The CED Clinic Research Digest surfaces peer-reviewed cannabis medicine literature scored for clinical relevance, study design quality, and direct applicability to patient care. This digest covers publications identified during the week of February 27, 2026.
Table of Contents
- High-Priority Findings
- Additional Digest Candidates
- Efficacy and safety of monlunabant in adults with obesity and metabolic syndrome: a double-blind, randomised, placebo-controlled, phase 2a trial.
- Mid-Life Social and Health Outcomes Associated With Early-Onset Chronic Noncancer Pain: Findings from the Victorian Adolescent Health Cohort Study.
- Cannabinoids for Medical Purposes in Children: A Living Systematic Review.
- Universal, selective and indicated parenting interventions to prevent the development of adverse mental health outcomes in youth: a meta-review of systematic reviews.
- Systematic review: the impact of maternal pre-and postnatal cannabis use on the behavioral and emotional regulation in early childhood.
- Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies.
- Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference.
- Cannabis in Palliative Care: A Systematic Review of Current Evidence.
- Cannabis-based medicines for chronic neuropathic pain in adults.
- Full-spectrum extract from Cannabis sativa DKJ127 for chronic low back pain: a phase 3 randomized placebo-controlled trial.
- Research on Eating and Adolescent Lifestyle (REAL) 2.0: 15-year follow-up study of eating disorders and weight-related trajectories, mental health and substance use health from early adolescence to early adulthood-a Canadian cohort profile.
- Novel psychoactive substances and psychosis: A comprehensive systematic review of epidemiology, clinical features, neurobiology, and treatment.
- Screening for Nonmedical Use and Misuse of Prescription Medication by Adolescents.
- Safety and Tolerability of Natural and Synthetic Cannabinoids in Older Adults: A Systematic Review and Meta-Analysis of Open-Label Trials and Observational Studies.
- Cannabinoids for the treatment of dementia.
- Detection of Δ9-Tetrahydrocannabinol Impairment Using Resting-State Functional Near-Infrared Spectroscopy: A Randomized Clinical Trial.
- Influences on the mental health and well-being of retired professional athletes from high contact team sports: a mixed methods systematic review.
- Pharmacotherapies for cannabis use disorder.
- Adolescent Cannabis Use and Risk of Psychotic, Bipolar, Depressive, and Anxiety Disorders.
- A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Changes in seizure frequency and adverse events.
- Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.
- Prevalence of Gastrointestinal Adverse Events of Therapeutic Cannabinoids in Children: A Systematic Review and Meta-Analysis.
- Intrinsic brain activity and multiscale mechanisms of auditory verbal hallucinations in schizophrenia: A systematic review and meta-analysis.
- Therapeutic Use of Cannabis Derivatives and Their Analogs for Autism Spectrum Disorder: A Systematic Review.
- Emerging therapeutic approaches for Tourette syndrome and other tic disorders – a systematic review of current clinical trials.
- Maternal Cannabis Use in Pregnancy and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring.
- Primary-level worker interventions for the care of people living with mental disorders and distress in low- and middle-income countries.
- Cannabinoids for the treatment of dementia.
- Effectiveness of the Minder Mobile Mental Health and Substance Use Intervention for University Students: Randomized Controlled Trial.
- Cannabis use and trauma-focused treatment for co-occurring posttraumatic stress disorder and substance use disorders: A meta-analysis of individual patient data.
- Growing Concerns: A systematic review and Meta-Analysis of cannabis use and mental health risks in youth.
- Cannabis Use During Pregnancy Is Associated with the Suppression of Circulating Maternal Cytokines.
- A Pilot Randomized Placebo-Controlled Crossover Trial of Medicinal Cannabis in Adolescents with Tourette Syndrome.
- Effectiveness and safety of psychosocial interventions for the treatment of cannabis use disorder: A systematic review and meta-analysis.
- An integrated alcohol and suicide intervention for adolescents in inpatient psychiatric treatment.
- Associations of Parental Monitoring and Behavioral Control with Substance Use in Adolescents and Emerging Adults: A Meta-Analysis.
- Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks.
- Cannabidiol blood metabolite levels after cannabidiol treatment are associated with broadband EEG changes and improvements in visuomotor and non-verbal cognitive abilities in boys with autism requiring higher levels of support.
- Neurodevelopmental, Pharmacological and Substance Use Factors in the Association Between ADHD and First-Episode Non-Affective Psychosis: A Systematic Review.
- Impact of Glucagon-like Peptide-1 Receptor Agonists on Mental Illness: Evidence from a Mendelian Randomization Study.
- GPR3 in neuro-metabolic-immune-reproductive nexus – a potential therapeutic target for Multi-System diseases.
- Therapeutic Potential for Cannabidiol on Alzheimer’s Disease-Related Neuroinflammation: A Systematic Review and Meta-Analysis.
- The prevalence of benzodiazepines and other hypnotics and their impact on injury severity among older adults involved in motor vehicle collisions: a multicenter retrospective cohort study.
- Examination of Correlates of OUD Outcomes in Young Adults: Secondary Analysis From the XBOT Trial.
- Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis.
High-Priority Findings
Cannabis-Based Products for Chronic Pain : An Updated Systematic Review.
Citation: Chou Roger et al.. Cannabis-Based Products for Chronic Pain : An Updated Systematic Review.. Annals of internal medicine. 2026. PMID: 41429020.
Abstract: BACKGROUND: Benefits and harms of cannabinoids for chronic pain are uncertain. PURPOSE: To update an evidence synthesis on cannabinoids for chronic pain. DATA SOURCES: Ovid MEDLINE, PsycINFO, Embase, the Cochrane Library, and Scopus to 28 July 2025. STUDY SELECTION: Randomized placebo-controlled trials. DATA EXTRACTION: Data extraction, risk of bias, and strength of evidence were dually reviewed. Cannabinoids were categorized by tetrahydrocannabinol (THC)-to-cannabidiol (CBD) ratio (high, comparable, or low), source (synthetic, purified, extracted), and administration method. DATA SYNTHESIS: 25 short-term (1 to 6 months) randomized controlled trials (n = 2303; 64% neuropathic pain) assessed cannabinoids. Oral synthetic/purified high THC-to-CBD (THC only) may slightly reduce and oromucosal, extracted, comparable THC-to-CBD ratio products probably slightly reduce pain severity (pooled differences, -0.78 and -0.54 points, respectively, [0 to 10 scale]), with moderate or large increased dizziness, sedation, and nausea. Among THC-only products, nabilone moderately reduced pain severity but dronabinol did not (pooled differences, -1.59 and -0.23 points, respectively). Low THC-to-CBD interventions may not improve outcomes. Although low THC-to-CBD mixed THC/CBD products may increase dizziness, sedation, and nausea, CBD alone may not increase harms. LIMITATION: Variability within categories; lack of product details; unclear U.S. availability of studied products; restricted to English-language studies. CONCLUSION: Comparable and high THC-to-CBD ratio cannabinoid products may result in small improvements in pain and increased common adverse events during short-term treatment of primarily neuropathic pain; among high-ratio THC-only products, nabilone (but not dronabinol) reduced pain. Low THC-to-CBD products may not improve outcomes. Studies are needed on long-term outcomes and other cannabis product types. PRIMARY FUNDING SOURCE: Agency for Healthcare Research and Quality, U.S
Additional Digest Candidates
Efficacy and safety of monlunabant in adults with obesity and metabolic syndrome: a double-blind, randomised, placebo-controlled, phase 2a trial.
Citation: Knop Filip K et al.. Efficacy and safety of monlunabant in adults with obesity and metabolic syndrome: a double-blind, randomised, placebo-controlled, phase 2a trial.. The lancet. Diabetes & endocrinology. 2025. PMID: 41038215.
Abstract: BACKGROUND: Monlunabant, a novel cannabinoid receptor 1 (CB1R) inverse agonist, has shown encouraging weight loss efficacy and tolerability. We aimed to evaluate the efficacy and safety of monlunabant in individuals with obesity and metabolic syndrome. METHODS: This 16-week, randomised, double-blind, placebo-controlled, dose-ranging phase 2a trial, conducted at 25 outpatient research centres in Canada, enrolled adults with obesity and metabolic syndrome. Participants were randomly assigned (1:1:1:1) by means of an interactive response system to once-daily oral tablets of monlunabant 10 mg, 20 mg, 50 mg, or placebo. The participants, site staff, sponsor, and contract research organisation were masked to treatment allocation. The primary endpoint was mean bodyweight (kg) change from baseline at week 16 versus placebo, assessed in all eligible randomised participants, whereas the safety analysis was done in all randomised participants who received at least one dose of trial product. The estimator for the primary estimand was analysed using a mixed model for repeated measures, assuming missing data are missing at random. This trial is registered with ClinicalTrials.gov (NCT05891834) and is complete. FINDINGS: From Sept 8, 2023, to Jan 26, 2024, 409 individuals were screened for eligibility. In total, 243 individuals were randomly assigned to monlunabant 10 mg (n=61), monlunabant 20 mg (n=61), monlunabant 50 mg (n=60), and placebo (n=61); 242 participants received treatment, including 167 (69%) females and 75 (31%) males. 183 (76%) of 242 participants completed the trial: 50 (82%) of 61 received monlunabant 10 mg, 42 (70%) of 60 received monlunabant 20 mg, 34 (57%) of 60 received monlunabant 50 mg, and 57 (93%) of 61 received placebo. At week 16, participants receiving monlunabant showed statistically significant weight loss compared with those receiving placebo (least squares mean difference vs placebo of -6·4 kg [95% CI -8·0 to -4·9] for monlunabant 10 mg, -6·9 kg [-8·
Mid-Life Social and Health Outcomes Associated With Early-Onset Chronic Noncancer Pain: Findings from the Victorian Adolescent Health Cohort Study.
Citation: Campbell Gabrielle et al.. Mid-Life Social and Health Outcomes Associated With Early-Onset Chronic Noncancer Pain: Findings from the Victorian Adolescent Health Cohort Study.. The Clinical journal of pain. 2026. PMID: 41084870.
