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Drug Design, Development and Therapy 2024Psilocybin, a tryptamine psychedelic, has been touted in the media both historically and recently as a potential game-changing mental health therapeutic.... (Observational Study)
Observational Study
INTRODUCTION
Psilocybin, a tryptamine psychedelic, has been touted in the media both historically and recently as a potential game-changing mental health therapeutic. ClinicalTrials.gov has over one hundred and thirty psilocybin clinical trials listed covering the last twenty years. The single most important aspect of any therapeutic is to gain approval for marketing and thus enter the real-world phase of development. A typical new chemical entity progresses from inception to US Food and Drug Administration (FDA) approval in approximately 12 years and seeks approval for a single indication.
METHODS
An observational study was conducted with the available information on the ClinicalTrials.gov site to observe the extent of progress made demonstrating the clinical utility of psilocybin.
RESULTS
The results showed 134 psilocybin trials typically unblinded studies of 10-20 participants, recruited over years at a single site. Additionally, there have been only three advanced trials (1 Phase 2/3 and 2 Phase 3) submitted, and only in the last two years.
DISCUSSION
The hundreds of psilocybin clinical trials initiated over the past twenty years comprising a myriad of potential indications may actually be slowing this potential game-changing mental health therapeutic agent's approval and is costing excessive amounts of capital. To fully evaluate the actual potential of psilocybin, purposeful clinical trials need to be designed well, executed efficiently, and analyzed utilizing sequential and statistically valid processes for each potential indication. This will require a change from the current exploratory forays to defined, well-funded, sequential pharmaceutical development practices, including adequate and appropriate blinding of studies, statistical design to determine the number of participants and more importantly, professional expertise in conducting multicenter trials. Unfortunately, these results demonstrate little real progress towards FDA approval of psilocybin and a field with no clear direction forward.
Topics: United States; Humans; Psilocybin; Hallucinogens; Drug Development; Marketing; Research Design
PubMed: 38618282
DOI: 10.2147/DDDT.S443177 -
Npj Mental Health Research Feb 2024Psilocybin is a serotonergic psychedelic shown to have enduring antidepressant effects. Currently, the mechanism for its enduring effects is not well understood. Empathy... (Review)
Review
Psilocybin is a serotonergic psychedelic shown to have enduring antidepressant effects. Currently, the mechanism for its enduring effects is not well understood. Empathy and prosocial behavior may be important for understanding the therapeutic benefit of psilocybin. In this article we review the effect of psilocybin on empathy and prosocial behavior. Moreover, we propose that psilocybin may induce a positive feedback loop involving empathy and prosocial behavior which helps explain the observed, enduring antidepressant effects.
PubMed: 38609500
DOI: 10.1038/s44184-023-00053-8 -
Journal of Psychopharmacology (Oxford,... May 2024Reference to an intrinsic healing mechanism or an 'inner healer' is commonplace amongst psychedelic drug-using cultures. The 'inner healer' refers to the belief that... (Randomized Controlled Trial)
Randomized Controlled Trial
BACKGROUND
Reference to an intrinsic healing mechanism or an 'inner healer' is commonplace amongst psychedelic drug-using cultures. The 'inner healer' refers to the belief that psychedelic compounds, plants or concoctions have an intrinsically regenerative action on the mind and brain, analogous to intrinsic healing mechanisms within the physical body, for example, after sickness or injury.
AIMS
Here, we sought to test and critique this idea by devising a single subjective rating item pertaining to perceived 'inner healing' effects.
METHODS
The item was issued to 59 patients after a single high (25 mg, = 30) or 'placebo' (1 mg, = 29) dose of psilocybin in a double-blind randomised controlled trial of psilocybin for depression.
RESULTS
Inner healer scores were higher after the high versus placebo dose of psilocybin ( = 3.88, < 0.001). Within the high-dose sub-sample only, inner healer scores predicted improved depressive symptomatology at 2 weeks post-dosing.
CONCLUSIONS
The principle of activating inner healing mechanisms via psychedelics is scientifically nascent; however, this study takes a positivist and pragmatic step forward, asking whether it warrants further examination.
