survey. Scientific reports, 7(1), 15201. 10.1038/s41598-017-14700-6
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LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation

November 8, 2017 / LSD, Papers, Phenomenology, Philosophy, Psychiatry, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Rationale: Stimulation of serotonin 2A (5-HT2A) receptors by lysergic acid diethylamide (LSD) and related compounds such as psilocybin has previously been shown to increase primary process thinking – an ontologically and evolutionary early, implicit, associative, and automatic mode of thinking which is typically occurring during altered states of consciousness such as dreaming. However, it is still largely unknown whether LSD induces primary process thinking under placebo-controlled, standardized experimental conditions and whether these effects are related to subjective experience and 5-HT2A receptor activation. Therefore, this study aimed to test the hypotheses that LSD increases primary process thinking and that primary process thinking depends on 5-HT2A receptor activation and is related to subjective drug effects.

Methods: Twenty-five healthy subjects performed an audio-recorded mental imagery task 7 h after drug administration during three drug conditions: placebo, LSD (100 mcg orally) and LSD together with the 5-HT2A receptor antagonist ketanserin (40 mg orally). The main outcome variable in this study was primary index (PI), a formal measure of primary process thinking in the imagery reports. State of consciousness was evaluated using the Altered State of Consciousness (5D-ASC) rating scale.

Results: LSD, compared with placebo, significantly increased primary index (p < 0.001, Bonferroni-corrected). The LSD-induced increase in primary index was positively correlated with LSD-induced disembodiment (p < 0.05, Bonferroni-corrected), and blissful state (p < 0.05, Bonferroni-corrected) on the 5D-ASC. Both LSD-induced increases in primary index and changes in state of consciousness were fully blocked by ketanserin.

Conclusion: LSD induces primary process thinking via activation of 5-HT2A receptors and in relation to disembodiment and blissful state. Primary process thinking appears to crucially organize inner experiences during both dreams and psychedelic states of consciousness.

Kraehenmann, R., Pokorny, D., Aicher, H., Preller, K. H., Pokorny, T., Bosch, O. G., … & Vollenweider, F. X. (2017). LSD Increases Primary Process Thinking via Serotonin 2A Receptor Activation. Frontiers in Pharmacology, 8, 814. 10.3389/fphar.2017.00814
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Psilocybin with psychological support for treatment-resistant depression: six-month follow-up

November 8, 2017 / Depression, Mushrooms / Psilocybin, Papers, Psychiatry, Psychology, Psychotherapy, Publications / By / , , , , , ,

Abstract

Rationale

Recent clinical trials are reporting marked improvements in mental health outcomes with psychedelic drug-assisted psychotherapy.

Objectives

Here, we report on safety and efficacy outcomes for up to 6 months in an open-label trial of psilocybin for treatment-resistant depression.

Methods

Twenty patients (six females) with (mostly) severe, unipolar, treatment-resistant major depression received two oral doses of psilocybin (10 and 25 mg, 7 days apart) in a supportive setting. Depressive symptoms were assessed from 1 week to 6 months post-treatment, with the self-rated QIDS-SR16 as the primary outcome measure.

Results

Treatment was generally well tolerated. Relative to baseline, marked reductions in depressive symptoms were observed for the first 5 weeks post-treatment (Cohen’s d = 2.2 at week 1 and 2.3 at week 5, both p < 0.001); nine and four patients met the criteria for response and remission at week 5. Results remained positive at 3 and 6 months (Cohen’s d = 1.5 and 1.4, respectively, both p < 0.001). No patients sought conventional antidepressant treatment within 5 weeks of psilocybin. Reductions in depressive symptoms at 5 weeks were predicted by the quality of the acute psychedelic experience.

Conclusions

Although limited conclusions can be drawn about treatment efficacy from open-label trials, tolerability was good, effect sizes large and symptom improvements appeared rapidly after just two psilocybin treatment sessions and remained significant 6 months post-treatment in a treatment-resistant cohort. Psilocybin represents a promising paradigm for unresponsive depression that warrants further research in double-blind randomised control trials.

Carhart-Harris, R. L., Bolstridge, M., Day, C. M. J., Rucker, J., Watts, R., Erritzoe, D. E., … & Rickard, J. A. (2017). Psilocybin with psychological support for treatment-resistant depression: six-month follow-up. Psychopharmacology, 1-10. 10.1007/s00213-017-4771-x
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Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences

November 7, 2017 / Mushrooms / Psilocybin, Other substances, Papers, Phenomenology, Psychology, Publications / By / , , ,

Abstract

Rationale

Although psilocybin and dextromethorphan (DXM) are hallucinogens, they have different receptor mechanisms of action and have not been directly compared.

Objective

This study compared subjective, behavioral, and physiological effects of psilocybin and dextromethorphan under conditions that minimized expectancy effects.

Methods

Single, acute oral doses of psilocybin (10, 20, 30 mg/70 kg), DXM (400 mg/70 kg), and placebo were administered under double-blind conditions to 20 healthy participants with histories of hallucinogen use. Instructions to participants and staff minimized expectancy effects. Various subjective, behavioral, and physiological effects were assessed after drug administration.

