Vaporized D-limonene selectively mitigates the acute anxiogenic effects of Δ9-tetrahydrocannabinol in healthy adults who intermittently use cannabis.

BACKGROUND: Cannabis contains hundreds of chemical constituents beyond delta-9-tetrahydrocannabinol (THC), which is believed to drive most of its acute pharmacodynamic effects. The entourage effect theory asserts that non-THC constituents can impact acute cannabis effects, but few empirical studies have systematically evaluated this theory in humans. This study assessed whether the cannabis terpenoid d-limonene mitigates the acute anxiogenic effects of THC. METHODS: Twenty healthy adults completed nine, double-blind outpatient sessions in which they inhaled vaporized THC alone (15mg or 30mg), d-limonene alone (1mg or 5mg), the same doses of THC and d-limonene together, or placebo; a subset of participants (n=12) completed a tenth session in which 30mg THC+15mg d-limonene was administered. Outcomes included subjective drug effects, cognitive/psychomotor performance, vital signs, and plasma THC and d-limonene concentrations. RESULTS: When d-limonene was administered alone, pharmacodynamic outcomes did not differ from placebo. Administration of 15mg and 30mg THC alone produced subjective, cognitive, and physiological effects typical of acute cannabis exposure. Ratings of anxiety-like subjective effects qualitatively decreased as d-limonene dose increased and concurrent administration of 30mg THC+15mg d-limonene significantly reduced ratings of "anxious/nervous" and "paranoid" compared with 30mg THC alone. Other pharmacodynamic effects were unchanged by d-limonene. D-limonene plasma concentrations were dose orderly, and concurrent administration of d-limonene did not alter THC pharmacokinetics. CONCLUSIONS: D-limonene selectively attenuated THC-induced anxiogenic effects, suggesting this terpenoid could increase the therapeutic index of THC. Future research should determine whether this effect extends to oral dose formulations and evaluate the interactions between other cannabis terpenoids or cannabinoids and THC.

Psilocybin enhances insightfulness in meditation: a perspective on the global topology of brain imaging during meditation.

In this study, for the first time, we explored a dataset of functional magnetic resonance images collected during focused attention and open monitoring meditation before and after a five-day psilocybin-assisted meditation retreat using a recently established approach, based on the Mapper algorithm from topological data analysis. After generating subject-specific maps for two groups (psilocybin vs. placebo, 18 subjects/group) of experienced meditators, organizational principles were uncovered using graph topological tools, including the optimal transport (OT) distance, a geometrically rich measure of similarity between brain activity patterns. This revealed characteristics of the topology (i.e. shape) in space (i.e. abstract space of voxels) and time dimension of whole-brain activity patterns during different styles of meditation and psilocybin-induced alterations. Most interestingly, we found that (psilocybin-induced) positive derealization, which fosters insightfulness specifically when accompanied by enhanced open-monitoring meditation, was linked to the OT distance between open-monitoring and resting state. Our findings suggest that enhanced meta-awareness through meditation practice in experienced meditators combined with potential psilocybin-induced positive alterations in perception mediate insightfulness. Together, these findings provide a novel perspective on meditation and psychedelics that may reveal potential novel brain markers for positive synergistic effects between mindfulness practices and psilocybin.

A phase III multisite randomised controlled trial to compare the efficacy of cannabidiol to placebo in the treatment of cannabis use disorder: the CBD-CUD study protocol.

