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Biocatalytic production of psilocybin and derivatives in tryptophan synthase-enhanced reactions

/ Mushrooms / Psilocybin, Neuroscience, Papers, Pharmacology & Chemistry, Publications / / , , ,

Abstract

Psilocybin (4-phosphoryloxy-N,N-dimethyltryptamine) is the main alkaloid of the fungal genus Psilocybe, the so-called “magic mushrooms.” The pharmaceutical interest in this psychotropic natural product as a future medication to treat depression and anxiety is strongly re-emerging. Here, we present an enhanced enzymatic route of psilocybin production by adding TrpB, the tryptophan synthase of the mushroom Psilocybe cubensis, to the reaction. We capitalized on its substrate flexibility and show psilocybin formation from 4-hydroxyindole and l-serine, which are less cost-intensive substrates, compared to the previous method. Furthermore, we show enzymatic production of 7-phosphoryloxytryptamine (isonorbaeocystin), a non-natural congener of the Psilocybe alkaloid norbaeocystin (4-phosphoryloxytryptamine), and of serotonin (5-hydroxytryptamine) by means of the same in vitro approach.

Blei, F., Baldeweg, F., Fricke, J., & Hoffmeister, D. (2018). Biocatalytic Production of Psilocybin and Derivatives in Tryptophan Synthase‐Enhanced Reactions. Chemistry–A European Journal, 24(40), 10028-10031., 10.1002/chem.201801047.
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Are Ecstasy Induced Serotonergic Alterations Overestimated For The Majority Of Users?

/ MDMA, Papers, Psychology, Publications / / , ,

Abstract

BACKGROUND:
Neuroimaging studies imply that the regular use of ±3,4-methylenedioxymethamphetamine (MDMA), the major constituent of ecstasy pills, alters the brain’s serotonergic system in a dose-dependent manner. However, the relevance of these findings remains unclear due to limited knowledge about the ecstasy/MDMA use pattern of real-life users.
AIMS:
We examined the representativeness of ecstasy users enrolled in neuroimaging studies by comparing their ecstasy use habits with the use patterns of a large, international sample.
METHODS:
A systematic literature search revealed 10 imaging studies that compare serotonin transporter levels in recreational ecstasy users to matched controls. To characterize the ecstasy use patterns we relied on the Global Drug Survey, the world’s largest self-report database on drug use. The basis of the dose comparison were the Usual Amount (pills/session), Use Frequency (sessions/month) and Dose Intensity (pills/year) variables.
RESULTS:
Both the average Usual Amount (pills/session) and Use Frequency (sessions/month) of neuroimaging study participants corresponded to the top 5-10% of the Global Drug Survey sample and imaging participants, on average, consumed 720% more pills over a year than the Global Drug Survey participants.
CONCLUSIONS:
Our findings suggest that the serotonin brain imaging literature has focused on unusually heavy ecstasy use and therefore the conclusions from these studies are likely to overestimate the extent of serotonergic alterations experienced by the majority of people who use ecstasy.
Szigeti, B., Winstock, A. R., Erritzoe, D., & Maier, L. J. (2018). Are Ecstasy Induced Serotonergic Alterations Overestimated For The Majority Of Users?. Journal of Psychopharmacology, 0269881118767646.
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Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: a potential role?

/ LSD, Mushrooms / Psilocybin, Papers, Psychiatry & Medicine, Psychology, Publications / / ,

Abstract

Recently, there has been interest in lysergic acid diethylamide (LSD) and psilocybin for depression, anxiety and fear of death in terminal illness. The aim of this review is to discuss the potential use of LSD and psilocybin for patients with persistent pain. LSD and psilocybin are 5-hydroxytryptamine receptor agonists and may interact with nociceptive and antinociceptive processing. Tentative evidence from a systematic review suggests that LSD (7 studies, 323 participants) and psilocybin (3 studies, 92 participants) may be beneficial for depression and anxiety associated with distress in life-threatening diseases. LSD and psilocybin are generally safe if administered by a healthcare professional, although further investigations are needed to assess their utility for patients with persistent pain, especially associated with terminal illness.
Whelan, A., & Johnson, M. I. (2018). Lysergic acid diethylamide and psilocybin for the management of patients with persistent pain: a potential role?. Pain management, 8(3), 217-229. 10.2217/pmt-2017-0068
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3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial.