Topics: Humans; Hallucinogens; Psilocybin; Double-Blind Method; Adult; Male; Female; Middle Aged; Depression; Young Adult; Dose-Response Relationship, Drug
PubMed: 38605658
DOI: 10.1177/02698811241239206 -
Addiction Biology Apr 2024Alcohol use disorder (AUD) remains one of the most prevalent psychiatric disorders worldwide with high economic costs. Current treatment options show modest efficacy and... (Review)
Review
Alcohol use disorder (AUD) remains one of the most prevalent psychiatric disorders worldwide with high economic costs. Current treatment options show modest efficacy and relapse rates are high. Furthermore, there are increases in the treatment gap and few new medications have been approved in the past 20 years. Recently, psychedelic-assisted therapy with psilocybin and lysergic acid diethylamide has garnered significant attention in the treatment of AUD. Yet, they require significant amounts of therapist input due to prolonged subjective effects (~4-12 h) leading to high costs and impeding implementation. Accordingly, there is an increasing interest in the rapid and short-acting psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). This paper offers a first look at potential therapeutic mechanisms for AUD by reviewing the current literature on 5-MeO-DMT. Primarily, 5-MeO-DMT is able to induce mystical experiences and ego-dissolution together with increases in psychological flexibility and mindfulness. This could decrease AUD symptoms through the alleviation of psychiatric mood-related comorbidities consistent with the negative reinforcement and self-medication paradigms. In addition, preliminary evidence indicates that 5-MeO-DMT modulates neural oscillations that might subserve ego-dissolution (increases in gamma), psychological flexibility and mindfulness (increases in theta), and the reorganization of executive control networks (increases in coherence across frequencies) that could improve emotion regulation and inhibition. Finally, animal studies show that 5-MeO-DMT is characterized by neuroplasticity, anti-inflammation, 5-HT receptor agonism, and downregulation of metabotropic glutamate receptor 5 with clinical implications for AUD and psychiatric mood-related comorbidities. The paper concludes with several recommendations for future research to establish the purported therapeutic mechanisms of action.
Topics: Animals; Humans; Hallucinogens; N,N-Dimethyltryptamine; Methoxydimethyltryptamines; Alcoholism; Alcohol Drinking
PubMed: 38600715
DOI: 10.1111/adb.13386 -
JAMA Network Open Apr 2024Psilocybin has been studied in the treatment of depression and anxiety disorders. Clinical studies have mainly focused on efficacy, with systematic reviews showing... (Meta-Analysis)
Meta-Analysis
IMPORTANCE
Psilocybin has been studied in the treatment of depression and anxiety disorders. Clinical studies have mainly focused on efficacy, with systematic reviews showing favorable efficacy; however, none have primarily focused on psilocybin safety.
OBJECTIVE
To evaluate the acute adverse effects of psilocybin at therapeutic doses in the treatment of depression and anxiety.
DATA SOURCES
MEDLINE via PubMed, Web of Science, and ClinicalTrials.gov were searched for publications available between 1966 and November 30, 2023.
STUDY SELECTION
Randomized, double-blind clinical trials that reported adverse effects of psilocybin in patients treated for depression and anxiety were screened.
DATA EXTRACTION AND SYNTHESIS
Data were independently extracted by 2 authors and verified by 2 additional authors following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guideline. The inverse variance method with the Hartung-Knapp adjustment for the random-effects model was used, with a continuity correction of 0.5 for studies with 0 cell frequencies. Sensitivity analysis was conducted by sequentially removing 1 study at a time to assess the robustness of the results.
MAIN OUTCOMES AND MEASURES
The primary outcome was considered as the adverse effects of psilocybin at high and moderate (ie, therapeutic) dose regimens and compared with placebo, low-dose psilocybin, or other comparator in the treatment of depression and/or anxiety.
RESULTS
Six studies met the inclusion criteria with a total sample of 528 participants (approximately 51% female; median age 39.8 years; IQR, 39.8-41.2). Seven adverse effects were reported in multiple studies and included in the analysis. Among these, headache (relative risk [RR], 1.99; 95% CI 1.06-3.74), nausea (RR, 8.85; 95% CI, 5.68-13.79), anxiety (RR, 2.27; 95% CI, 1.11-4.64), dizziness (RR, 5.81; 95% CI, 1.02-33.03), and elevated blood pressure (RR, 2.29; 95% CI, 1.15- 4.53) were statistically significant. Psilocybin use was not associated with risk of paranoia and transient thought disorder.