BACKGROUND: Cannabis use disorder (CUD) is increasingly common and contributes to a range of health and social problems. Cannabidiol (CBD) is a non-intoxicating cannabinoid recognised for its anticonvulsant, anxiolytic and antipsychotic effects with no habit-forming qualities. Results from a Phase IIa randomised clinical trial suggest that treatment with CBD for four weeks reduced non-prescribed cannabis use in people with CUD. This study examines the efficacy, safety and quality of life of longer-term CBD treatment for patients with moderate-to-severe CUD. METHODS/DESIGN: A phase III multi-site, randomised, double-blinded, placebo controlled parallel design of a 12-week course of CBD to placebo, with follow-up at 24 weeks after enrolment. Two hundred and fifty adults with moderate-to-severe CUD (target 20% Aboriginal), with no significant medical, psychiatric or other substance use disorders from seven drug and alcohol clinics across NSW and VIC, Australia will be enrolled. Participants will be administered a daily dose of either 4 mL (100 mg/mL) of CBD or a placebo dispensed every 3-weeks. All participants will receive four-sessions of Cognitive Behavioural Therapy (CBT) based counselling. Primary endpoints are self-reported cannabis use days and analysis of cannabis metabolites in urine. Secondary endpoints include severity of CUD, withdrawal severity, cravings, quantity of use, motivation to stop and abstinence, medication safety, quality of life, physical/mental health, cognitive functioning, and patient treatment satisfaction. Qualitative research interviews will be conducted with Aboriginal participants to explore their perspectives on treatment. DISCUSSION: Current psychosocial and behavioural treatments for CUD indicate that over 80% of patients relapse within 1-6 months of treatment. Pharmacological treatments are highly effective with other substance use disorders but there are no approved pharmacological treatments for CUD. CBD is a promising candidate for CUD treatment due to its potential efficacy for this indication and excellent safety profile. The anxiolytic, antipsychotic and neuroprotective effects of CBD may have added benefits by reducing many of the mental health and cognitive impairments reported in people with regular cannabis use. TRIAL REGISTRATION: Australian and New Zealand Clinical Trial Registry: ACTRN12623000526673 (Registered 19 May 2023).

Psychedelic Therapy: A Primer for Primary Care Clinicians-Psilocybin.

BACKGROUND: The primary psychoactive drug in magic mushrooms, psilocybin, induces profound alterations in consciousness through the 5-HT2A receptor. This review consolidates current research findings to elucidate the pharmacology, safety profile, and clinical applications of psilocybin. AREAS OF UNCERTAINTY: Despite initial concerns that psilocybin could cause psychosis, contemporary research has demonstrated that psilocybin is generally safe. The most common adverse effects are nausea and headache, yet both tend to be transient. Serious adverse events can generally be avoided in controlled settings such as clinical trials. However, in the largest clinical trial to date, there were a total of 7 reported cases of suicidal ideation, up to 12 weeks after receiving a single 25 mg dose of psilocybin. That being said, all 7 cases did not respond to the treatment. Although selective serotonin reuptake inhibitors may blunt the hallucinogenic qualities of psilocybin, preliminary research suggests that they may enhance its antidepressant effects. THERAPEUTIC ADVANCES: In clinical trials, psilocybin has shown promise for treating major depressive disorder and treatment-resistant depression. Initial studies indicated that 42%-57% of patients underwent remission after psilocybin-assisted therapy, which suggests that psilocybin is more effective than existing antidepressant medications. Clinical data have also demonstrated that psilocybin can manage substance use disorders and end-of-life anxiety with clinical outcomes that are sustained for months and sometimes years after 1 or 2 doses. LIMITATIONS: However, larger Phase II trials with more than 100 depressed participants have shown a much smaller remission rate of 25%-29%, though these studies still observed that psilocybin causes a significant reduction in depressive symptoms. CONCLUSIONS: Aside from ketamine, psilocybin is the most clinically well-researched psychedelic drug, with trials that have enrolled hundreds of participants and multiple therapeutic applications. Phase III trials will determine whether psilocybin lives up to the promise that it showed in previous clinical trials.

Associations between cannabis policies and state-level specialty cannabis use disorder treatment in the United States, 2004-2019.