Abstract: OBJECTIVES: Little is known about how those with early life experiences of chronic pain fare in middle adulthood. The current study examines the association of adolescent, young adult, and adult chronic pain onset with middle-aged sociodemographic, physical and mental health, and substance use profiles. METHODS: The Victorian Adolescent Health Cohort Study (VAHCS) commenced in 1992 as a population-representative sample of 1943 14 to 15-year-old adolescents who have been followed across 11 waves into middle adulthood. We analysed data from Wave 11 (2019 to 2021, n=1412, age 43 years [mid-life]) to describe the midlife sociodemographic, physical and mental health, and substance use profiles of those who retrospectively reported adolescent (10 to 24 y), young adult (25 to 34 y), and adult (35 to 44 y) onset chronic pain. We also describe associations by sex at birth. RESULTS: Two in 5 participants (41%) reported experiencing chronic pain by age 43 years. This was higher in females than in males (44.6% vs. 36.4%, respectively). Of these, just under half (45%) reported adolescent-onset chronic pain, 30% reported young adult-onset, and 25% reported adult-onset chronic pain. Compared with later onset pain, adolescent-onset was associated with a greater risk for financial hardship (particularly in males), past 12-month major illness, generalised anxiety disorder (among males), and more frequent cannabis use in mid-adult life. DISCUSSION: Our findings suggest that chronic pain in midlife commonly starts early, across adolescence and young adulthood, and that many with earlier life histories of chronic pain are not faring well across a range of indicators in middle adult life, particularly those with the onset of chronic pain in adolescence.
Cannabinoids for Medical Purposes in Children: A Living Systematic Review.
Citation: Chhabra Manik et al.. Cannabinoids for Medical Purposes in Children: A Living Systematic Review.. Acta paediatrica (Oslo, Norway : 1992). 2025. PMID: 40437694.
Abstract: AIM: We developed a living systematic review (LSR) that will continuously map the safety and reported benefit data related to cannabinoid use for medical purposes in children. METHODS: MEDLINE, Embase, PsycInfo, and the Cochrane Library were searched from inception to April 2023. Studies involving at least one child 20% studies) in studies enrolling children were somnolence, diarrhoea, vomiting, and decreased appetite. CONCLUSION: These findings will continue to be updated to inform practice and reveal knowledge gaps for future research.
Universal, selective and indicated parenting interventions to prevent the development of adverse mental health outcomes in youth: a meta-review of systematic reviews.
Citation: Han Meredith X et al.. Universal, selective and indicated parenting interventions to prevent the development of adverse mental health outcomes in youth: a meta-review of systematic reviews.. BMJ mental health. 2025. PMID: 40615152.
Abstract: BACKGROUND: Preventive interventions in the form of parenting support can reduce the risk of mental disorders in children. Summarising the effectiveness of parenting interventions across different levels of prevention can inform the prioritisation of the intervention. OBJECTIVES: We conducted a meta-review of systematic reviews and meta-analyses on universal, selective and indicated parenting interventions to prevent adverse mental health outcomes in youth. STUDY SELECTION AND ANALYSIS: PubMed, Ovid, Embase and PsycNet were searched. Systematic reviews consisting of randomised controlled trials of preventative parenting interventions were included. We provided a narrative synthesis of the results and assessed the quantity and quality of evidence for each level of prevention (ie, universal, selective, indicated) and mental health outcome. FINDINGS: We identified 32 systematic reviews and meta-analyses, which included 354 randomised controlled trials, consisting of over 74 558 children and adolescents. Universal parenting interventions were effective in delaying the initiation of alcohol and cannabis use, but did not have consistent findings in preventing disruptive behaviour and mood disorders. Selective interventions were predominantly beneficial for disruptive behavioural problems across a variety of risk factors. Indicated interventions found substantial and consistent evidence for reducing problems in children with behavioural problems. Caution is warranted when interpreting findings, as the overall confidence rating of most reviews was very low, especially in the reporting of study selection and justifying exclusions in the AMSTAR-2. CONCLUSIONS: Our findings highlight the need for robust evidence synthesis. Despite the limitations of the current evidence base, parenting interventions hold promise for preventing mental health disorders.
Systematic review: the impact of maternal pre-and postnatal cannabis use on the behavioral and emotional regulation in early childhood.
Citation: Reyentanz Emely et al.. Systematic review: the impact of maternal pre-and postnatal cannabis use on the behavioral and emotional regulation in early childhood.. European child & adolescent psychiatry. 2025. PMID: 38878224.
Abstract: Prenatal exposure to alcohol and tobacco has been associated with child regulatory abilities and problems, but less is known about the associations with cannabis exposure. This review seeks to address this gap primarily focusing on the effects of maternal cannabis use on the child. Thus, we investigate the association between pre- and postnatal cannabis exposure of the child and regulatory abilities and problems, as well as the underlying neurobiological mechanisms potentially mediating the associations. According to the PRISMA guidelines, a systematic literature review was performed based on a systematic literature search through Medline (PubMed), Web of Science and PsycInfo, including studies assessing children aged 0-6 years with cannabis exposure in the preconception, pre-or postnatal period (preconception, pre- and postnatal cannabis exposure [PCE]) and investigating child regulatory abilities, regulatory problems or neurobiological mechanisms. Of n = 1061 screened articles, n = 33 were finally included. Diminished regulatory abilities are more likely to be found in infants after PCE, while specific regulatory problems tend to be more frequently found after two years of age. Possible mechanisms are related to changes in methylation and expression of key genes involved in endocannabinoid, dopaminergic and opioid systems, increased cortisol reactivity and altered Secretory Immunoglobulin A levels. Furthermore, PCE has been associated with changes in brain structure and connectivity. Current findings indicate that PCE is associated with both age-dependent alterations in self-regulation and neurobiological changes in young children. However, evidence is limited due to the number of studies, small sample sizes and lack of control for maternal psychopathology. Longitudinal studies including psychometric data from mothers are needed in order to further understand the implications of PCE.Trial registration: The review is registered with PROSPERO (ID: CRD42023425115).
Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies.
Citation: Solmi Marco et al.. Age at onset of mental disorders worldwide: large-scale meta-analysis of 192 epidemiological studies.. Molecular psychiatry. 2022. PMID: 34079068.
Abstract: Promotion of good mental health, prevention, and early intervention before/at the onset of mental disorders improve outcomes. However, the range and peak ages at onset for mental disorders are not fully established. To provide robust, global epidemiological estimates of age at onset for mental disorders, we conducted a PRISMA/MOOSE-compliant systematic review with meta-analysis of birth cohort/cross-sectional/cohort studies, representative of the general population, reporting age at onset for any ICD/DSM-mental disorders, identified in PubMed/Web of Science (up to 16/05/2020) (PROSPERO:CRD42019143015). Co-primary outcomes were the proportion of individuals with onset of mental disorders before age 14, 18, 25, and peak age at onset, for any mental disorder and across International Classification of Diseases 11 diagnostic blocks. Median age at onset of specific disorders was additionally investigated. Across 192 studies (n = 708,561) included, the proportion of individuals with onset of any mental disorders before the ages of 14, 18, 25 were 34.6%, 48.4%, 62.5%, and peak age was 14.5 years (k = 14, median = 18, interquartile range (IQR) = 11-34). For diagnostic blocks, the proportion of individuals with onset of disorder before the age of 14, 18, 25 and peak age were as follows: neurodevelopmental disorders: 61.5%, 83.2%, 95.8%, 5.5 years (k = 21, median=12, IQR = 7-16), anxiety/fear-related disorders: 38.1%, 51.8%, 73.3%, 5.5 years (k = 73, median = 17, IQR = 9-25), obsessive-compulsive/related disorders: 24.6%, 45.1%, 64.0%, 14.5 years (k = 20, median = 19, IQR = 14-29), feeding/eating disorders/problems: 15.8%, 48.1%, 82.4%, 15.5 years (k = 11, median = 18, IQR = 15-23), conditions specifically associated with stress disorders: 16.9%, 27.6%, 43.1%, 15.5 years (k = 16, median = 30, IQR = 17-48), substance use disorders/addictive behaviours: 2.9%, 15.2%, 48.8%, 19.5 years (k = 58, median = 25, IQR = 20-41), schizophrenia-spectrum disorders/primary psychotic states: 3
Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference.
Citation: Velayudhan Latha et al.. Adverse events caused by cannabinoids in middle aged and older adults for all indications: a meta-analysis of incidence rate difference.. Age and ageing. 2024. PMID: 39602500.
Abstract: BACKGROUND: Cannabinoid-based medicines (CBMs) are being used widely in older people. However, information on the incidence of adverse events (AEs) is limited. OBJECTIVE: To quantify the incidence rate difference (IRD) of AEs in middle aged and older adults of age ≥50 years receiving CBMs and also examine associations with weekly doses. DESIGN: Systematic review and meta-analysis. DATA SOURCES: MEDLINE, PubMed, EMBASE, CINAHL, PsychInfo, Cochrane Library and ClinicalTrials.gov (1st Jan 1990-12th June 2023). METHODS: We included randomised clinical trials (RCTs) using CBMs with mean participant age ≥50 years for medicinal purposes for all clinical indications. Paired reviewers independently screened studies, extracted data and appraised risk of bias. We estimated pooled effect-sizes IRD under the random-effects model. RESULTS: Data from 58 RCTs (37 moderate-high quality studies, pooled n = 6611, mean age range 50-87 years, 50% male, n = 3450 receiving CBMs) showed that compared with controls, the incidence of all-cause and treatment-related AEs attributable to delta-9-tetrahydrocannabinol (THC)-containing CBMs were: THC alone [IRD:18.83(95% Confidence Interval [CI], 1.47-55.79) and 16.35(95% CI, 1.25-48.56)] respectively; THC:cannabidiol (CBD) combination [IRD:19.37(95% CI, 4.24-45.47) and 11.36(95% CI, 2.55-26.48)] respectively. IRDs of serious AEs, withdrawals and deaths were not significantly greater for CBMs containing THC with or without CBD. THC dose-dependently increased the incidence of dry mouth, dizziness/lightheadedness, mobility/balance/coordination difficulties, dissociative/thinking/perception problems and somnolence/drowsiness. The interaction of weekly THC:CBD doses played a role in mostly neurological, psychiatric and cardiac side-effects. CONCLUSIONS: Although CBMs in general are safe and acceptable in middle aged and older adults, one needs to be mindful of certain common dose-dependent side-effects of THC-containing CBMs.