CONCLUSIONS AND RELEVANCE
In this meta-analysis, the acute adverse effect profile of therapeutic single-dose psilocybin appeared to be tolerable and resolved within 48 hours. However, future studies need to more actively evaluate the appropriate management of adverse effects.
Topics: Humans; Female; Adult; Male; Psilocybin; Drug-Related Side Effects and Adverse Reactions; Anxiety Disorders; Anxiety; Dizziness; Randomized Controlled Trials as Topic
PubMed: 38598236
DOI: 10.1001/jamanetworkopen.2024.5960 -
Pharmacology & Therapeutics Jun 2024Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current... (Review)
Review
Major depression is an established risk factor for subsequent dementia, and depression in late life may also represent a prodromal state of dementia. Considering current challenges in the clinical development of disease modifying therapies for dementia, the focus of research is shifting towards prevention and modification of risk factors to alter the neurodegenerative disease trajectory. Understanding mechanistic commonalities underlying affective symptoms and cognitive decline may reveal biomarkers to aid early identification of those at risk of progressing to dementia during the preclinical phase of disease, thus allowing for timely intervention. Adult hippocampal neurogenesis (AHN) is a phenomenon that describes the birth of new neurons in the dentate gyrus throughout life and it is associated with spatial learning, memory and mood regulation. Microglia are innate immune system macrophages in the central nervous system that carefully regulate AHN via multiple mechanisms. Disruption in AHN is associated with both dementia and major depression and microgliosis is a hallmark of several neurodegenerative diseases. Emerging evidence suggests that psychedelics promote neuroplasticity, including neurogenesis, and may also be immunomodulatory. In this context, psilocybin, a serotonergic agonist with rapid-acting antidepressant properties has the potential to ameliorate intersecting pathophysiological processes relevant for both major depression and neurodegenerative diseases. In this narrative review, we focus on the evidence base for the effects of psilocybin on adult hippocampal neurogenesis and microglial form and function; which may suggest that psilocybin has the potential to modulate multiple mechanisms of action, and may have implications in altering the progression from major depression to dementia in those at risk.
Topics: Humans; Dementia; Animals; Neurodegenerative Diseases; Depressive Disorder, Major; Neurogenesis; Psilocybin; Hippocampus; Hallucinogens; Antidepressive Agents; Microglia
PubMed: 38583670
DOI: 10.1016/j.pharmthera.2024.108641 -
Lakartidningen Apr 2024In the last 20 years there has been an increased interest in research on psychedelic compounds for treatment of psychiatric conditions such as depression, anxiety and... (Review)
Review
In the last 20 years there has been an increased interest in research on psychedelic compounds for treatment of psychiatric conditions such as depression, anxiety and substance use disorders. Despite existing treatments being efficacious for many patients, this is not the case for up to a third of the patients with depression. Additionally, treatments are often long and associated with side effects. This review focuses on the psychedelic compound psilocybin, a serotonin-2A-receptor agonist that has been seen to reduce depression and anxiety in patients after administration of only a single dose, with effects lasting several weeks. Recent findings from phase II studies suggest that psilocybin treatment for depression is safe and efficacious. A phase III study is currently recruiting. Whether psychedelics will become a part of standard healthcare remains to be seen, but findings do give rise to cautious optimism.
Topics: Humans; Hallucinogens; Psilocybin; Anxiety Disorders; Psychiatry
PubMed: 38572715
DOI: No ID Found -
Network Neuroscience (Cambridge, Mass.) 2024The emerging neuroscientific frontier of brain fingerprinting has recently established that human functional connectomes (FCs) exhibit idiosyncratic features, which map...
