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ACS Medicinal Chemistry Letters Jun 2024This Patent Highlight explores advancements in pharmacology, focusing on the novel delivery and application of psychoactive substances. It highlights the development of...
This Patent Highlight explores advancements in pharmacology, focusing on the novel delivery and application of psychoactive substances. It highlights the development of transdermal formulations for psychoactive alkaloids, neuroenhancement techniques to augment emotional responses, and the intravenous infusion of psilocybin or psilocin for various therapeutic purposes. Additionally, it delves into the characterization and potential uses of crystalline forms of tryptamine derivatives. These innovations signify significant progress in drug delivery systems, neurostimulation methods, and the therapeutic use of psychedelic compounds, potentially revolutionizing the treatment of psychological and neurological disorders.
PubMed: 38894903
DOI: 10.1021/acsmedchemlett.4c00181 -
Journal of Psychopharmacology (Oxford,... Jun 2024Voter initiatives in Oregon and Colorado authorize legal frameworks for supervised psilocybin services, but no measures monitor safety or outcomes.
BACKGROUND
Voter initiatives in Oregon and Colorado authorize legal frameworks for supervised psilocybin services, but no measures monitor safety or outcomes.
AIMS
To develop core measures of best practices.
METHODS
A three-phase e-Delphi process recruited 36 experts with 5 or more years' experience facilitating psilocybin experiences in various contexts (e.g., ceremonial settings, indigenous practices, clinical trials), or other pertinent psilocybin expertise. Phase I, an on-line survey with qualitative, open-ended text responses, generated potential measures to assess processes, outcomes, and structure reflecting high quality psilocybin services. In Phase II, experts used seven-point Likert scales to rate the importance and feasibility of the Phase I measures. Measures were priority ranked. Qualitative interviews and analysis in Phase III refined top-rated measures.
RESULTS
Experts ( = 36; 53% female; 71% white; 56% heterosexual) reported currently providing psilocybin services (64%) for a mean of 15.2 [SD 13.1] years, experience with indigenous psychedelic practices (67%), and/or conducting clinical trials (36%). Thematic analysis of Phase I responses yielded 55 candidate process measures (e.g., preparatory hours with client, total dose of psilocybin administered, documentation of touch/sexual boundaries), outcome measures (e.g., adverse events, well-being, anxiety/depression symptoms), and structure measures (e.g., facilitator training in trauma informed care, referral capacity for medical/psychiatric issues). In Phase II and III, experts prioritized a core set of 11 process, 11 outcome, and 17 structure measures that balanced importance and feasibility.
CONCLUSION
Service providers and policy makers should consider standardizing core measures developed in this study to monitor the safety, quality, and outcomes of community-based psilocybin services.
PubMed: 38888164
DOI: 10.1177/02698811241257839 -
Biotechnology Progress Jun 2024N-methylated tryptamines, such as the hallucinogenic natural products, psilocybin and N,N-dimethyltryptamine (DMT), are gaining interest from the medical community due...
N-methylated tryptamines, such as the hallucinogenic natural products, psilocybin and N,N-dimethyltryptamine (DMT), are gaining interest from the medical community due to their potential as next generation treatments for mental health disorders. The clinical relevance of these compounds has driven scientists to develop biosynthetic production routes to a number of tryptamine drug candidates, and efforts are ongoing to expand and further develop these biosynthetic capabilities. To that end, we have further characterized the substrate preferences of two enzymes involved in tryptamine biosynthesis: TrpM, a tryptophan N-methyltransferase from Psilocybe serbica, and PsiD, the gateway decarboxylase of the psilocybin biosynthesis pathway. Here, we show that TrpM can N-methylate the non-native amino acid substrate, 4-hydroxytryptophan, a key intermediate in the Escherichia coli-based recombinant psilocybin biosynthesis pathway. However, the ability to incorporate TrpM into a functional psilocybin biosynthesis pathway was thwarted by PsiD's inability to use N,N-dimethyl-4-hydroxytryptophan as substrate, under the culturing conditions tested, despite demonstrating activity on N-methylated and 4-hydroxylated tryptophan derivatives individually. Taken together, this work expands upon the known substrates for TrpM and PsiD, further increasing the diversity of tryptamine biosynthetic products.