Cannabis in Palliative Care: A Systematic Review of Current Evidence.
Citation: Doppen Marjan et al.. Cannabis in Palliative Care: A Systematic Review of Current Evidence.. Journal of pain and symptom management. 2022. PMID: 35705116.
Abstract: CONTEXT: Palliative care aims to improve the quality of life in patients with incurable illness. Medicinal cannabis (MC) has been used in the palliative care setting to address multiple symptoms in patients. OBJECTIVES: To evaluate the full scope of available literature investigating the effects and potential harms of MC on symptom management and quality of life in palliative care. METHODS: PubMed, Embase, The Cochrane Library and clinicaltrials.gov were searched for eligible articles, published between 1960 and September 9, 2021. Quality of the evidence was assessed in accordance with Grading of Recommendations, Assessment, Development and Evaluations. Risk of bias was assessed using the RoB 2 tool for randomised controlled trials and the Risk of Bias in Non-randomized Studies-of Interventions (ROBINS-I) tool for non-randomized trials. RESULTS: Fifty-two studies (20 randomised; 32 non-randomised) with 4786 participants diagnosed with cancer (n = 4491), dementia (n = 43), AIDS (n = 235), spasticity (n = 16), NORSE syndrome (n = 1) were included. The quality of evidence was ‘very low’ or ‘low’ for all studies, and low for only two randomised controlled trials. Positive treatment effects (statistical significance with P < 0.05) were seen for some MC products in pain, nausea and vomiting, appetite, sleep, fatigue, chemosensory perception and paraneoplastic night sweats in patients with cancer, appetite and agitation in patients with dementia and appetite, nausea and vomiting in patients with AIDS. Meta-analysis was unable to be performed due to the wide range of cannabis products used and the heterogeneity of the study outcomes. CONCLUSION: While positive treatment effects have been reported for some MC products in the palliative care setting, further high quality evidence is needed to support recommendations for its use in clinical practice.
Cannabis-based medicines for chronic neuropathic pain in adults.
Citation: Ateş Gülay et al.. Cannabis-based medicines for chronic neuropathic pain in adults.. The Cochrane database of systematic reviews. 2026. PMID: 41548880.
Abstract: RATIONALE: Estimates of the population prevalence of chronic pain with neuropathic components range from 6% to 10%. Current pharmacological treatments for neuropathic pain help only a minority. New treatments are needed. Cannabis is increasingly promoted in the media as a treatment for chronic pain. This is an update of a review first published in 2018. OBJECTIVES: To assess the benefits and harms of cannabis-based medicines (herbal, plant-based, synthetic) compared to placebo or conventional drugs for chronic neuropathic pain conditions in adults. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and three trial registries, together with reference checking. The latest search date was 29 January 2025. ELIGIBILITY CRITERIA: We selected randomised, double-blind controlled trials of medical cannabis, plant-derived and synthetic cannabinoids, against placebo or any other active treatment for chronic neuropathic pain conditions in adults, with a treatment duration of at least two weeks. We excluded studies whose double-blind duration was less than two weeks and studies which did not explicitly state that the pain was of a neuropathic nature. OUTCOMES: Critical outcomes were the number of participants reporting pain relief of at least 50%, a Patient Global Impression of Change (PGIC) rating of ‘much’ or ‘very much’ improved, serious adverse events, and withdrawals due to adverse events. RISK OF BIAS: We assessed the risk of bias (RoB) for seven outcomes reported in three summary of findings tables using the Cochrane RoB 1 tool. SYNTHESIS METHODS: We synthesised results for each outcome using meta-analysis with a random-effects model by calculating absolute risk differences (RD) and standardised mean differences (SMD) with 95% confidence intervals (CI) for dichotomous outcomes and continuous outcomes, respectively. We used GRADE to assess the certainty of evidence for prespecified outcomes. INCLUDED STUDIES: We included six new studies involving 450 participants, along
Full-spectrum extract from Cannabis sativa DKJ127 for chronic low back pain: a phase 3 randomized placebo-controlled trial.
Citation: Karst Matthias et al.. Full-spectrum extract from Cannabis sativa DKJ127 for chronic low back pain: a phase 3 randomized placebo-controlled trial.. Nature medicine. 2025. PMID: 41023483.
Abstract: Chronic low back pain (CLBP) affects over half a billion people worldwide. Current pharmacologic treatments offer limited efficacy and carry substantial risks, warranting the development of safe and effective alternatives. This multicenter, randomized, placebo-controlled phase 3 trial evaluated the efficacy and safety of VER-01 in CLBP. It enrolled 820 adults with CLBP (VER-01, n = 394; placebo, n = 426) and included a double-blind 12-week treatment phase (phase A), a 6-month open-label extension (phase B), followed by either a 6-month continuation (phase C) or randomized withdrawal (phase D). The primary endpoint of phase A was a change in mean numeric rating scale (NRS) pain intensity, with a change in total neuropathic pain symptom inventory (NPSI) score as a key secondary endpoint in participants with a neuropathic pain component (PainDETECT > 18). The primary endpoint for phase D was time to treatment failure. The study met its primary endpoint in phase A, with a mean pain reduction of -1.9 NRS points in the VER-01 group (mean difference (MD) versus placebo = -0.6, 95% confidence interval (CI) = -0.9 to -0.3; P < 0.001). Pain further decreased to -2.9 NRS points in phase B, with effects sustained through phase C. The study also met its key secondary endpoint of phase A, with a mean NPSI decrease of -14.4 (standard error, 3.3) points from baseline in the VER-01 arm (MD versus placebo = -7.3, 95% CI = -13.2 to -1.3; P = 0.017). Although phase D did not meet its primary endpoint (hazard ratio = 0.75, 95% CI = 0.44-1.27; P = 0.288), pain increased significantly more with placebo upon withdrawal (MD = 0.5, 95% CI = 0.0-1.0; P = 0.034). In phase A, the incidence of adverse events-mostly mild to moderate and transient-was higher with VER-01 than with placebo (83.3% versus 67.3%; P < 0.001). VER-01 was well-tolerated, with no signs of dependence or withdrawal. VER-01 shows potential as a new, safe and effective treatment for CLBP. ClinicalTrials.gov registration: NCT04
Citation: Obeid Nicole et al.. Research on Eating and Adolescent Lifestyle (REAL) 2.0: 15-year follow-up study of eating disorders and weight-related trajectories, mental health and substance use health from early adolescence to early adulthood-a Canadian cohort profile.. BMJ open. 2026. PMID: 41526025.
Abstract: PURPOSE: Few studies have examined how psychosocial risk and protective factors in adolescence shape mental health outcomes and other multimorbid conditions in adulthood, particularly among Canadian youth. The Research on Eating and Adolescent Lifestyle (REAL) 2.0 study was a 15-year follow-up cohort study designed to investigate how early etiological factors, including body image and disordered eating symptoms in adolescence, contribute to the development of eating, weight-related concerns, mental health and substance use health problems in early adulthood. In this paper, we describe the REAL 2.0 cohort’s demographic and clinical characteristics alongside an overview of the study procedures, laying the groundwork for collaboration on future learnings with this unique data. PARTICIPANTS: The cross-sectional REAL study initially surveyed middle and high school students from 2004 to 2010 (n=3043) across 43 schools in the Ottawa, Canada region. Of those, respondents in grade 7 or 9 (n=1197 from 25 of the 43 original schools) were asked to participate in a longitudinal arm of the study that consisted of yearly follow-ups. From the longitudinal cohort, there were 278 participants (29.1% male; Mage=28.6) from those who consented to be re-contacted (n=912), who completed the REAL 2.0 survey electronically (30.4%), providing comprehensive data on demographic, clinical, eating and weight-related behaviour, psychological, social, environmental and substance use health factors in adulthood. FINDINGS TO DATE: 9.4% of REAL 2.0 participants met DSM-5 criteria for an eating disorder, while 17.6% met criteria for disordered eating. Moderate to severe anxiety was reported by 28% of participants, while 21.6% experienced moderate to severe depressive symptoms. Regarding substance use, 16.9% engaged in hazardous drinking, 16.9% used cannabis daily or almost daily, and 4.3% reported daily tobacco use. FUTURE PLANS: REAL 2.0 has the potential to answer multiple research questions about s
Novel psychoactive substances and psychosis: A comprehensive systematic review of epidemiology, clinical features, neurobiology, and treatment.
Citation: Ricci Valerio et al.. Novel psychoactive substances and psychosis: A comprehensive systematic review of epidemiology, clinical features, neurobiology, and treatment.. Neuroscience and biobehavioral reviews. 2025. PMID: 41015167.