The emerging neuroscientific frontier of brain fingerprinting has recently established that human functional connectomes (FCs) exhibit idiosyncratic features, which map onto heterogeneously distributed behavioral traits. Here, we harness brain-fingerprinting tools to extract FC features that predict subjective drug experience induced by the psychedelic psilocybin. Specifically, in neuroimaging data of healthy volunteers under the acute influence of psilocybin or a placebo, we show that, post psilocybin administration, FCs become more idiosyncratic owing to greater intersubject dissimilarity. Moreover, whereas in placebo subjects idiosyncratic features are primarily found in the frontoparietal network, in psilocybin subjects they concentrate in the default mode network (DMN). Crucially, isolating the latter revealed an FC pattern that predicts subjective psilocybin experience and is characterized by reduced within-DMN and DMN-limbic connectivity, as well as increased connectivity between the DMN and attentional systems. Overall, these results contribute to bridging the gap between psilocybin-mediated effects on brain and behavior, while demonstrating the value of a brain-fingerprinting approach to pharmacological neuroimaging.
PubMed: 38562294
DOI: 10.1162/netn_a_00349 -
ACS Central Science Mar 2024Research into natural products emerged from humanity's curiosity about the nature of matter and its role in the of diverse civilizations. Plants and fungi, in... (Review)
Review
Research into natural products emerged from humanity's curiosity about the nature of matter and its role in the of diverse civilizations. Plants and fungi, in particular, supplied materials that altered behavior, perception, and well-being profoundly. Many active principles remain well-known today: strychnine, morphine, psilocybin, ephedrine. The potential to circumvent the constraints of natural supply and explore the properties of these materials led to the field of natural product synthesis. This research delivered new molecules with new properties, but also led to fundamental insights into the chemistry of the nonmetal elements H, C, N, O, P, S, Se, and their combinations, i.e., organic chemistry. It also led to a potent culture focused on bigger molecules and races to the finish line, perhaps at the expense of actionable next steps. About 20 years ago, the field began to contract in the United States. Research that focused solely on chemical reaction development, especially catalysis, filled the void. After all, new reactions and mechanistic insight could be immediately implemented by the chemistry community, so it became hard to justify the lengthy procurement of a complex molecule that sat in the freezer unused. This shift coincided with a divestment of natural product portfolios by pharmaceutical companies and an emphasis in academic organic chemistry on applications-driven research, perhaps at the expense of more fundamental science. However, as bioassays and the tools of chemical biology become widespread, synthesis finds a new and powerful ally that allows us to better deliver on the premise of the field. And the hard-won insights of complex synthesis can be better encoded digitally, mined by data science, and applied to new challenges, as chemists perturb and even surpass the properties of complex natural products. The 21st century promises powerful developments, both in fundamental organic chemistry and at the interface of synthesis and biology, if the community of scientists fosters its growth. This essay tries to contextualize natural product synthesis for a broad audience, looks ahead to its transformation in the coming years, and expects the future to be bright.
PubMed: 38559299
DOI: 10.1021/acscentsci.3c01518 -
Nature Communications Mar 2024Psilocybin, the natural hallucinogen produced by Psilocybe ("magic") mushrooms, holds great promise for the treatment of depression and several other mental health...
Psilocybin, the natural hallucinogen produced by Psilocybe ("magic") mushrooms, holds great promise for the treatment of depression and several other mental health conditions. The final step in the psilocybin biosynthetic pathway, dimethylation of the tryptophan-derived intermediate norbaeocystin, is catalysed by PsiM. Here we present atomic resolution (0.9 Å) crystal structures of PsiM trapped at various stages of its reaction cycle, providing detailed insight into the SAM-dependent methylation mechanism. Structural and phylogenetic analyses suggest that PsiM derives from epitranscriptomic N-methyladenosine writers of the METTL16 family, which is further supported by the observation that bound substrates physicochemically mimic RNA. Inherent limitations of the ancestral monomethyltransferase scaffold hamper the efficiency of psilocybin assembly and leave PsiM incapable of catalysing trimethylation to aeruginascin. The results of our study will support bioengineering efforts aiming to create novel variants of psilocybin with improved therapeutic properties.
Topics: Psilocybin; Phylogeny; Hallucinogens; Agaricales; Psilocybe
PubMed: 38548735
DOI: 10.1038/s41467-024-46997-z