/ Anxiety Disorders / PTSD, MDMA, Papers, Psychology, Publications / / , , , , ,

Abstract

BACKGROUND:
Post-traumatic stress disorder (PTSD) is prevalent in military personnel and first responders, many of whom do not respond to currently available treatments. This study aimed to assess the efficacy and safety of 3,4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for treating chronic PTSD in this population.
METHODS:
We did a randomised, double-blind, dose-response, phase 2 trial at an outpatient psychiatric clinic in the USA. We included service personnel who were 18 years or older, with chronic PTSD duration of 6 months or more, and who had a Clinician-Administered PTSD Scale (CAPS-IV) total score of 50 or greater. Using a web-based randomisation system, we randomly assigned participants (1:1:2) to three different dose groups of MDMA plus psychotherapy: 30 mg (active control), 75 mg, or 125 mg. We masked investigators, independent outcome raters, and participants until after the primary endpoint. MDMA was administered orally in two 8-h sessions with concomitant manualised psychotherapy. The primary outcome was mean change in CAPS-IV total score from baseline to 1 month after the second experimental session. Participants in the 30 mg and 75 mg groups subsequently underwent three 100-125 mg MDMA-assisted psychotherapy sessions in an open-label crossover, and all participants were assessed 12 months after the last MDMA session. Safety was monitored through adverse events, spontaneously reported expected reactions, vital signs, and suicidal ideation and behaviour. This study is registered with ClinicalTrials.gov, number NCT01211405.
FINDINGS:
Between Nov 10, 2010, and Jan 29, 2015, 26 veterans and first responders met eligibility criteria and were randomly assigned to receive 30 mg (n=7), 75 mg (n=7), or 125 mg (n=12) of MDMA plus psychotherapy. At the primary endpoint, the 75 mg and 125 mg groups had significantly greater decreases in PTSD symptom severity (mean change CAPS-IV total scores of -58·3 [SD 9·8] and -44·3 [28·7]; p=0·001) than the 30 mg group (-11·4 [12·7]). Compared with the 30 mg group, Cohen’s d effect sizes were large: 2·8 (95% CI 1·19-4·39) for the 75 mg group and 1·1 (0·04-2·08) for the 125 mg group. In the open-label crossover with full-dose MDMA (100-125 mg), PTSD symptom severity significantly decreased in the group that had previously received 30 mg (p=0·01), whereas no further significant decreases were observed in the group that previously achieved a large response after 75 mg doses in the blinded segment (p=0·81). PTSD symptoms were significantly reduced at the 12-month follow-up compared with baseline after all groups had full-dose MDMA (mean CAPS-IV total score of 38·8 [SD 28·1] vs 87·1 [16·1]; p<0·0001). 85 adverse events were reported by 20 participants. Of these adverse events, four (5%) were serious: three were deemed unrelated and one possibly related to study drug treatment.
INTERPRETATION:
Active doses (75 mg and 125 mg) of MDMA with adjunctive psychotherapy in a controlled setting were effective and well tolerated in reducing PTSD symptoms in veterans and first responders.
FUNDING:
Multidisciplinary Association for Psychedelic Studies.
Mithoefer, M. C., Mithoefer, A. T., Feduccia, A. A., Jerome, L., Wagner, M., Wymer, J., … & Doblin, R. (2018). 3, 4-methylenedioxymethamphetamine (MDMA)-assisted psychotherapy for post-traumatic stress disorder in military veterans, firefighters, and police officers: a randomised, double-blind, dose-response, phase 2 clinical trial. The Lancet Psychiatry, 5(6), 486-497, 10.1016/S2215-0366(18)30135-4
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The epidemiology of 5-methoxy- N,N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption

/ DMT, Papers, Psychology, Publications, Substance Use Disorder / / , , , ,

Abstract

BACKGROUND/AIM:
5-Methoxy- N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive compound found in several plants and in high concentrations in Bufo alvarius toad venom. Synthetic, toad, and plant-sourced 5-MeO-DMT are used for spiritual and recreational purposes and may have psychotherapeutic effects. However, the use of 5-MeO-DMT is not well understood. Therefore, we examined patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences associated with 5-MeO-DMT use.
METHODS:
Using internet-based advertisements, 515 respondents ( Mage=35.4. SD=11.7; male=79%; White/Caucasian=86%; United States resident=42%) completed a web-based survey.
RESULTS:
Most respondents consumed 5-MeO-DMT infrequently (<once/year), for spiritual exploration, and had used less than four times in their lifetime. The majority (average of 90%) reported moderate-to-strong mystical-type experiences ( Mintensity=3.64, SD=1.11; range 0-5; e.g., ineffability, timelessness, awe/amazement, experience of pure being/awareness), and relatively fewer (average of 37%) experienced very slight challenging experiences ( Mintensity=0.95, SD=0.91; range 0-5; e.g., anxiousness, fear). Less than half (39%) reported repeated consumption during the same session, and very few reported drug craving/desire (8%), or legal (1%), medical (1%), or psychiatric (1%) problems related to use. Furthermore, of those who reported being diagnosed with psychiatric disorders, the majority reported improvements in symptoms following 5-MeO-DMT use, including improvements related to post-traumatic stress disorder (79%), depression (77%), anxiety (69%), and alcoholism (66%) or drug use disorder (60%).
CONCLUSION:
Findings suggest that 5-MeO-DMT is used infrequently, predominantly for spiritual exploration, has low potential for addiction, and might have psychotherapeutic effects. Future research should examine the safety and pharmacokinetics of 5-MeO-DMT administration in humans using rigorous experimental designs.
Davis, A. K., Barsuglia, J. P., Lancelotta, R., Grant, R. M., & Renn, E. (2018). The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption. Journal of Psychopharmacology, 0269881118769063. 10.1177/0269881118769063
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The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption

/ DMT, Papers, Psychology, Publications / / , , , ,

Abstract

Background/aim:

5-Methoxy-N,N-dimethyltryptamine (5-MeO-DMT) is a psychoactive compound found in several plants and in high concentrations in Bufo alvarius toad venom. Synthetic, toad, and plant-sourced 5-MeO-DMT are used for spiritual and recreational purposes and may have psychotherapeutic effects. However, the use of 5-MeO-DMT is not well understood. Therefore, we examined patterns of use, motivations for consumption, subjective effects, and potential benefits and consequences associated with 5-MeO-DMT use.

Methods:

Using internet-based advertisements, 515 respondents (Mage=35.4. SD=11.7; male=79%; White/Caucasian=86%; United States resident=42%) completed a web-based survey.

Results:

Most respondents consumed 5-MeO-DMT infrequently (<once/year), for spiritual exploration, and had used less than four times in their lifetime. The majority (average of 90%) reported moderate-to-strong mystical-type experiences (Mintensity=3.64, SD=1.11; range 0–5; e.g., ineffability, timelessness, awe/amazement, experience of pure being/awareness), and relatively fewer (average of 37%) experienced very slight challenging experiences (Mintensity=0.95, SD=0.91; range 0–5; e.g., anxiousness, fear). Less than half (39%) reported repeated consumption during the same session, and very few reported drug craving/desire (8%), or legal (1%), medical (1%), or psychiatric (1%) problems related to use. Furthermore, of those who reported being diagnosed with psychiatric disorders, the majority reported improvements in symptoms following 5-MeO-DMT use, including improvements related to post-traumatic stress disorder (79%), depression (77%), anxiety (69%), and alcoholism (66%) or drug use disorder (60%).

Conclusion:

Findings suggest that 5-MeO-DMT is used infrequently, predominantly for spiritual exploration, has low potential for addiction, and might have psychotherapeutic effects. Future research should examine the safety and pharmacokinetics of 5-MeO-DMT administration in humans using rigorous experimental designs.

Davis, A. K., Barsuglia, J. P., Lancelotta, R., Grant, R. M., & Renn, E. (2018). The epidemiology of 5-methoxy-N, N-dimethyltryptamine (5-MeO-DMT) use: Benefits, consequences, patterns of use, subjective effects, and reasons for consumption. Journal of Psychopharmacology, 0269881118769063.
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Gnosis Potency: DMT Breakthroughs and Paragnosis

/ DMT, Papers, Psychology, Publications / /

Abstract

DMT (N,N-dimethyltryptamine) is a powerful tryptamine that has experienced growing appeal in the last decade, independent from ayahuasca, the Amazonian visionary brew in which it is an integral ingredient. Investigating user reports available from literary and online sources, this chapter focuses on the gnosis potency associated with the DMT “breakthrough” experience. I explore the parameters of the tryptaminal state and, in particular, the extraordinary paragnosis associated with the DMT event, perceived contact with “entities,” and the transmission of visual language. As the reports discussed illustrate, for milieus of the disenchanted, among other entheogens, DMT is venerated as a gift that enables connection to a reality (nature, the universe, divinity) from which modern humanity is imagined to have grown alienated. Through an exploration of the legacy of principal actors, including Terence McKenna, Jonathan Ott, Jim DeKorne, and Nick Sand, the chapter navigates the significance of DMT in modern Western esotericism.