Abstract: BACKGROUND: Novel psychoactive substances (NPS) have shown increasing prevalence worldwide, yet their relationship with psychotic disorders remains incompletely characterized despite growing clinical concern. OBJECTIVE: To systematically evaluate the epidemiological evidence, clinical characteristics, neurobiological mechanisms, vulnerability factors, and management approaches for NPS-associated psychosis. METHODS: A comprehensive systematic review following PRISMA guidelines was conducted across five major databases from January 2005 through December 2022. Quality assessment was performed using the Newcastle-Ottawa Scale and Joanna Briggs Institute checklist. Of 684 initially identified records, 85 studies met inclusion criteria, comprising case reports/series (n = 38), retrospective cohort studies (n = 25), cross-sectional studies (n = 10), case-control studies (n = 7), experimental studies (n = 3), and prospective cohort studies (n = 2). RESULTS: Epidemiological evidence consistently suggested higher psychosis risk with NPS compared to traditional substances (OR 4.4-5.2 for synthetic cannabinoids versus cannabis). Distinctive clinical profiles emerged: synthetic cannabinoid-induced “spiceophrenia” featured visual hallucinations (73-84 %), agitation (79-91 %), and anxiety (62-76 %); cathinone-induced psychosis presented with extreme agitation (81-94 %) and stereotyped behaviors (47-63 %); phenethylamine-induced states showed perceptual disturbances including synesthesia (37-54 %). Neurobiological investigations indicated different mechanisms across substance classes. Key vulnerability factors included pre-existing psychiatric conditions, adolescent exposure, and polysubstance use. CONCLUSION: NPS use is associated with elevated psychosis risk and distinctive clinical presentations across substance classes. Standardized assessment approaches and rigorous longitudinal investigations are needed to better establish causality, refine substance-specific treatment protoc
Screening for Nonmedical Use and Misuse of Prescription Medication by Adolescents.
Citation: Levy Sharon et al.. Screening for Nonmedical Use and Misuse of Prescription Medication by Adolescents.. Substance use & addiction journal. 2025. PMID: 39629781.
Abstract: BACKGROUND: Several screening tools have been developed to identify youth with alcohol, cannabis, and tobacco/nicotine use disorders, although less attention has been paid to other substances, including the nonmedical use of prescription medication or prescription medication misuse. OBJECTIVE: To evaluate the proportion of youth reporting the use of substances other than alcohol, cannabis, and nicotine on 3 screening tools that have been developed and validated for identifying alcohol, cannabis, and nicotine use disorders among adolescent primary care patients. METHODS: Adolescents (N = 757) from primary care pediatric practices were randomized to complete substance use screening tools (Screening to Brief Intervention [S2BI, N = 242], Brief Screener for Alcohol, Tobacco, and Other Drugs [BSTAD, N = 253], Tobacco, Alcohol, Prescription Medication, and Other Substance Use [TAPS, N = 262]) and then complete a brief electronic assessment battery and a structured diagnostic interview that assessed for past-year use of opioids and benzodiazepines. A total of 716 adolescents with complete data for each screening tool and the structured interview were analyzed for this report. RESULTS: Rates of the nonmedical use of prescription medication or prescription medication misuse varied by tool: S2BI: 20 (8.5%), BSTAD: 4 (1.7%), and TAPS: 3 (1.3%). No participant endorsed benzodiazepine or opioid use on the World Mental Health Composite International Diagnostic Interview Substance Abuse Module. CONCLUSION: Rates of reporting the nonmedical use of prescription medication or prescription medication misuse vary by screen, and some exceed national estimates. Nonmedical use of prescription medication or prescription medication misuse may be more common than previously reported, although some responses may be false positives. Refining questions could elucidate an especially concerning behavior given widespread fentanyl contamination.
Safety and Tolerability of Natural and Synthetic Cannabinoids in Older Adults: A Systematic Review and Meta-Analysis of Open-Label Trials and Observational Studies.
Citation: Pisani Sara et al.. Safety and Tolerability of Natural and Synthetic Cannabinoids in Older Adults: A Systematic Review and Meta-Analysis of Open-Label Trials and Observational Studies.. Drugs & aging. 2021. PMID: 34235645.
Abstract: BACKGROUND AND OBJECTIVE: Although cannabinoid-based medications are increasingly used by older adults, their safety and tolerability in this age group remain unclear. The purpose of this systematic review was to examine the safety and tolerability of cannabinoid-based medications by conducting a meta-analysis of open-label observational studies of cannabinoid-based medications for all indications in individuals with a mean age of ≥50 years. METHODS: A systematic search was conducted on PubMed, PsycINFO, MEDLINE, EMBASE and CINHAL. Study quality was assessed using an adapted version of the Grading of Recommendations Assessment, Development and Evaluation criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses guidelines were followed. We included studies that (a) were published from 1990 onwards; (b) included older adults (mean age ≥50 years); and (c) provided data on the safety and tolerability of medical cannabinoids. Data were pooled using a random-effects approach. Risk of adverse events, serious adverse events and withdrawals was computed as the incidence rate (IR). Separate analyses were conducted by the cannabinoid-based medication used, for delta-9-tetrahydrocannabinol (THC), cannabidiol (CBD) and a combination of THC and CBD (THC:CBD). RESULTS: Thirty-eight studies were identified (THC = 23; CBD = 6; THC:CBD = 9; N = 2341, mean age: 63.19 ± 8.08 years, men: 53.86%). THC had a very low incidence of all-cause and treatment-related adverse events (IR: 122.18, 95% confidence interval [CI] 38.23-253.56; IR: 84.76, 95% CI 0.13-326.01, respectively) and negligible serious adverse events (IR = 0). Similar IRs for CBD (all cause, IR: 111.91, 95% CI 1.24-495.93; treatment related, IR: 1.76, 95% CI 4.63-23.05) and no serious adverse events (IR = 0). CBD was not associated with a risk of treatment-related withdrawals. THC had a low risk of all-cause and treatment-related withdrawals (IR: 25.18, 95% CI 12.35-42.52; IR: 7.83, 95% CI 3.26-14.38, re
Cannabinoids for the treatment of dementia.
Citation: Bosnjak Kuharic Dina et al.. Cannabinoids for the treatment of dementia.. The Cochrane database of systematic reviews. 2021. PMID: 34532852.
Abstract: BACKGROUND: Dementia is a common chronic condition, mainly affecting older adults, characterised by a progressive decline in cognitive and functional abilities. Medical treatments for dementia are limited. Cannabinoids are being investigated for the treatment of dementia. OBJECTIVES: To determine the efficacy and safety of cannabinoids for the treatment of dementia. SEARCH METHODS: We searched ALOIS – the Cochrane Dementia and Cognitive Improvement Group’s Specialised Register – on 8 July 2021, using the terms cannabis or cannabinoid or endocannabinoid or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The register contains records from all major healthcare databases (the Cochrane Library, MEDLINE, Embase, PsycINFO, CINAHL, LILACS), as well as from many clinical trials registries and grey literature sources. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of cannabinoids for the treatment of dementia. We included participants of any age and of either sex with diagnosed dementia of any subtype, or with unspecified dementia of any severity, from any setting. We considered studies of cannabinoids administered by any route, at any dose, for any duration, compared with placebo, no treatment, or any active control intervention. DATA COLLECTION AND ANALYSIS: Two review authors independently screened and selected studies for inclusion, extracted data, and assessed the risk of bias in included studies. When necessary, other review authors were involved in reaching consensus decisions. We conducted meta-analyses using a generic inverse variance fixed-effect model to derive estimates of effect size. We used GRADE methods to assess our confidence in the effect estimates. MAIN RESULTS: We included four studies (126 participants) in this review. Most participants had Alzheimer’s disease; a few had vascular dementia or mixed dementia. Three studies had low risk of bias across all domains; one stu
Detection of Δ9-Tetrahydrocannabinol Impairment Using Resting-State Functional Near-Infrared Spectroscopy: A Randomized Clinical Trial.
Citation: Berchansky Moshe et al.. Detection of Δ9-Tetrahydrocannabinol Impairment Using Resting-State Functional Near-Infrared Spectroscopy: A Randomized Clinical Trial.. JAMA network open. 2026. PMID: 41615687.
Abstract: IMPORTANCE: The primary psychoactive compound in cannabis, ∆9-tetrahydrocannabinol (THC) induces intoxication and functional impairment, raising safety concerns in driving. The traditional impairment detection method, behavioral field sobriety tests (FSTs), are subject to bias. OBJECTIVE: To determine whether resting-state functional near-infrared spectroscopy (fNIRS) can detect THC-related impairment with greater accuracy and a lower rate of false positives than FSTs. DESIGN, SETTING, AND PARTICIPANTS: This double-blind, randomized, crossover trial was conducted from January 2017 to January 2021 at a single site. Eligible participants were adults aged 18 to 55 years who used cannabis. Analyses were performed from November 2024 to November 2025. INTERVENTIONS: Participants received a single oral dose of synthetic THC (range, 5-80 mg) intended to induce intoxication or placebo in separate visits. MAIN OUTCOME AND MEASURES: fNIRS scans were acquired before and approximately 100 and 200 minutes after study drug administration to assess prefrontal cortex responses at rest and during a working memory task. Machine learning models trained on fNIRS data were then used to identify clinically determined THC-induced impairment. The primary outcome of this study was accuracy of THC-induced impairment classification using fNIRS data as compared with an FST. Model performance was quantified using false-positive rate, precision, recall, F1 score, and area under the receiver operating curve (ROC-AUC). RESULTS: A total of 183 participants (mean [SD] age, 25.3 [6.3] years; 90 [49.2%] female) who used cannabis for a median (IQR) of 6.5 (4-7) days per week completed at least 1 study visit. fNIRS data collected during rest produced a classifier for impairment, with an ROC-AUC of 0.87 (95% CI, 0.83 to 0.91), accuracy of 0.90 (95% CI, 0.88 to 0.92), and false-positive rate of 0.05 (95% CI, 0.04 to 0.07), using clinical impairment assessment as ground truth. The FST showed an ROC-AUC of 0
Influences on the mental health and well-being of retired professional athletes from high contact team sports: a mixed methods systematic review.
Citation: Vella Jordan D et al.. Influences on the mental health and well-being of retired professional athletes from high contact team sports: a mixed methods systematic review.. British journal of sports medicine. 2026. PMID: 40930571.
