Effect of chemically synthesized psilocybin and psychedelic mushroom extract on molecular and metabolic profiles in mouse brain.

Psilocybin, a naturally occurring, tryptamine alkaloid prodrug, is currently being investigated for the treatment of a range of psychiatric disorders. Preclinical reports suggest that the biological effects of psilocybin-containing mushroom extract or "full spectrum" (psychedelic) mushroom extract (PME), may differ from those of chemically synthesized psilocybin (PSIL). We compared the effects of PME to those of PSIL on the head twitch response (HTR), neuroplasticity-related synaptic proteins and frontal cortex metabolomic profiles in male C57Bl/6j mice. HTR measurement showed similar effects of PSIL and PME over 20 min. Brain specimens (frontal cortex, hippocampus, amygdala, striatum) were assayed for the synaptic proteins, GAP43, PSD95, synaptophysin and SV2A, using western blots. These proteins may serve as indicators of synaptic plasticity. Three days after treatment, there was minimal increase in synaptic proteins. After 11 days, PSIL and PME significantly increased GAP43 in the frontal cortex (p = 0.019; p = 0.039 respectively) and hippocampus (p = 0.015; p = 0.027) and synaptophysin in the hippocampus (p = 0.041; p = 0.05) and amygdala (p = 0.035; p = 0.004). PSIL increased SV2A in the amygdala (p = 0.036) and PME did so in the hippocampus (p = 0.014). In the striatum, synaptophysin was increased by PME only (p = 0.023). There were no significant effects of PSIL or PME on PSD95 in any brain area when these were analyzed separately. Nested analysis of variance (ANOVA) showed a significant increase in each of the 4 proteins over all brain areas for PME versus vehicle control, while significant PSIL effects were observed only in the hippocampus and amygdala and were limited to PSD95 and SV2A. Metabolomic analyses of the pre-frontal cortex were performed by untargeted polar metabolomics utilizing capillary electrophoresis - Fourier transform mass spectrometry (CE-FTMS) and showed a differential metabolic separation between PME and vehicle groups. The purines guanosine, hypoxanthine and inosine, associated with oxidative stress and energy production pathways, showed a progressive decline from VEH to PSIL to PME. In conclusion, our synaptic protein findings suggest that PME has a more potent and prolonged effect on synaptic plasticity than PSIL. Our metabolomics data support a gradient of effects from inert vehicle via chemical psilocybin to PME further supporting differential effects. Further studies are needed to confirm and extend these findings and to identify the molecules that may be responsible for the enhanced effects of PME as compared to psilocybin alone.

Could psychedelic drugs have a role in the treatment of schizophrenia? Rationale and strategy for safe implementation.

Schizophrenia is a widespread psychiatric disorder that affects 0.5-1.0% of the world's population and induces significant, long-term disability that exacts high personal and societal cost. Negative symptoms, which respond poorly to available antipsychotic drugs, are the primary cause of this disability. Association of negative symptoms with cortical atrophy and cell loss is widely reported. Psychedelic drugs are undergoing a significant renaissance in psychiatric disorders with efficacy reported in several conditions including depression, in individuals facing terminal cancer, posttraumatic stress disorder, and addiction. There is considerable evidence from preclinical studies and some support from human studies that psychedelics enhance neuroplasticity. In this Perspective, we consider the possibility that psychedelic drugs could have a role in treating cortical atrophy and cell loss in schizophrenia, and ameliorating the negative symptoms associated with these pathological manifestations. The foremost concern in treating schizophrenia patients with psychedelic drugs is induction or exacerbation of psychosis. We consider several strategies that could be implemented to mitigate the danger of psychotogenic effects and allow treatment of schizophrenia patients with psychedelics to be implemented. These include use of non-hallucinogenic derivatives, which are currently the focus of intense study, implementation of sub-psychedelic or microdosing, harnessing of entourage effects in extracts of psychedelic mushrooms, and blocking 5-HT2A receptor-mediated hallucinogenic effects. Preclinical studies that employ appropriate animal models are a prerequisite and clinical studies will need to be carefully designed on the basis of preclinical and translational data. Careful research in this area could significantly impact the treatment of one of the most severe and socially debilitating psychiatric disorders and open an exciting new frontier in psychopharmacology.