BACKGROUND: Cannabis use disorder (CUD) treatment prevalence decreased in the US between 2002 and 2019, yet structural mechanisms for this decrease are poorly understood. We tested associations between cannabis laws becoming effective and self-reported CUD treatment. METHODS: Restricted-use 2004-2019 National Surveys on Drug Use and Health included people ages 12+ classified as needing CUD treatment (i.e., past-year DSM-5-proxy CUD or last/current specialty treatment for cannabis). Time-varying indicators of medical cannabis laws (MCL) with/without cannabis dispensary provisions differentiated state-years before/after laws using effective dates. Multi-level logistic regressions with random state intercepts estimated individual- and state-adjusted CUD treatment odds by MCLs and model-based changes in specialty CUD treatment state-level prevalence. Secondary analyses tested associations between CUD treatment and MCL or recreational cannabis laws (RCL). RESULTS: Using a broad treatment need sample definition in 2004-2014, specialty CUD treatment prevalence decreased by 1.35 (95 % CI = -2.51, -0.18) points after MCL without dispensaries and by 2.15 points (95 % CI = -3.29, -1.00) after MCL with dispensaries provisions became effective, compared to before MCL. Among people with CUD in 2004-2014, specialty treatment decreased only in MCL states with dispensary provisions (aPD = -0.91, 95 % CI = -1.68, -0.13). MCL were not associated with CUD treatment use in 2015-2019. RCL were associated with lower CUD treatment among people classified as needing CUD treatment, but not among people with past-year CUD. CONCLUSIONS: Policy-related reductions in specialty CUD treatment were concentrated in states with cannabis dispensary provisions in 2004-2014, but not 2015-2019, and partly driven by reductions among people without past-year CUD. Other mechanisms (e.g., CUD symptom identification, criminal-legal referrals) could contribute to decreasing treatment trends.

Clarifying and measuring the characteristics of experiences that involve a loss of self or a dissolution of its boundaries.

Mystical experience, non-dual awareness, selflessness, self-transcendent experience, and ego-dissolution have become increasingly prominent constructs in meditation and psychedelic research. However, these constructs and their measures tend to be highly overlapping, imprecise, and poorly integrated with similar pathological experiences. The present study seeks to clarify the common factors involved in the characteristics of these experiences using precise distinctions across an array of experience contexts (including meditation, psychedelics, and psychopathology). Participants (N = 386) completed an online survey about an experience that involved either a dissolution of self-boundaries or a loss of selfhood. Confirmatory factor analyses resulted in 16 experience characteristics, including multiple types of changes in sense of self, co-occurring phenomenology, and cognitive and affective responses. Qualitative thematic analysis provided rich descriptions of experience characteristics. Taken together, results lead to a more specific measurement model and descriptive account of experiences involving a loss of self or self-boundary.

Anti-staphylococcal activity of soilless cultivated cannabis across the whole vegetation cycle under various nutritional treatments in relation to cannabinoid content.

Antibiotic resistance in staphylococcal strains and its impact on public health and agriculture are global problems. The development of new anti-staphylococcal agents is an effective strategy for addressing the increasing incidence of bacterial resistance. In this study, ethanolic extracts of Cannabis sativa L. made from plant parts harvested during the whole vegetation cycle under various nutritional treatments were assessed for in vitro anti-staphylococcal effects. The results showed that all the cannabis extracts tested exhibited a certain degree of growth inhibition against bacterial strains of Staphylococcus aureus, including antibiotic-resistant and antibiotic-sensitive forms. The highest antibacterial activity of the extracts was observed from the 5th to the 13th week of plant growth across all the nutritional treatments tested, with minimum inhibitory concentrations ranging from 32 to 64 µg/mL. Using HPLC, Δ9-tetrahydrocannabinolic acid (THCA) was identified as the most abundant cannabinoid in the ethanolic extracts. A homolog of THCA, tetrahydrocannabivarinic acid (THCVA), reduced bacterial growth by 74%. These findings suggest that the cannabis extracts tested in this study can be used for the development of new anti-staphylococcal compounds with improved efficacy.

Contingency management is associated with positive changes in attitudes and reductions in cannabis use even after discontinuation of incentives among non-treatment seeking youth.