Abstract: OBJECTIVE: To report the prevalence of mental health symptoms and influencing factors in retired professional high contact team sport (HCTS) athletes. DESIGN: Mixed-methods systematic review. DATA SOURCES: PsycINFO, Embase, Medline, SPORTDiscus and Scopus were searched in July 2023 and March 2025. ELIGIBILITY CRITERIA FOR SELECTING STUDIES: Studies that investigated mental health and/or influencing factors within retired professional HCTS athletes were included. Studies that were non-peer-reviewed, could not obtain full text, used secondary data or focused on non-elite/individual/low-contact sports were excluded. RESULTS: 85 studies were included in the final review, comprising 53 996 participants (females; n=247, 0.46%) from six sports (Australian Football League, Canadian Football League, football/soccer, ice hockey, National Football League and rugby). Prevalence ranges varied for each condition; smoking (0.9%-16%), depression (3%-49%), anxiety (4.3%-42%), cannabis use (5%-15.7%), adverse alcohol use (6.4%-68.8%), opioid use (7%-23.6%), stress (8.7%-26.9%), illicit drug use (10%-63.2%), anxiety/depression (10.2%-39%) and adverse nutritional behaviour (23.8%-64.5%). Of the studies including M and SD of validated scales, scores for depression, anxiety and sleep disturbance were equivalent to population norms, whereas mild or higher scores were reported for stress and adverse alcohol use. Concussion, pain, injury, neurological factors and declined physical function were shown to have a negative influence on mental health. Both negative and positive influences were observed for: athletic identity, psychosocial support, retirement autonomy, life events, osteoarthritis, retirement and cognitive function. 48% of studies had good methodological quality; however, most studies were cross-sectional, relied on self-report measures and lacked follow-up data and female athletes. CONCLUSION: Retired HCTS athletes experience high levels of psychological distress and adverse alco
Pharmacotherapies for cannabis use disorder.
Citation: Spiga Francesca et al.. Pharmacotherapies for cannabis use disorder.. The Cochrane database of systematic reviews. 2025. PMID: 41025421.
Abstract: RATIONALE: Globally, cannabis use is prevalent and widespread. There are currently no pharmacotherapies approved for the treatment of cannabis use disorder (a problematic pattern of cannabis use that leads to clinically significant impairment or distress). This is the second update of a Cochrane Review first published in the Cochrane Library in Issue 12, 2014. OBJECTIVES: To assess the effectiveness and safety of pharmacotherapies as compared with each other, placebo or no pharmacotherapy (supportive care) for reducing symptoms of cannabis withdrawal and promoting cessation or reduction of cannabis use. SEARCH METHODS: We updated our searches of the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and PsycINFO in May 2024. ELIGIBILITY CRITERIA: Randomised controlled trials (RCTs) and quasi-RCTs of medications to treat cannabis withdrawal and/or to promote cessation or reduction of cannabis use, in comparison with other medications, placebo or no medication in people diagnosed as cannabis dependent or who are likely to be dependent. OUTCOMES: Critical outcomes were: 1) abstinence at the end of treatment; 2) intensity of withdrawal including craving; 3) nature, incidence and frequency of adverse events (AE) and 4) severe AE (SAE); 5) withdrawal from treatment due to adverse effects and whether the planned medication regimen was modified in response to adverse effects; 6) completion of scheduled treatment. Important outcomes were: 1) cannabis use at the end of treatment; 2) number of participants engaged in further treatment; 3) economic outcomes. RISK OF BIAS: We assessed the risk of bias in results included in meta-analyses using the risk of bias 2 (RoB 2) tool. SYNTHESIS METHODS: We synthesised results for each outcome using random-effect meta-analysis where possible. Where this was not possible due to the nature of the data, we reported results narratively. We used GRADE to assess the certainty of evidence. INCLUDED STUDIES: We included 37
Adolescent Cannabis Use and Risk of Psychotic, Bipolar, Depressive, and Anxiety Disorders.
Citation: Young-Wolff Kelly C et al.. Adolescent Cannabis Use and Risk of Psychotic, Bipolar, Depressive, and Anxiety Disorders.. JAMA health forum. 2026. PMID: 41719031.
Abstract: IMPORTANCE: As cannabis becomes more accessible and socially accepted, concerns have grown about its potential implications for adolescent mental health. While prior research has linked adolescent cannabis use to psychiatric symptoms, few large, population-based, longitudinal studies have examined associations with clinically diagnosed psychiatric disorders. OBJECTIVE: To evaluate whether adolescent cannabis use is associated with an increased risk of incident psychotic, bipolar, depressive, and anxiety disorders during adolescence and young adulthood. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included adolescents aged 13 to 17 years who were screened for past-year cannabis use at Kaiser Permanente Northern California from 2016 to 2023. Adolescents were followed up through age 25 years or until December 31, 2023. Data were analyzed from February 21, 2024, to August 27, 2025. EXPOSURE: Time-varying self-reported past-year cannabis use based on universal, confidential screening during standard pediatric care. MAIN OUTCOMES AND MEASURES: Incident clinician-diagnosed psychotic, bipolar, depressive, and anxiety disorders, which were identified through electronic health records using International Classification of Disease codes. Cox proportional hazards regression models were used to measure the strength of associations between adolescent cannabis use and incident psychiatric diagnoses, with adjustments for sex, race and ethnicity, neighborhood deprivation index, insurance type, and time-varying alcohol and other substance use. RESULTS: Of 463 396 adolescents (234 114 males [50.5%]; mean [SD] age, 14.5 [1.3] years) included in the sample, 136 708 were Hispanic individuals (29.5%), 93 737 were non-Hispanic Asian individuals (20.2%), 35 346 were non-Hispanic Black individuals (7.6%), 153 102 were non-Hispanic White individuals (33.0%), and 18 795 individuals were multiracial or of other races or ethnicities (4.1%). At baseline, 26 345 adolescents (5.7%) self-rep
A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Changes in seizure frequency and adverse events.
Citation: Coppola Antonietta et al.. A systematic review of highly purified cannabidiol in developmental and epileptic encephalopathies and complex treatment-resistant epilepsies: Changes in seizure frequency and adverse events.. Epilepsy research. 2026. PMID: 41558068.
Abstract: OBJECTIVE: The efficacy and safety of a highly purified plant-derived cannabidiol (CBD) oral solution (Epidiolex® [US]/Epidyolex® [EU], EPX) have been established for the treatment of seizures in patients with Lennox-Gastaut syndrome, Dravet syndrome, or tuberous sclerosis complex. These conditions involve diverse etiologies, suggesting EPX may have broad utility across different seizure types. This systematic literature review (SLR) evaluated studies reporting CBD effectiveness and tolerability in patients with other developmental and epileptic encephalopathies (DEEs) and complex treatment-resistant epilepsies (TREs). METHODS: In accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, an SLR was conducted in March 2024 using Embase, PubMed, and Cochrane libraries for publications on complex TREs, CBD, seizure outcomes, and adverse events (AEs). Results were narratively summarized according to epilepsy type. RESULTS: Seizure frequency-related changes were reported in 57 studies including 37 DEEs/TREs comprising 971 patients; most (n = 33) were case reports/small case series. Most common diagnoses were focal/multifocal-onset epilepsy (n = 401) and Angelman syndrome (n = 188). Overall, 47 studies reported seizure frequency reduction in ≥ 1 patient; definitions/thresholds included seizure reduction (n = 18 studies; 20-100 % of patients) and mean/median percent seizure reduction (n = 8 studies; 12-99 % reduction). Twenty-two studies reported ≥ 1 patient was seizure-free for ≥ 48 days. AEs experienced while taking CBD were generally mild or moderate and most commonly gastrointestinal, including diarrhea (17-50 %), decreased appetite (7-45 %), and vomiting (5-86 %). CONCLUSION: CBD may reduce seizure frequency in patients with a range of DEEs and complex TREs. These findings support future studies in these populations.
Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.
Citation: Berry-Kravis Elizabeth et al.. Long-term safety and tolerability of transdermal cannabidiol gel in children and adolescents with Fragile X syndrome (ZYN2-CL-017): an interim analysis of an ongoing open-label extension study.. Journal of neurodevelopmental disorders. 2025. PMID: 41254489.
Abstract: BACKGROUND: Dysregulated endocannabinoid signaling is involved in Fragile X syndrome (FXS), suggesting a potential role for the endocannabinoid signaling modulator, cannabidiol, in treatment. ZYN002 is a synthetic cannabidiol that has been uniquely formulated as a gel for transdermal delivery and is currently under investigation for the treatment of behavioral symptoms associated with FXS. DESIGN: ZYN2-CL-017 is an ongoing, long-term, open-label extension (OLE) safety trial of ZYN002 in patients with FXS. We are enrolling patients from past and current ZYN002 clinical trials to evaluate the safety and tolerability of ZYN002 in patients with FXS. METHODS: Primary safety assessments were conducted in patients who enrolled into the OLE from 2 completed ZYN002 trials. Secondary analyses, conducted in a subgroup enrolled from a completed placebo-controlled trial of ZYN002, included the FXS-specific Aberrant Behavior Checklist-Community Social Avoidance and Irritability subscales (ABC-CFXS SA and ABC-CFXS Irr, examined change from baseline of the randomized study) and the Caregiver Global Impression of Change (CaGI-C, examined change from baseline of the OLE), in which caregivers were asked to rate the change in their child’s overall behavior. RESULTS: At the time of this interim analysis data cut (January 31, 2024), 240 patients had been enrolled from 2 completed ZYN002 trials. Mean age at entry to the OLE was 9.7 years (range 3-17 years), and the majority were male (76.3%) and White (80.4%). Mean exposure to ZYN002 during the initial trials and OLE was 28 months. Treatment-related adverse events (AEs) were reported in 12.9% of patients; the most common (6.7% of patients) was short-term application site pain. The highest degree of skin irritation reported by investigators was moderate erythema in 7 patients (2.9%). In the secondary analysis cohort (n=196 evaluable patients), patients demonstrated clinically meaningful changes in ABC-CFXS SA, ABC-CFXS Irr, and CaGI-C scor
Prevalence of Gastrointestinal Adverse Events of Therapeutic Cannabinoids in Children: A Systematic Review and Meta-Analysis.