Results

High doses of both drugs produced similar increases in participant ratings of peak overall drug effect strength, with similar times to maximal effect and time-course. Psilocybin produced orderly dose-related increases on most participant-rated subjective measures previously shown sensitive to hallucinogens. DXM produced increases on most of these same measures. However, the high dose of psilocybin produced significantly greater and more diverse visual effects than DXM including greater movement and more frequent, brighter, distinctive, and complex (including textured and kaleidoscopic) images and visions. Compared to DXM, psilocybin also produced significantly greater mystical-type and psychologically insightful experiences and greater absorption in music. In contrast, DXM produced larger effects than psilocybin on measures of disembodiment, nausea/emesis, and light-headedness. Both drugs increased systolic blood pressure, heart rate, and pupil dilation and decreased psychomotor performance and balance.

Conclusions

Psilocybin and DXM produced similar profiles of subjective experiences, with psilocybin producing relatively greater visual, mystical-type, insightful, and musical experiences, and DXM producing greater disembodiment.

Carbonaro, T. M., Johnson, M. W., Hurwitz, E., & Griffiths, R. R. (2017). Double-blind comparison of the two hallucinogens psilocybin and dextromethorphan: similarities and differences in subjective experiences. Psychopharmacology, 1-14. 10.1007/s00213-017-4769-4
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Why MDMA therapy for alcohol use disorder? And why now?

November 7, 2017 / MDMA, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Substance Use Disorder / By /

Abstract

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.

Sessa, B. (2017). Why MDMA therapy for alcohol use disorder? And why now?. Neuropharmacology. 10.1016/j.neuropharm.2017.11.004
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Multipotent and Poly-therapeutic Fungal Alkaloids of Claviceps purpurea

November 4, 2017 / LSD, Mushrooms / Psilocybin, Other subjects, Papers, Psychopharmacology, Publications / By / , , , , , ,

Abstract

Claviceps are a group of phytopathogenic ascomycetes which includes around 50 known species. Claviceps purpurea, Claviceps fusiformis, Claviceps paspali, Claviceps africana, and Claviceps lutea are the most common and well-characterized fungi. Ergot alkaloids and other constituents derived from Claviceps are beneficial for various clinical applications in humans and animals. However, they also contain certain chemicals that are extremely addictive, abusive, and lethal. Ergot derivatives exhibit interesting pharmacokinetic and pharmacodynamic effects. Their pharmacodynamic actions are attributed to their agonistic, partial agonistic, and antagonistic effects on different receptors pertaining to the monoaminergic neurotransmitters. Due to their binding (with or without intrinsic effects) ability on the receptors, they induce numerous pharmacological effects which have potential medical values. Methysergide, ergotamine, dihydroergotamine, ergometrine (ergonovine), pergolide, ergoloid mesylates, and bromocriptine are the most popular ergot-based drugs used globally for treating numerous diseases. These drugs have been used to treat inflammatory-, infectious-, neurological-, cardiovascular-, gastrointestinal-, endocrinological-, sexual-, and urological-related pathologies. Hence, they are considered as a multipotent and poly-therapeutic fungus.

Majrashi, M., Ramesh, S., Deruiter, J., Mulabagal, V., Pondugula, S., Clark, R., & Dhanasekaran, M. (2017). Multipotent and Poly-therapeutic Fungal Alkaloids of Claviceps purpurea. In Medicinal Plants and Fungi: Recent Advances in Research and Development (pp. 229-252). Springer, Singapore. 10.1007/978-981-10-5978-0_8
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Additive Effects of 3,4-Methylenedioxymethamphetamine (MDMA) and Compassionate Imagery on Self-Compassion in Recreational Users of Ecstasy

November 4, 2017 / MDMA, Papers, Personality, Psychology, Psychotherapy, Publications / By / , , , , , ,

Abstract

3,4-Methylenedioxymethylamphetamine (MDMA;‘ecstasy’) produces prosocial subjective effects that may extend to affiliative feelings towards the self. Behavioural techniques can produce similar self-directed affiliation. For example, compassionate imagery (CI) and ecstasy reduce self-criticism and increase self-compassion to a similar extent, with the effects of CI enhanced in the presence of ecstasy. Here, we examine self-compassion and self-criticism in recreational users who consumed chemically verified MDMA in a within-subjects crossover study. In a naturalistic setting, polydrug-using participants performed a self-focused CI exercise on two occasions separated by ≥6 days: once having consumed self-sourced MDMA and once not. Effects on state self-criticism, self-compassion and emotional empathy were assessed before and after MDMA use (or over an extended baseline period on the occasion that MDMA was not consumed) and reassessed after CI. In participants (n = 20; 8 women) whose ecstasy contained MDMA and no other drug, CI and MDMA appeared to separately increase emotional empathy (to critical facial expressions) and self-compassion. The effects of CI and MDMA on self-compassion also appeared to be additive. Establishing the observed effects in controlled studies will be critical for determining the combined utility of these approaches in fostering adaptive self-attitudes in a therapeutic context.

Kamboj, S. K., Walldén, Y. S., Falconer, C. J., Alotaibi, M. R., Blagbrough, I. S., Husbands, S. M., & Freeman, T. P. (2017). Additive Effects of 3, 4-Methylenedioxymethamphetamine (MDMA) and Compassionate Imagery on Self-Compassion in Recreational Users of Ecstasy. Mindfulness, 1-12. 10.1007/s12671-017-0849-0
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