PubMed: 38888046
DOI: 10.1002/btpr.3492 -
Frontiers in Pharmacology 2024One of the most important developments in psychopharmacology in the past decade has been the emergence of novel treatments for mood disorders, such as psilocybin for... (Review)
Review
One of the most important developments in psychopharmacology in the past decade has been the emergence of novel treatments for mood disorders, such as psilocybin for treatment-resistant depression. Psilocybin is most commonly found in different species of mushroom; however, the literature on mushroom and fungus extracts with potential antidepressant activity extends well beyond just psilocybin-containing mushrooms, and includes both psychedelic and non-psychedelic species. In the current review, we systematically review the preclinical literature on mushroom and fungus extracts, and their effects of animal models of depression and tests of antidepressant activity. The PICO structure, PRISMA checklist and the Cochrane Handbook for systematic reviews of intervention were used to guide the search strategy. A scoping search was conducted in electronic databases PubMed, CINAHL, Embase and Web of Science. The literature search identified 50 relevant and suitable published studies. These included 19 different species of mushrooms, as well as seven different species of other fungi. Nearly all studies reported antidepressant-like effects of treatment with extracts. Treatments were most commonly delivered orally, in both acute and chronically administered studies to predominantly male rodents. Multiple animal models of depression were used, the most common being unpredictable chronic mild stress, while the tail suspension test and forced swim test were most frequently used as standalone antidepressant screens. Details on each experiment with mushroom and fungus species are discussed in detail, while an evaluation is provided of the strengths and weaknesses of these studies.
PubMed: 38887548
DOI: 10.3389/fphar.2024.1387158 -
Cannabis and Cannabinoid Research Jun 2024In Colorado, both cannabis and psilocybin are legal and becoming more commonly used. However, there is almost no research detailing the public health concerns regarding...
In Colorado, both cannabis and psilocybin are legal and becoming more commonly used. However, there is almost no research detailing the public health concerns regarding negative outcomes (e.g., dependence) of cannabis and psilocybin co-use and motives that may perpetuate these negative outcomes (e.g., coping, boredom). Using data from a larger observational study on cannabis and metabolic processes, regular cannabis users (use ≥7 times/month; = 97, 35.1% female, 89.7% WHITE) who used psilocybin in the past 3 months ( = 34) were compared with those who had not used psilocybin in the past 3 months ( = 63) on cannabis dependence as measured by the Marijuana Dependence Scale and endorsement of 12 cannabis motives from the Comprehensive Marijuana Motives Questionnaire. Correlations between motives and dependence were also examined and compared across groups. Findings revealed that individuals who had recently used psilocybin had greater cannabis dependence scores than those who had not used recently [ (1, 95) = 5.53, = 0.02], and more strongly endorsed that their cannabis use was motivated by enjoyment [ (1, 91) = 4.31, = 0.04], boredom [ (1, 91) = 9.10, < 0.01], and availability [ (1, 91) = 9.46, < 0.01]. Correlations between dependence scores and coping and boredom motives were also significantly positive for both groups (all values <0.05) whereas positive correlations with experimentation, celebration, and availability motives were only significant for recent psilocybin users (all values <0.05). These results suggest there are motivational differences for cannabis use among those who co-use cannabis and psilocybin, and there may be a greater risk for harm for these individuals.
PubMed: 38885938
DOI: 10.1089/can.2024.0059 -
IScience Jun 2024Serotonergic psychedelics hold promise as a treatment modality for various psychiatric disorders and are currently applied in psychedelic-assisted psychotherapy. We...
Serotonergic psychedelics hold promise as a treatment modality for various psychiatric disorders and are currently applied in psychedelic-assisted psychotherapy. We investigated the learning effects of the serotonin receptor agonist psilocybin in a probabilistic cue-reward task with emotional cues in the form of neutral or fearful faces, presented either consciously or subconsciously. This study represents the first investigation into reinforcement learning with psilocybin. Across different dosages, psilocybin preserved learning effects and was statistically noninferior compared to placebo, while suggesting a higher exploratory behavior. Notably, the 20 mg group exhibited significantly better learning rates against the placebo group. Psilocybin induced inferior results with subconscious cues compared to placebo, and better results with conscious neutral cues in some conditions. These findings suggest that modulating serotonin signaling in the brain with psilocybin sufficiently preservers reinforcement learning.