Citation: Karimi Parsa et al.. Prevalence of Gastrointestinal Adverse Events of Therapeutic Cannabinoids in Children: A Systematic Review and Meta-Analysis.. Cannabis and cannabinoid research. 2025. PMID: 39967452.
Abstract: Introduction: The endocannabinoid system plays a crucial role in gastrointestinal homeostasis; although some gastrointestinal adverse events have been reported with therapeutic cannabinoids in children, the complete profile of gastrointestinal adverse events in the pediatric population remains unknown. Through a systematic review and meta-analysis, we aimed to identify the prevalence of gastrointestinal adverse events from therapeutic cannabinoids in children. Materials and Methods: A literature search of OVID MEDLINE, EMBASE, CINAHL, Web of Science, and The Cochrane Library was performed from inception to May 19, 2023. Selected studies included randomized controlled trials, retrospective cohort studies, uncontrolled before-after studies, and observational retrospective studies in English, French, or Spanish that reported gastrointestinal adverse events in the pediatric population under therapeutic cannabinoid interventions. The study was registered with PROSPERO and followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses reporting guidelines. A random-effects model was used to pool and analyze the extracted data. Extracted data included the presence of adverse gastrointestinal events by analyzing the type of cannabinoid, duration of treatment, dosage, and type of study. A subgroup meta-analysis was also performed, focusing on patients’ conditions. Results: Twenty-five studies were included, comprising 1,201 pediatric patients receiving therapeutic cannabinoids, of whom 451 experienced gastrointestinal adverse events, representing a cumulative prevalence of 33.91% (95% confidence interval [CI]: 21.49% to 49.04%). Interventional studies reported a higher prevalence of GI adverse events (47.36%; 95% CI: 31% to 64%) compared with observational studies (17.6%; 95% CI: 8.5% to 32.7%). As most studies focused on patients with epilepsy, a subanalysis was performed within this population, revealing that patients with Dravet syndrome had a higher prev
Intrinsic brain activity and multiscale mechanisms of auditory verbal hallucinations in schizophrenia: A systematic review and meta-analysis.
Citation: Xie Yuanjun et al.. Intrinsic brain activity and multiscale mechanisms of auditory verbal hallucinations in schizophrenia: A systematic review and meta-analysis.. Neuroscience and biobehavioral reviews. 2026. PMID: 41605340.
Abstract: Auditory verbal hallucinations (AVH) represent one of the most debilitating symptoms in schizophrenia. The amplitude of low-frequency fluctuation (ALFF) and fractional ALFF (fALFF), derived from resting-state fMRI, serve as robust metrics for intrinsic brain activity; however, the network-level architecture and biological substrates underlying AVH-related ALFF/fALFF alternations have not yet been systematically elucidated. In this study, we conducted a comprehensive systematic review and meta-analysis of ALFF/fALFF studies in schizophrenia patients with AVH, integrating neurochemical mapping and transcriptomic annotation to provide a multilevel mechanistic perspective. Across studies, AVH were consistently associated with increased intrinsic activity in auditory and language networks, reward and motivation circuits, and executive control regions, along with decreased activity within sensorimotor network, whereas alternations within default mode network regions were more heterogeneous. Meta-analysis further highlighted the involvement of thalamic-frontal circuitry in distinguishing AVH patients from non-AVH patients. Spatial correlation analysis demonstrated significant coupling between AVH-related functional changes and the normaltive distribution of key neurotransmitter systems, including the cannabinoid (CB1), dopaminergic (D2), noradrenergic (NAT), and metabotropic glutamate (mGluR5) . Gene enrichment analysis additionally revealed that implicated regions were transcriptionally characterized by biological pathways related to neurodevelopment, neural circuit formation, and regulation of neural excitability. By integrating these convergent results, we propose a systems-level model in which early genetic and neurodevelopmental vulnerabilities interacts with ongoing neurotransmitter dysregulation and large-scale network dysfunction, ultimately driving the emergence and persistence of AVH in schizophrenia. These findings underscore the importance of multidimensional b
Therapeutic Use of Cannabis Derivatives and Their Analogs for Autism Spectrum Disorder: A Systematic Review.
Citation: Riera Rachel et al.. Therapeutic Use of Cannabis Derivatives and Their Analogs for Autism Spectrum Disorder: A Systematic Review.. Journal of clinical pharmacology. 2025. PMID: 40605143.
Abstract: Autism spectrum disorders are characterized by some difficulties with social interactions and communication, atypical patterns of behavior, and unusual reactions to emotions. Studies have found promising results regarding the effects of cannabis on autism. We conducted a systematic review of randomized clinical trials on the effects of cannabis derivatives and their analogs for autism. This review was developed according to the Cochrane Handbook for Systematic Reviews of Interventions and reported according to PRISMA 2020. The protocol was prospectively published in the PROSPERO database (CRD42023468300). We included randomized controlled trials with autism-diagnosed participants treated with any cannabis derivate or its analogs for therapeutic purposes. Two reviewers assessed titles and abstracts independently and potentially eligible full texts were assessed to confirm eligibility. After that, they extracted data using a standardized worksheet. Searches retrieved 1264 references, only 11 RCTs were included, four with available results for children/adolescents with autism. Five different cannabis presentations were tested. One trial pointed that cannabis may improve global assessment symptoms, but for other outcomes results were uncertain. No included study assessed quality of life. The certainty of evidence ranged from very low to low certainty for the assessed outcomes. Cannabis whole plant extract may improve global assessment symptoms, but the different cannabis presentations, outcome assessments and very low certainty of evidence from the included studies make it difficult to draw conclusions about cannabis for people with autism. This scenario of uncertainties impacts directly clinical practice and decision making.
Emerging therapeutic approaches for Tourette syndrome and other tic disorders – a systematic review of current clinical trials.
Citation: Häge Alexander et al.. Emerging therapeutic approaches for Tourette syndrome and other tic disorders – a systematic review of current clinical trials.. European child & adolescent psychiatry. 2025. PMID: 39714607.
Abstract: Tourette syndrome and other tic disorders are prevalent neurodevelopmental disorders typically treated with behavioral techniques or pharmacological interventions, primarily antipsychotics. However, many patients do not achieve sufficient response to conventional treatments, underscoring the need for further research in this area. To provide a comprehensive overview of ongoing research activities, we systematically searched the clinical registries of the World Health Organization (WHO) and of the United States National Institutes of Health (NIH) for currently planned or ongoing registered clinical studies. Our search identified 21 registered studies, of which seven focus specifically on pharmacological interventions. Potential candidates include the dopamine D1 antagonist ecopipam, the phosphodiesterase inhibitor gemlapodect, and cannabis-based therapies. Additionally, several studies are exploring behavioral interventions including Comprehensive Behavioral Interventions for Tics (CBIT) and mindfulness training, neurostimulation including MRI-navigated transcranial stimulation, theta burst stimulation, and deep brain stimulation, traditional Chinese medicine, and other approaches such as microbiota transplantation. Despite the range of research activities underway, the overall landscape remains limited. In this report we will discuss the findings, current developments, and relevant aspects concerning future research including clinical, scientific, and patient perspectives.
Maternal Cannabis Use in Pregnancy and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring.
Citation: Andrade Chittaranjan. Maternal Cannabis Use in Pregnancy and Autism Spectrum Disorder or Attention-Deficit/Hyperactivity Disorder in Offspring.. The Journal of clinical psychiatry. 2024. PMID: 39724097.
Abstract: Up to 10% of women may use cannabis during pregnancy; this is of concern because constituents of cannabis cross the placental barrier and potentially influence neurodevelopment by acting on cannabinoid receptors in the developing fetal brain. In this context, a recent meta analysis of 13 observational studies found that gestational exposure to cannabis was associated with a small increase in the risk of autism spectrum disorder (ASD; relative risk [RR], 1.30) and with an even smaller increase in the risk of attention deficit/hyperactivity disorder (ADHD; RR, 1.13); the latter finding was probably supported by publication bias. In this meta-analysis, 4 studies provided information on ASD (pooled N = 178,565) and 10 on ADHD (pooled N = 203,783). In a large (n = 222,534) retrospectively ascertained cohort study published after the meta-analysis, cannabis use disorder (CUD) recorded before pregnancy, during pregnancy, and during pregnancy plus the year after delivery were associated with closely similar increased risks of ASD (RRs, 3.02-3.21). The risks were smaller in smokers (RRs, 1.74-1.87) than in nonsmokers (RRs, 4.55-4.83) but differed little between male (RRs, 3.01-3.06) and female (RRs, 2.71-2.85) offspring. Although the cohort study had many strengths, its limitations permitted only the conclusion that peri-pregnancy exposure to CUD is associated with a large increase in the risk of ASD in offspring; it remained possible that much of the risk was driven by genetic, environmental, or behavioral variables. The field is nascent; the total number of cannabis exposed pregnancies (with ASD and ADHD as the outcomes) in world literature is small. However, cannabis use during pregnancy is, at the very least, a clear marker for adverse neurodevelopmental outcomes, besides the adverse maternal, fetal, and neonatal outcomes identified in other studies. Healthcare providers who manage women who use cannabis during pregnancy need to be aware of these adverse outcomes.
Primary-level worker interventions for the care of people living with mental disorders and distress in low- and middle-income countries.
Citation: van Ginneken Nadja et al.. Primary-level worker interventions for the care of people living with mental disorders and distress in low- and middle-income countries.. The Cochrane database of systematic reviews. 2021. PMID: 34352116.