St John, G. (2018). Gnosis Potency: DMT Breakthroughs and Paragnosis. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 205-222. 10.1007/978-3-319-76720-8_12
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Integrating Psychedelic Medicines and Psychiatry: Theory and Methods of a Model Clinic

/ Ayahuasca, Biology & Ethnobotany, Mushrooms / Psilocybin, Papers, Psychology, Publications / /

Abstract

The past two decades has seen a significant increase in both popular and scientific interest in psychedelic substances and plants as therapeutics for mental illness, addictions, and psychospiritual suffering. Current psychiatric practice privileges a biological paradigm in which the brain is considered the locus of mental illness and symptom-focused treatments are delivered to patients as passive recipients. In contrast, a psychedelic healing paradigm, constructed through examination of different ontologic understandings of plant medicines, is based on a complex multidimensional perspective of human beings and their suffering. This paradigm actively engages the sufferer in addressing root causes of illness through healing on multiple levels of existence, including spiritual and energetic domains. Numerous theoretical, methodological, and ethical challenges complicate the integration of the psychedelic healing paradigm into psychiatric practice. These include developing coherent therapeutic narratives that account for the complex processes by which psychedelic healing occurs and overcoming reductionist tendencies in the medical sciences. Tasked with overcoming such challenges, a model clinic is proposed that seeks to implement and study the psychedelic healing paradigm in a critical, interdisciplinary, and reflexive manner. Such “critical paradigm integration” would employ multimodal patient formulation and treatments, as well as a range of knowledge generation and sharing practices. Outcomes-oriented research would seek to establish an evidence base for the model, while critical dialogues would advance understandings of psychedelic substances and plants and related practices more generally. The clinic would serve as proof of concept for a new model of studying, conceptualizing, and treating mental illness.

Sloshower, J. (2018). Integrating Psychedelic Medicines and Psychiatry: Theory and Methods of a Model Clinic. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 113-132. 10.1007/978-3-319-76720-8_7
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Psychedelic Naturalism and Interspecies Alliance: Views from the Emerging Do-It-Yourself Mycology Movement

/ Biology & Ethnobotany, Mushrooms / Psilocybin, Papers, Publications / /

Abstract

Do-it-yourself (DIY) mycology is a movement that has emerged in the last decade in North America. DIY mycologists specialize in easy and accessible methods of mushroom cultivation and mycological experimentation and mobilize a discourse of alliance with the fungal kingdom. They draw primarily on home cultivation methods innovated by Psilocybe cultivators in the 1970s and on creative applications popularized by commercial mycologist and psychedelic enthusiast Paul Stamets in the 2000s. As a counterpoint to the newfound visibility and legitimacy of lab-synthesized psilocybin in clinical psychiatry, DIY mycology exemplifies an alternate history of this multispecies engagement. Drawing on ethnographic fieldwork in the San Francisco Bay Area and the Pacific Northwest, this chapter begins with the tacit premise of the psychedelic/entheogenic movement that the use of psychedelics fosters ecological concern. Many DIY mycologists express biocentric ethics and eco-spiritual principles, but interviews revealed a diverse and nuanced relationship to psychedelics. I argue that DIY mycology is best understood as an interspecies (or cross-kingdom) engagement that is part of an emergent ecological ethics and deep ecology worldview, one that subsumes psychedelic experiences as one manifestation of that engagement. DIY mycology exemplifies how the spread of mycological know-how, fascination, and enthusiasm has fostered an engagement with fungi that extends far beyond psychedelics. To understand this engagement, I contextualize it within wider social and cultural shifts, particularly those that reformulated our practical, ethical, and conceptual relationship with the natural world. This movement attests to the existence of multiple means to enact these ethics and to foster meaningful relationality with nonhuman life in contemporary North American society and culture.

Steinhardt, J. (2018). Psychedelic Naturalism and Interspecies Alliance: Views from the Emerging Do-It-Yourself Mycology Movement. Plant Medicines, Healing and Psychedelic Science: Cultural Perspectives, 167-184. 10.1007/978-3-319-76720-8_10
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Journal Club #28: Efficacy and Safety of Psilocybin in Treatment-Resistant Depression: Results of the EPIsoDE Trial - October 6

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