Striking Long Term Beneficial Effects of Single Dose Psilocybin and Psychedelic Mushroom Extract in the SAPAP3 Rodent Model of OCD-Like Excessive Self-Grooming.

Obsessive compulsive disorder (OCD) is a highly prevalent disorder that causes serious disability. Available treatments leave 40% or more of people with OCD significantly symptomatic. There is an urgent need for novel therapeutic approaches. Mice that carry a homozygous deletion of the SAPAP3 gene (SAPAP3 KO) manifest a phenotype of excessive self-grooming, tic-like head-body twitches and anxiety. These behaviors closely resemble pathological self-grooming behaviors observed in humans in conditions that overlap with OCD. Following a preliminary report that the tryptaminergic psychedelic, psilocybin, may reduce symptoms in patients with OCD, we undertook a randomized controlled trial of psilocybin in 50 SAPAP3 KO mice (28 male, 22 female). Mice that fulfilled inclusion criteria were randomly assigned to a single intraperitoneal injection of psilocybin (4.4 mg/kg), psychedelic mushroom extract (encompassing the same psilocybin dose) or vehicle control and were evaluated after 2, 4 and 21 days by a rater blind to treatment allocation for grooming characteristics, head-body twitches, anxiety and other behavioral features. Mice treated with vehicle (n=18) manifested a 118.71±95.96 % increase in total self-grooming (the primary outcome measure) over the 21-day observation period. In contrast, total self-grooming decreased by 14.60%±17.90% in mice treated with psilocybin (n=16) and by 19.20±20.05% in mice treated with psychedelic mushroom extract (n=16) (p=.001 for effect of time; p=.0001 for time × treatment interaction). 5 mice were dropped from the vehicle group because they developed skin lesions; 4 from the psilocybin group and none from the psychedelic mushroom extract group. Secondary outcome measures such as head-body twitches and anxiety all showed a significant improvement over 21 days. Notably, in mice that responded to psilocybin (n=12) and psychedelic mushroom extract (n=13), the beneficial effect of a single treatment persisted up to 7 weeks. Mice initially treated with vehicle and non-responsive, showed a clear and lasting therapeutic response when treated with a single dose of psilocybin or psychedelic mushroom extract and followed for a further 3 weeks. While equivalent to psilocybin in overall effect on self-grooming, psychedelic mushroom extract showed superior effects in alleviating head-body twitches and anxiety. These findings strongly justify clinical trials of psilocybin in the treatment of OCD and further studies aimed at elucidating mechanisms that underlie the long-term effects to alleviate excessive self-grooming observed in this study.

Effects of psilocybin, psychedelic mushroom extract and 5-hydroxytryptophan on brain immediate early gene expression: Interaction with serotonergic receptor modulators.

Background: Immediate early genes (IEGs) are rapidly activated and initiate diverse cellular processes including neuroplasticity. We report the effect of psilocybin (PSIL), PSIL-containing psychedelic mushroom extract (PME) and 5-hydroxytryptophan (5-HTP) on expression of the IEGs, cfos, egr1, and egr2 in mouse somatosensory cortex (SSC). Methods: In our initial experiment, male C57Bl/6j mice were injected with PSIL 4.4 mg/kg or 5-HTP 200 mg/kg, alone or immediately preceded by serotonergic receptor modulators. IEG mRNA expression 1 hour later was determined by real time qPCR. In a replication study a group of mice treated with PME was added. Results: In our initial experiment, PSIL but not 5-HTP significantly increased expression of all three IEGs. No correlation was observed between the head twitch response (HTR) induced by PSIL and its effect on the IEGs. The serotonergic receptor modulators did not significantly alter PSIL-induced IEG expression, with the exception of the 5-HT2C antagonist (RS102221), which significantly enhanced PSIL-induced egr2 expression. 5-HTP did not affect IEG expression. In our replication experiment, PSIL and PME upregulated levels of egr1 and cfos while the upregulation of egr2 was not significant. Conclusions: We have shown that PSIL and PME but not 5-HTP (at a dose sufficient to induce HTR), induced a significant increase in cfos and egr1 expression in mouse SSC. Our findings suggest that egr1 and cfos expression may be associated with psychedelic effects.