BACKGROUND: It is important to identify interventions that reduce harm in youth not motivated to change their cannabis use. This study evaluated how short-duration contingency management (CM) impacts cannabis use attitudes and behavior after abstinence incentives are discontinued among non-treatment seeking youth. METHODS: Participants (N=220) were randomized to 4 weeks of abstinence-based CM (CB-Abst; n=126) or monitoring (CB-Mon; n=94). Participants completed self-report and provided biochemical measures of cannabis exposure at baseline, end-of-intervention, and 4-week follow-up. Changes in self-reported cannabis use frequency (days/week; times/week) and biochemically verified creatinine-adjusted 11-nor-9-carboxy-tetrahydrocannabinol concentrations (CN-THCCOOH) were analyzed between groups from baseline to follow-up. In CB-Abst, cannabis use goals at end-of-intervention were described and changes in cannabis use at follow-up were explored by goals and cannabis use disorder (CUD) diagnosis. RESULTS: There was a group by visit interaction on cannabis use (days: beta=0.93, p=0.005; times: beta=0.71, p<0.001; CN-THCCOOH: beta=0.26, p=0.004), with reductions at follow-up detected only in CB-Abst. Following 4 weeks of abstinence, 68.4% of CB-Abst participants wanted to reduce or abstain from cannabis use following completion of CM. Those in CB-Abst who set end-of-intervention reduction goals and were without CUD had greater decreases in cannabis use frequency at follow-up (Goals*time on days/week: beta=-2.27, p<0.001; CUD*time on times/week: beta=0.48, SE=0.24, t=2.01, p=0.048). CONCLUSIONS: Findings support the utility of brief incentivized abstinence for generating motivation to reduce cannabis use and behavior change even after incentives end. This study supports CM as a potentially viable harm reduction strategy for those not yet ready to quit.

The Effect of Oil-Based Cannabis Extracts on Metabolic Parameters and Microbiota Composition of Mice Fed a Standard and a High-Fat Diet.

The prevalence of obesity and obesity-related pathologies is lower in frequent cannabis users compared to non-users. It is well established that the endocannabinoid system has an important role in the development of obesity. We recently demonstrated that prolonged oral consumption of purified Δ-9 Tetrahydrocannabinol (THC), but not of cannabidiol (CBD), ameliorates diet-induced obesity and improves obesity-related metabolic complications in a high-fat diet mouse model. However, the effect of commercially available medical cannabis oils that contain numerous additional active molecules has not been examined. We tested herein the effects of THC- and CBD-enriched medical cannabis oils on obesity parameters and the gut microbiota composition of C57BL/6 male mice fed with either a high-fat or standard diet. We also assessed the levels of prominent endocannabinoids and endocannabinoid-like lipid mediators in the liver. THC-enriched extract prevented weight gain by a high-fat diet and attenuated diet-induced liver steatosis concomitantly with reduced levels of the lipid mediators palmitoyl ethanolamide (PEA) and docosahexaenoyl ethanolamide (DHEA) in the liver. In contrast, CBD-enriched extract had no effect on weight gain, but, on the contrary, it even exacerbated liver steatosis. An analysis of the gut microbiota revealed that mainly time but not treatment exerted a strong effect on gut microbiota alterations. From our data, we conclude that THC-enriched cannabis oil where THC is the main constituent exerts the optimal anti-obesity effects.

Criticality supports cross-frequency cortical-thalamic information transfer during conscious states.

Consciousness is thought to be regulated by bidirectional information transfer between the cortex and thalamus, but the nature of this bidirectional communication - and its possible disruption in unconsciousness - remains poorly understood. Here, we present two main findings elucidating mechanisms of corticothalamic information transfer during conscious states. First, we identify a highly preserved spectral channel of cortical-thalamic communication that is present during conscious states, but which is diminished during the loss of consciousness and enhanced during psychedelic states. Specifically, we show that in humans, mice, and rats, information sent from either the cortex or thalamus via δ/θ/α waves (∼1-13 Hz) is consistently encoded by the other brain region by high γ waves (52-104 Hz); moreover, unconsciousness induced by propofol anesthesia or generalized spike-and-wave seizures diminishes this cross-frequency communication, whereas the psychedelic 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT) enhances this low-to-high frequency interregional communication. Second, we leverage numerical simulations and neural electrophysiology recordings from the thalamus and cortex of human patients, rats, and mice to show that these changes in cross-frequency cortical-thalamic information transfer may be mediated by excursions of low-frequency thalamocortical electrodynamics toward/away from edge-of-chaos criticality, or the phase transition from stability to chaos. Overall, our findings link thalamic-cortical communication to consciousness, and further offer a novel, mathematically well-defined framework to explain the disruption to thalamic-cortical information transfer during unconscious states.

The Neurotherapeutic Arsenal in Cannabis sativa: Insights into Anti-Neuroinflammatory and Neuroprotective Activity and Potential Entourage Effects.