PubMed: 38883812
DOI: 10.1016/j.isci.2024.110034 -
Addiction (Abingdon, England) Jun 2024
PubMed: 38881433
DOI: 10.1111/add.16589 -
Current Medical Research and Opinion Jun 2024There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a... (Review)
Review
There is an increasing demand for effective treatments for depression, particularly for individuals grappling with treatment-resistant depression. Over recent years, a surge of interest has focused on exploring the safety and efficacy of psilocybin as a potential treatment for depression. However, preliminary findings from phase 2 studies have been inconclusive, prompting critical examination of issues such as maintaining blinding and the role of adjunctive psychotherapy. The maintenance of double-blinding and the role of adjunctive psychotherapy introduce biases that complicate the attainment of conclusive results in clinical research. Examining historical data reveals a recurrent pattern linked to the use of psychoactive substances, which starts with an excess of optimism and ends with general addictive behaviors and a heightened risk of serious public health problems. Considering these findings, a cautious and measured approach is imperative, given that the efficacy and safety of psilocybin treatment have yet to be unequivocally established. The potential for excessive optimism among researchers is a notable concern, as unwarranted enthusiasm may inadvertently facilitate the widespread adoption of this treatment without sufficient empirical support. In navigating the complexities of depression treatment, it is necessary to strike a balance between innovation and prudence to ensure evidence-based advancement of therapeutic approaches.
PubMed: 38880945
DOI: 10.1080/03007995.2024.2368725 -
Journal of Psychopharmacology (Oxford,... Jun 2024Some recent research and commentary have suggested that most or all the effects reported by people who microdose psychedelics may be explained by expectations or placebo... (Review)
Review
Some recent research and commentary have suggested that most or all the effects reported by people who microdose psychedelics may be explained by expectations or placebo effects. In this rapid review, we aimed to evaluate the strength of evidence for a placebo explanation of the reported effects of microdosing. We conducted a PubMed search for all studies investigating psychedelic microdosing with controlled doses and a placebo comparator. We identified 19 placebo-controlled microdosing studies and summarised all positive and null findings across this literature. Risk of bias was assessed using the Cochrane risk-of-bias tool for randomised trials. The reviewed papers indicated that microdosing with LSD and psilocybin leads to changes in neurobiology, physiology, subjective experience, affect, and cognition relative to placebo. We evaluate methodological gaps and challenges in microdosing research and suggest eight reasons why current claims that microdosing is predominately a placebo are premature and possibly wrong: (1) there have been only a small number of controlled studies; (2) studies have had small sample sizes; (3) there is evidence of dose-dependent effects; (4) studies have only investigated the effects of a small number of doses; (5) the doses investigated may have been too small; (6) studies have looked only at non-clinical populations; (7) studies so far have been susceptible to selection bias; and (8) the measured impact of expectancy is small. Considering the available evidence, we conclude that it is not yet possible to determine whether microdosing is a placebo.
PubMed: 38877715
DOI: 10.1177/02698811241254831 -
Toxicology Letters Jun 2024Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to...
Several fungi belonging to the genus Psilocybe, also called "magic mushrooms", contain the hallucinogenic drugs psilocybin and psilocin. They are chemically related to serotonin (5-HT). In addition to being abused as drugs, they are now also being discussed or used as a treatment option for depression. Here, we hypothesized that psilocybin and psilocin may act also on cardiac serotonin receptors and studied them in vitro in atrial preparations of our transgenic mouse model with cardiac myocytes-specific overexpression of the human 5-HT receptor (5-HT-TG) as well as in human atrial preparations. Both psilocybin and psilocin enhanced the force of contraction in isolated left atrial preparations from 5-HT-TG, increased the beating rate in isolated spontaneously beating right atrial preparations from 5-HT-TG and augmented the force of contraction in the human atrial preparations. The inotropic and chronotropic effects of psilocybin and psilocin at 10 µM were smaller than that of 1 µM 5-HT on the left and right atria from 5-HT-TG, respectively. Psilocybin and psilocin were inactive in WT. In the human atrial preparations, inhibition of the phosphodiesterase III by cilostamide was necessary to unmask the positive inotropic effects of psilocybin or psilocin. The effects of 10 µM psilocybin and psilocin were abrogated by 10 µM tropisetron or by 1 µM GR125487, a more selective 5-HT receptor antagonist. In summary, we demonstrated that psilocin and psilocybin act as agonists on cardiac 5-HT receptors.
PubMed: 38876450
DOI: 10.1016/j.toxlet.2024.06.006