Abstract: BACKGROUND: Community-based primary-level workers (PWs) are an important strategy for addressing gaps in mental health service delivery in low- and middle-income countries. OBJECTIVES: To evaluate the effectiveness of PW-led treatments for persons with mental health symptoms in LMICs, compared to usual care. SEARCH METHODS: MEDLINE, Embase, CENTRAL, ClinicalTrials.gov, ICTRP, reference lists (to 20 June 2019). SELECTION CRITERIA: Randomised trials of PW-led or collaborative-care interventions treating people with mental health symptoms or their carers in LMICs. PWs included: primary health professionals (PHPs), lay health workers (LHWs), community non-health professionals (CPs). DATA COLLECTION AND ANALYSIS: Seven conditions were identified apriori and analysed by disorder and PW examining recovery, prevalence, symptom change, quality-of-life (QOL), functioning, service use (SU), and adverse events (AEs). Risk ratios (RRs) were used for dichotomous outcomes; mean difference (MDs), standardised mean differences (SMDs), or mean change differences (MCDs) for continuous outcomes. For SMDs, 0.20 to 0.49 represented small, 0.50 to 0.79 moderate, and ≥0.80 large clinical effects. Analysis timepoints: T1 (6 months) post-intervention. MAIN RESULTS: Description of studies 95 trials (72 new since 2013) from 30 LMICs (25 trials from 13 LICs). Risk of bias Most common: detection bias, attrition bias (efficacy), insufficient protection against contamination. Intervention effects *Unless indicated, comparisons were usual care at T2. “Probably”, “may”, or “uncertain” indicates “moderate”, “low,” or “very low” certainty evidence. Adults with common mental disorders (CMDs) LHW-led interventions a. may increase recovery (2 trials, 308 participants; RR 1.29, 95%CI 1.06 to 1.56); b. may reduce prevalence (2 trials, 479 participants; RR 0.42, 95%CI 0.18 to 0.96); c. may reduce symptoms (4 trials, 798 participants; SMD -0.59, 95%CI -1.01 to
Cannabinoids for the treatment of dementia.
Citation: Krishnan Sarada et al.. Cannabinoids for the treatment of dementia.. The Cochrane database of systematic reviews. 2009. PMID: 19370677.
Abstract: BACKGROUND: Following the discovery of an endogenous cannabinoid system and the identification of specific cannabinoid receptors in the central nervous system, much work has been done to investigate the main effects of these compounds. There is increasing evidence that the cannabinoid system may regulate neurodegenerative processes such as excessive glutamate production, oxidative stress and neuroinflammation. Neurodegeneration is a feature common to the various types of dementia and this has led to interest in whether cannabinoids may be clinically useful in the treatment of people with dementia. Recent studies have also shown that cannabinoids may have more specific effects in interrupting the pathological process in Alzheimer’s disease. OBJECTIVES: To determine from available research whether cannabinoids are clinically effective in the treatment of dementia. SEARCH STRATEGY: The Specialized Register of the Cochrane Dementia and Cognitive Improvement Group (CDCIG), The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL and LILACS were searched on 11 April 2008 using the terms: cannabis or cannabinoid* or endocannabinoid* or cannabidiol or THC or CBD or dronabinol or delta-9-tetrahydrocannabinol or marijuana or marihuana or hashish. The CDCIG Specialized Register contains records from all major health care databases (The Cochrane Library, MEDLINE, EMBASE, PsycINFO, CINAHL, LILACS) as well as from many clinical trials registries and grey literature sources. SELECTION CRITERIA: All double-blind and single (rater)-blind randomized placebo controlled trials assessing the efficacy of cannabinoids at any dose in the treatment of people with dementia. DATA COLLECTION AND ANALYSIS: Two reviewers independently examined the retrieved studies for inclusion according to the selection criteria. They then independently assessed the methodological quality of selected trials and extracted data where possible. MAIN RESULTS: Only one study met the inclusion criteria. The data in t
Effectiveness of the Minder Mobile Mental Health and Substance Use Intervention for University Students: Randomized Controlled Trial.
Citation: Vereschagin Melissa et al.. Effectiveness of the Minder Mobile Mental Health and Substance Use Intervention for University Students: Randomized Controlled Trial.. Journal of medical Internet research. 2024. PMID: 38536225.
Abstract: BACKGROUND: University attendance represents a transition period for students that often coincides with the emergence of mental health and substance use challenges. Digital interventions have been identified as a promising means of supporting students due to their scalability, adaptability, and acceptability. Minder is a mental health and substance use mobile app that was codeveloped with university students. OBJECTIVE: This study aims to examine the effectiveness of the Minder mobile app in improving mental health and substance use outcomes in a general population of university students. METHODS: A 2-arm, parallel-assignment, single-blinded, 30-day randomized controlled trial was used to evaluate Minder using intention-to-treat analysis. In total, 1489 participants were recruited and randomly assigned to the intervention (n=743, 49.9%) or waitlist control (n=746, 50.1%) condition. The Minder app delivers evidence-based content through an automated chatbot and connects participants with services and university social groups. Participants are also assigned a trained peer coach to support them. The primary outcomes were measured through in-app self-assessments and included changes in general anxiety symptomology, depressive symptomology, and alcohol consumption risk measured using the 7-item General Anxiety Disorder scale, 9-item Patient Health Questionnaire, and US Alcohol Use Disorders Identification Test-Consumption Scale, respectively, from baseline to 30-day follow-up. Secondary outcomes included measures related to changes in the frequency of substance use (cannabis, alcohol, opioids, and nonmedical stimulants) and mental well-being. Generalized linear mixed-effects models were used to examine each outcome. RESULTS: In total, 79.3% (589/743) of participants in the intervention group and 83% (619/746) of participants in the control group completed the follow-up survey. The intervention group had significantly greater average reductions in anxiety symptoms measure
Cannabis use and trauma-focused treatment for co-occurring posttraumatic stress disorder and substance use disorders: A meta-analysis of individual patient data.
Citation: Hill Melanie L et al.. Cannabis use and trauma-focused treatment for co-occurring posttraumatic stress disorder and substance use disorders: A meta-analysis of individual patient data.. Journal of anxiety disorders. 2024. PMID: 38266511.
Abstract: High rates of cannabis use among people with posttraumatic stress disorder (PTSD) have raised questions about the efficacy of evidence-based PTSD treatments for individuals reporting cannabis use, particularly those with co-occurring alcohol or other substance use disorders (SUDs). Using a subset of four randomized clinical trials (RCTs) included in Project Harmony, an individual patient meta-analysis of 36 RCTs (total N = 4046) of treatments for co-occurring PTSD+SUD, we examined differences in trauma-focused (TF) and non-trauma-focused (non-TF) treatment outcomes for individuals who did and did not endorse baseline cannabis use (N = 410; 70% male; 33.2% endorsed cannabis use). Propensity score-weighted mixed effects modeling evaluated main and interactive effects of treatment assignment (TF versus non-TF) and baseline cannabis use (yes/no) on attendance rates and within-treatment changes in PTSD, alcohol, and non-cannabis drug use severity. Results revealed significant improvements across outcomes among participants in all conditions, with larger PTSD symptom reductions but lower attendance among individuals receiving TF versus non-TF treatment in both cannabis groups. Participants achieved similar reductions in alcohol and drug use across all conditions. TF outperformed non-TF treatments regardless of recent cannabis use, underscoring the importance of reducing barriers to accessing TF treatments for individuals reporting cannabis use.
Growing Concerns: A systematic review and Meta-Analysis of cannabis use and mental health risks in youth.
Citation: Sanz-Pérez A et al.. Growing Concerns: A systematic review and Meta-Analysis of cannabis use and mental health risks in youth.. Addictive behaviors. 2026. PMID: 41145103.
Abstract: Cannabis is the most widely consumed illicit drug globally. In 2021, 46 % of countries identified cannabis as the predominant substance associated with drug abuse disorders, with 34 % indicating it as the primary cause for seeking treatment. Young individuals represent the largest consumer demographic, experiencing substantial negative health effects. Despite extensive research on its mental health impacts, many aspects remain unclear. This study examines cannabis use among young people including anxiety, depression, and suicidal behavior. Studies involving individuals aged 15-30 were included. Data sources included PubMed, Mendeley, Embase, WOS, CINAHL, and Scopus. After screening 6466 articles, 36 met the inclusion criteria, with 18 included in the meta-analysis. These studies were published between 2013 and 2025. The results indicated that the odds of depression were 51 % higher in young cannabis users (OR = 1.51, 95 %CI = 1.23-1.86), decreasing to 28 % after adjustment (aOR = 1.28, 95 %CI = 1.10-1.50). Anxiety showed a 58 % increase (OR = 1.58, 95 %CI = 1.15-2.15). For suicidal ideation, the increase ranged from 50 % in unadjusted models (OR = 1.50, 95 %CI = 1.05-2.14) to 65 % in adjusted models (aOR = 1.65 95 %CI = 1.40-1.93). Finally, the odds of suicide attempt were 87 % higher (OR = 1.87, 95 %CI = 1.25-2.80), remaining elevated at 80 % after adjustment (aOR = 1.80, 95 %CI = 1.30-2.49).
Cannabis Use During Pregnancy Is Associated with the Suppression of Circulating Maternal Cytokines.
Citation: Alshaarawy Omayma et al.. Cannabis Use During Pregnancy Is Associated with the Suppression of Circulating Maternal Cytokines.. Cannabis and cannabinoid research. 2026. PMID: 41104491.
Abstract: INTRODUCTION: The prevalence of prenatal cannabis use has nearly doubled in the United States. Cannabinoid 2 receptors are predominately expressed in cells of the human immune system, and delta-9 tetrahydrocannabinol (THC), the primary active component of cannabis, has been shown to suppress immune responses. Despite these findings, there is very little evidence on the impact of cannabis use on maternal immune system. Here, we evaluate the association between urine-verified cannabis use and the levels of T helper cytokines in the maternal circulation. METHODS: This was an ancillary study of a prospective cohort of pregnant women who participated in the Michigan Archive for Research on Child Health study. Pregnant women (age ≥18 years) were recruited from 22 prenatal clinics in Michigan and matched on age, race, and tobacco smoking (n = 144). The urinary metabolite of delta-9 THC, 11-nor-9-carboxy-delta-9-THC (THC-COOH), was used to define cannabis use status. A bead-based assay was used for the simultaneous detection of maternal cytokines associated with cannabis use and pregnancy outcomes in previous studies. RESULTS: Repeated-measures linear mixed models indicated that urine-verified cannabis use was associated with the suppression of maternal pro-inflammatory cytokines including interferon gamma (β = -0.5; 95% confidence interval [CI] = -0.8, -0.1) and interleukin (IL)-12 (β = -0.3; 95% CI = -0.6, -0.05), as well as the anti-inflammatory IL-4 (β = -0.7; 95% CI = -1.3, -0.2) and IL-10 (β = -0.4; 95% CI = -0.7, -0.03). Similar results were observed when heavy cannabis use was defined using the top tertile of urinary THC-COOH at each trimester. CONCLUSIONS: Urine-verified cannabis use was associated with the suppression of pro- and anti-inflammatory T helper cytokines in a cohort of pregnant women, suggesting that cannabis use can lead to modest dysregulation of the maternal immune system. Additional studies are needed to investigate the role of maternal immune resp
A Pilot Randomized Placebo-Controlled Crossover Trial of Medicinal Cannabis in Adolescents with Tourette Syndrome.