Cannabis, renowned for its historical medicinal use, harbours various bioactive compounds-cannabinoids, terpenes, and flavonoids. While major cannabinoids like delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD) have received extensive scrutiny for their pharmacological properties, emerging evidence underscores the collaborative interactions among these constituents, suggesting a collective therapeutic potential. This comprehensive review explores the intricate relationships and synergies between cannabinoids, terpenes, and flavonoids in cannabis. Cannabinoids, pivotal in cannabis's bioactivity, exhibit well-documented analgesic, anti-inflammatory, and neuroprotective effects. Terpenes, aromatic compounds imbuing distinct flavours, not only contribute to cannabis's sensory profile but also modulate cannabinoid effects through diverse molecular mechanisms. Flavonoids, another cannabis component, demonstrate anti-inflammatory, antioxidant, and neuroprotective properties, particularly relevant to neuroinflammation. The entourage hypothesis posits that combined cannabinoid, terpene, and flavonoid action yields synergistic or additive effects, surpassing individual compound efficacy. Recognizing the nuanced interactions is crucial for unravelling cannabis's complete therapeutic potential. Tailoring treatments based on the holistic composition of cannabis strains allows optimization of therapeutic outcomes while minimizing potential side effects. This review underscores the imperative to delve into the intricate roles of cannabinoids, terpenes, and flavonoids, offering promising prospects for innovative therapeutic interventions and advocating continued research to unlock cannabis's full therapeutic potential within the realm of natural plant-based medicine.

The Long-Term Relationship Between Cannabis and Heroin Use: An 18- to 20-year Follow-Up of the Australian Treatment Outcome Study (ATOS).

OBJECTIVE: Cannabis use is common among individuals with opioid use disorder, but it remains unclear whether cannabis use is associated with an increase or a reduction in illicit opioid use. To overcome limitations identified in previous longitudinal studies with limited follow-ups, the authors examined a within-person reciprocal relationship between cannabis and heroin use at several follow-ups over 18 to 20 years. METHODS: The Australian Treatment Outcome Study (ATOS) recruited 615 people with heroin dependence in 2001 and 2002 and reinterviewed them at 3, 12, 24, and 36 months as well as 11 and 18-20 years after baseline. Heroin and cannabis use were assessed at each time point using the Opiate Treatment Index. A random-intercept cross-lagged panel model analysis was conducted to identify within-person relationships between cannabis use and heroin use at subsequent follow-ups. RESULTS: After accounting for a range of demographic variables, other substance use, and mental and physical health measures, an increase in cannabis use 24 months after baseline was significantly associated with an increase in heroin use at 36 months (estimate=0.21, SE=0.10). Additionally, an increase in heroin use at 3 months and 24 months was significantly associated with a decrease in cannabis use at 12 months (estimate=-0.27, SE=0.09) and 36 months (estimate=-0.22, SE=0.08). All other cross-lagged associations were not significant. CONCLUSIONS: Although there was some evidence of a significant relationship between cannabis and heroin use at earlier follow-ups, this was sparse and inconsistent across time points. Overall, there was insufficient evidence to suggest a unidirectional or bidirectional relationship between the use of these substances.

Participation in Australian drug treatment programs for individuals engaging in high-risk substance use: Data from a nationally representative sample.

INTRODUCTION: Substance use, including drugs, alcohol and smoking have a significant health, social and economic impact. We aim to assess the rate and factors associated with treatment access among individuals with high-risk substance use. METHOD: This study is a cross-sectional analysis of the 2019 Australian National Drug Strategy Household Survey (N = 22,015). Participants were persons with high-risk substance use based on the Alcohol, Smoking and Substance Involvement Screening Test-Lite (ASSIST-Lite) and current smokers. We measured self-reports of past 12-month engagement in a tobacco, alcohol or other drugs treatment program. RESULTS: Overall, 0.4% had high-risk drug use (0.3% cannabis, 0.1% meth/amphetamine or 0.1% opioids), 7.4% had high-risk alcohol use, and 14.0% currently smoked. Among high-risk users, past 12-month treatment access rates were 50.6% [22.3-78.9%] for opioids, 27.1% [8.1-46.1%] for meth/amphetamine, 14.5% [4.3-24.7%] for cannabis, 9.6% [8.1-11.0%] for alcohol and 11.7% [10.6-12.9%] for current smoking. The primary source of treatment support was information and education (12.7% drugs, 4.6% alcohol, 4.0% smoking), followed by counselling (6.7% drugs, 4.5% alcohol, 3.0% smoking). Online or internet support was accessed by 5.9% (drug) and 1.6% (alcohol) people with high-risk use. Psychological distress was associated with treatment access (drugs: odds ratio 3.03 [0.77-11.95], p = 0.111; alcohol: odds ratio 3.16 [2.20-4.56], p ≤ 0.001; smoking: odds ratio 1.95 [1.52-2.49], p ≤ 0.001). DISCUSSION AND CONCLUSIONS: The proportion of people engaging in risky substance use who had used treatment programs remains low, especially for alcohol. Public health strategies to scale up treatment access are warranted.