COVID-19 vaccination and race - A nationwide survey of vaccination status, intentions, and trust in the US general population.

BACKGROUND: COVID-19 vaccine hesitancy for adults and children varies depending on societal factors, race, and trust ascribed to the source of vaccine information. OBJECTIVE: To assess COVID-19 vaccination rates and trust levels for vaccine information by race at 2 time points. METHODS: Online cross-sectional data from US adults were collected in February/March 2021 (T1) and November 2021 (T2). Questions included vaccination status, reasons for vaccine refusal, trust levels for vaccine information and the Wake Forest Physician Trust Scale. At T2, parents were asked about vaccination status of children aged 12-18 years and intent for children aged 5-11 years. Vaccination rates and trust levels for vaccine information were measured. Multivariable logistic regression was used to identify characteristics predictive of receiving COVID-19 vaccination. RESULTS: Vaccination rates were 20.2% and 70.8% at T1 and T2, respectively. At T1 and T2, higher proportions of White (23.2% and 72.0%) and Other race (14.4% and 75.2%) respondents were vaccinated relative to Black respondents (9.6% and 64.4%) (P < 0.05). In descending order, respondents' doctors, family members, and pharmacists were the most trusted information sources. Black parents, relative to White and Other parents with unvaccinated children aged 12-18 years or who were not very likely to vaccinate younger children, reported lowest physician trust (P < 0.01). At T1, being married, college educated, and older and having greater Wake Forest Physician Trust Scale scores and a higher number of comorbidities predicted a higher likelihood of being vaccinated. Being Black, having a median household income less than $100,000, and residing in the Northeast or Midwest, relative to the West, predicted a decreased likelihood of being vaccinated. At T2, race and comorbidities were no longer predictive of vaccination. CONCLUSIONS: Racial variation in vaccination status decreased from T1 to T2. Physician trust predicted vaccination status and intent regardless of race. Respondents' doctors, family members, and pharmacists are trusted sources of vaccine information, and targeting these influencers may reduce vaccination hesitancy. DISCLOSURES: Dr Brown reports personal fees from Taiho Oncology, outside the submitted work. Dr Morlock reports personal fees from Johnson and Johnson, Heron Therapeutics, Evofem Biosciences, Horizon Therapeutics, and Taiho Oncology, outside the submitted work. Amy Morlock reports personal fees from both AbbVie (formerly Allergan) and Ironwood, outside the submitted work. Drs Blakolmer and Heidari have nothing to disclose.

Accuracy of bile duct changes for the diagnosis of chronic liver allograft rejection: reliability of the 1999 Banff schema.

Chronic rejection (CR) after liver transplantation is thought to be a dynamic and potentially reversible process. The Banff working group has developed recommendations for its histopathologic staging. The 1999 Banff classification of CR (i.e., bile duct dystrophy >50% and/or bile duct loss >20%) was applied to: 1) biopsies from patients retransplanted for CR (N = 19) and pathologies other than CR (N = 21) to evaluate its specificity and sensitivity, especially of the early stage lesions of CR; and 2) biopsies from nonretransplanted patients (N = 21) to evaluate the evolution of CR lesions. Atypical forms of CR were also described. Including an early stage into the definition of CR has resulted in a much higher sensitivity for its diagnosis, as compared with the former classification (i.e., bile duct loss >50%) (89% vs. 33%; P =.0001), while keeping an acceptable specificity (74% vs. 100%; P =.03). In 55% of the nonretransplanted patients, CR lesions were reversible. No histologic feature reliably predicted CR outcome. Transient lobular hepatitis, unrelated to viral infection, and veno-occlusive disease were seen significantly more often in the CR group (P =.04 and P =.03, respectively). We conclude that the application of the 1999 Banff classification is superior to the previous classification for the diagnosis of CR. However, limited information can be drawn regarding the outcome of CR based on histology alone. Transient lobular hepatitis, unrelated to viral infection and veno-occlusive disease, may be an unusual expression of CR.