Medicinal Cannabis: Extended Stability of Cannabis Extracts Produced Using a New Ethanol-based Extraction Method.

Cannabis as a therapeutic agent is increasing in popularity all around the globe, particularly in Western countries, and its potential is now well assessed. On the other hand, each country has its own regulation for the preparation of cannabis macerated oils; in Italy, there are only a few preparation methods allowed. With this work, we aim to perform a stability study of cannabis oils produced with a novel method for the extraction of cannabinoids from cannabis inflorescence. Three different varieties of cannabis were used, with and without the adding of tocopherol acetate as an antioxidant. Cannabinoids were extracted using ethanol at room temperature; then, the solvent was evaporated under reduced pressure and the preparations reconstituted with olive oil. In this work, we assessed the stability of both cannabinoids and terpenes in these formulas over 8 months. Cannabinoid stability was assessed by monitoring the concentrations of THC and CBD, while terpene stability was assessed by monitoring ß-Caryophyllene and α-Humulene concentrations. Stability of the extracts was not influenced by the presence of tocopherol acetate, though refrigeration seems to be detrimental for a long storage of products, especially regarding THC concentrations. The improvements offered by this method reside in the flexibility in controlling the concentration of the extract and the ability to produce highly concentrated oils, alongside the possibility to produce standardized oils despite the variability of the starting plant material.

Correlates of Stimulant Use among People Who Use Heroin Undergoing Treatment in Out-Patient Facilities in France, 2010-2020.

Background: Polydrug use has been implicated in driving a "fourth wave" of the overdose crisis in North America, specifically through concurrent use of stimulants and opioids, especially fentanyl. In France, however, heroin has historically been and remains the easiest-to-access opioid, accounting for most drug treatment demand. Whether similar polydrug use is increasing in Western Europe remains understudied, despite severe health implications and potential inadequate public health responses.Methods: We take advantage of a nation-wide dataset containing information on all patients serviced in treatment centers in France from 2010 to 2020. We conduct Poisson regression to determine the main predictors of stimulant use among people who use heroin (PWUH) and opioids (PWUO) generally.Results: Heroin remains the primary opioid within drug treatment in France. A decreasing number of out-patients seeking treatment for heroin use has been accompanied by an increasing trend of stimulant use over time, most commonly with powder cocaine. Our results suggest a significant increase of crack cocaine use among the most vulnerable PWUH. Concurrent use of stimulants among PWUH was positively associated with use of alcohol, cannabis, unprescribed psychotropics and hallucinogens, and negatively with tobacco. Similar results were found for all in-treatment PWUO.Conclusions: Our results uncover heterogeneity in the profiles of PWUH that should be fully acknowledged to ensure better efficiency in substance use clinical practices and policy, while simultaneously drawing attention to trends in concurrent opioid-stimulant use outside North America. We advocate for an extension of the generalized risk framework and its implementation in prevention programs.

Longitudinal associations between psychedelic use and meditation practices in the United States and the United Kingdom.

BACKGROUND: Previous research has proposed that there may be potential synergies between psychedelic and meditation interventions, but there are still knowledge gaps that merit further investigation. METHODS: Using a longitudinal observational research design with samples representative of the US and UK adult population with regard to sex, age, and ethnicity (N = 9732), we investigated potential associations between self-reported psychedelic use and meditation practice. RESULTS: The follow-up survey was completed by 7667 respondents (79% retention rate), with 100 respondents reporting psychedelic use during the 2-month study period (1.3% of follow-up respondents). In covariate-adjusted regression models, psychedelic use during the study period was associated with greater increases in the number of days of mindfulness meditation practice in the past week (B = 0.40, p = 0.004). Among those who reported psychedelic use during the study period, covariate-adjusted regression models revealed that the subjective experience of insight during respondents' most intense psychedelic experience in that period was also associated with greater increases in the number of days of mindfulness and loving-kindness or compassion meditation practice in the past week (B = 0.42, p = 0.021; B = 0.38, p = 0.017). Notably, more days of loving-kindness or compassion meditation practice in the past week at baseline was associated with less severe subjective feelings of death or dying during respondents' most intense psychedelic experience in the study period (B = -0.29, p = 0.037). CONCLUSIONS: Psychedelic use might lead to greater engagement with meditation practices such as mindfulness meditation, while meditation practices such as loving-kindness or compassion medication might buffer against certain challenging experiences associated with psychedelic use.

Feasibility of a cannabidiol-dominant cannabis-based medicinal product for the treatment of long COVID symptoms: A single-arm open-label feasibility trial.

AIMS: To conduct a single-arm open-label feasibility trial of the safety and tolerability of a full-spectrum cannabidiol (CBD)-dominant cannabis-based medicinal product for treating the symptoms of long COVID. METHODS: The treatment phase ran for a total of 21 weeks, followed by ~3 weeks without the study drug. Participants received up to 3 mL of MediCabilis 5% CBD Oil (50 mg CBD/mL, <2 mg δ-9-tetrahydrocannabinol/mL) per day orally. Monthly patient-reported outcome measures of common symptoms and daily self-report of symptoms were collected via a smartphone app. Key measures of heart rate, activity, sleep and oxygen saturation were assessed using wearable technology. RESULTS: Twelve (1 male, 11 female) individuals diagnosed with long COVID were recruited into the trial. All participants adhered to the treatment protocol for the duration of the study and there were no serious adverse events. Response rates for the research assessments were high with over 90% completion of patient-reported outcome measures and daily self-report. CONCLUSION: The study drug was safe and well-tolerated, demonstrating feasibility of CBD-dominant cannabis-based medicinal products in individuals diagnosed with long COVID. However, there were limitations in research design related to recruitment strategy demonstrating a lack of feasibility in the approach implemented in this study. Future work with larger samples and incorporating a control group are required to test the efficacy of this treatment.

In Vitro Evidence of Selective Pro-Apoptotic Action of the Pure Cannabidiol and Cannabidiol-Rich Extract.

Plant cannabinoids, secondary metabolites of species belonging to the Cannabis genus, can mimic the endocannabinoids' action and exert biological effects. Considering the contribution of the endocannabinoid system in cell cycle and apoptotic regulation, there is an interest in exploring the potential anti-cancer activities of natural and synthetic cannabinoids. Cannabidiol (CBD), an abundant plant cannabinoid, reveals a low affinity to cannabinoid receptors and, contrary to various cannabinoids, lacks psychoactive action. Here, we present the in vitro assessment of the pro-apoptototic potential of CBD-rich extracts of Cannabis sativa L. (eCBD) compared to purified CBD (pCBD). As demonstrated, both eCBD and pCBD decreased the viability of breast cancer cell line MDA-MB-231 and human prostate cancer cell line PC-3 in a concentration-dependent fashion. Endoplasmic reticulum stress-related apoptosis and morphological changes were induced only in low-serum conditions. Moreover, the effects of eCDB and pCDB were also assessed in non-malignant cell lines (MCF-10A and PNT2) with no alterations of viability noted, ultimately suggesting a selective action of CBD in tumor cells. The results suggest the possible involvement of reactive oxygen species in the response mechanism to eCBD and pCBD, but no clear pattern was observed. We also demonstrated significant changes in gene expression involved in apoptosis and cell cycle control upon extract treatment. Altogether, our study shows the potential of eCBD and pCBD as novel pro-apoptototic agents that can be considered promising in future preclinical and clinical testing.