Citation: Efron Daryl et al.. A Pilot Randomized Placebo-Controlled Crossover Trial of Medicinal Cannabis in Adolescents with Tourette Syndrome.. Cannabis and cannabinoid research. 2025. PMID: 40082070.
Abstract: Introduction: Medicinal cannabis (MC) has potential therapeutic effects in Tourette Syndrome (TS), however there has been limited research in adolescent patients. This pilot study aimed to investigate the feasibility of conducting a randomized placebo-controlled crossover trial of MC in adolescents with TS. Method: This was a phase I/II double-blind, cross-over pilot study comparing MC with matched placebo in adolescents aged 12-18 years with TS. The active medication was Δ9-tetrahydrocannabinol (THC) 10 mg/mL and CBD 15 mg/mL in peppermint-flavored medium-chain triglyceride oil. The dose titration schedule was stratified into two participant weight bands: below 50 kg (max THC 10 mg/day) or ≥50 kg (max THC 20 mg/day). Each treatment phase lasted 10 weeks, with a 4-week washout period. Results: Ten adolescents were randomized (mean age 14.8 years, 50% male) and seven completed the full study protocol. Two adolescents discontinued due to adverse events (one on MC, one placebo) and one was lost to follow-up. The most common adverse event was dizziness (67%). There were no serious adverse events. Among actively enrolled participants, protocol adherence was excellent: study visits 100%, blood test completions 100%, and online questionnaire completion 97.6%. Medication adherence was acceptable in 63.6%. Parents reported a high degree of study design acceptability. On the Clinical Global Impression-Improvement scale, three participants were rated as much improved on MC compared with one on placebo at 10 weeks. Discussion: The findings suggest that the study protocol is feasible and acceptable to patients with TS and their families. A fully powered study is needed to evaluate the efficacy of MC in adolescent TS.
Citation: Halicka Monika et al.. Effectiveness and safety of psychosocial interventions for the treatment of cannabis use disorder: A systematic review and meta-analysis.. Addiction (Abingdon, England). 2025. PMID: 40318070.
Abstract: AIM: To evaluate the effectiveness, safety and cost-effectiveness of psychosocial interventions for cannabis use disorder (CUD). METHODS: A systematic review of randomized controlled trials (RCTs; PROSPERO protocol CRD42024553382) of psychosocial interventions for CUD lasting >4 sessions, delivered synchronously, to individuals with CUD aged ≥16 years, in inpatient, outpatient or community-based settings. We searched databases (MEDLINE/PsycInfo/Cochrane CENTRAL) to 12 June 2024. We assessed results using Risk of Bias 2 and conducted pairwise meta-analyses. Primary outcomes were continuous- and point-abstinence and withdrawal intensity at the end of treatment, treatment completion and adverse events. RESULTS: We included 22 RCTs (3304 participants). Relative to an inactive/non-specific comparator, cognitive-behavioural therapy with motivation enhancement (MET-CBT) increased point abstinence [odds ratio (OR) = 18.27; 95% confidence interval (9.00-37.07)] and continuous abstinence [OR = 2.72; (1.20-6.19)], but reduced treatment completion [OR = 0.53; (0.35-0.85)]. Dialectical behavioural/acceptance and commitment therapy increased point abstinence versus inactive/non-specific comparator [OR = 4.34; (1.74-10.80)]. The effect of MET-CBT plus affect management versus MET-CBT on point abstinence was OR = 7.85 (0.38-163.52). The effect of MET-CBT plus abstinence-based contingency management versus MET-CBT on point abstinence was OR = 3.78 (0.83-17.25), and on continuous abstinence OR = 1.81 (0.61-5.41). For MET-CBT plus abstinence-contingency management versus MET-CBT plus attendance-contingency management, the effect on point abstinence was OR = 1.61 (0.72-3.60), and on continuous abstinence OR = 2.04 (0.75-5.58). The effect of community reinforcement on point abstinence was OR = 0.29 (0.04-1.90) versus MET-CBT, and on continuous abstinence OR = 47.36 (16.00-140.21) versus non-specific comparator. Interventions other than MET-CBT may not affect treatment completion. No adv
An integrated alcohol and suicide intervention for adolescents in inpatient psychiatric treatment.
Citation: McManama O’Brien Kimberly H et al.. An integrated alcohol and suicide intervention for adolescents in inpatient psychiatric treatment.. Suicide & life-threatening behavior. 2025. PMID: 39513394.
Abstract: BACKGROUND: Despite the bidirectional relationship between alcohol use and STB, the two issues are often treated separately in adolescent inpatient psychiatric hospitals, highlighting the need for brief interventions that address both alcohol use and STB in an integrated fashion. AIMS: This study tested the feasibility, acceptability, and preliminary effectiveness of a brief integrated Alcohol and Suicide Intervention for Suicidal Teens (iASIST) with a post-discharge mHealth booster for adolescents in inpatient psychiatric treatment. METHODS: We conducted an RCT of iASIST relative to an attention-matched comparison condition with adolescents hospitalized following STB (N = 40). RESULTS: iASIST demonstrated feasibility and acceptability and mixed models indicated that both groups had significant decreases in substance use over the 3-month follow-up, but post-intervention group differences were not significant. In terms of cannabis use, however, iASIST participants significantly improved over time. Intervention group participants showed a significant decrease in suicide plans from baseline to follow-up, which was not the case for control group participants. DISCUSSION: Study findings suggest a larger RCT is warranted to test the effectiveness of the iASIST intervention. CONCLUSION: iASIST shows promise in its ability to target the public health problems of alcohol use and STB in an integrated fashion with a high-risk adolescent population receiving acute psychiatric care.
Associations of Parental Monitoring and Behavioral Control with Substance Use in Adolescents and Emerging Adults: A Meta-Analysis.
Citation: Pinquart Martin et al.. Associations of Parental Monitoring and Behavioral Control with Substance Use in Adolescents and Emerging Adults: A Meta-Analysis.. Substance use & misuse. 2025. PMID: 40390334.
Abstract: BACKGROUND: It is important to identify factors that may prevent and/or reduce substance use in adolescents and emerging adults. OBJECTIVES: The present meta-analysis tested how parental general behavioral control (e.g., rule setting, strictness) and aspects of monitoring relate to substance use in adolescents and emerging adults. The study has been preregistered at OSF. Search in electronic databases resulted in 571 studies with 2,006,077 participants that were included in hierarchic random-effects meta-analysis. RESULTS: We found a small to moderate bivariate association (r = -0.16), and analysis of cross-lagged associations identified bidirectional links between control/monitoring and substance use (r = -0.08 each). Trim-and-fill analysis found no evidence for a file-drawer problem. While results did not vary between consumption of different substances, we found strongest associations in studies that assessed parental knowledge and child disclosure while associations were weakest in studies assessing parental solicitation. Associations of parenting and substance use were strongest in mid-adolescence. Effect sizes were also stronger when focusing on the parental dyad rather than on mothers and fathers separately and when information on parenting and substance use came from the same source. CONCLUSIONS: We conclude that promotion of parental knowledge and child self-disclosure in mid-adolescence would be most promising for limiting young people’s substance use.
Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks.
Citation: Ertl Natalie et al.. Acute effects of different types of cannabis on young adult and adolescent resting-state brain networks.. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2024. PMID: 38806583.
Abstract: Adolescence is a time of rapid neurodevelopment and the endocannabinoid system is particularly prone to change during this time. Cannabis is a commonly used drug with a particularly high prevalence of use among adolescents. The two predominant phytocannabinoids are Delta-9-tetrahydrocannabinol (THC) and cannabidiol (CBD), which affect the endocannabinoid system. It is unknown whether this period of rapid development makes adolescents more or less vulnerable to the effects of cannabis on brain-network connectivity, and whether CBD may attenuate the effects of THC. Using fMRI, we explored the impact of vaporized cannabis (placebo, THC: 8 mg/75 kg, THC + CBD: 8 mg/75 kg THC & 24 mg/75 kg CBD) on resting-state networks in groups of semi-regular cannabis users (usage frequency between 0.5 and 3 days/week), consisting of 22 adolescents (16-17 years) and 24 young adults (26-29 years) matched for cannabis use frequency. Cannabis caused reductions in within-network connectivity in the default mode (F[2,88] = 3.97, P = 0.022, η² = 0.018), executive control (F[2,88] = 18.62, P < 0.001, η² = 0.123), salience (F[2,88] = 12.12, P < 0.001, η² = 0.076), hippocampal (F[2,88] = 14.65, P < 0.001, η² = 0.087), and limbic striatal (F[2,88] = 16.19, P < 0.001, η² = 0.102) networks compared to placebo. Whole-brain analysis showed cannabis significantly disrupted functional connectivity with cortical regions and the executive control, salience, hippocampal, and limbic striatal networks compared to placebo. CBD did not counteract THC’s effects and further reduced connectivity both within networks and the whole brain. While age-related differences were observed, there were no interactions between age group and cannabis treatment in any brain network. Overall, these results challenge the assumption that CBD can make cannabis safer, as CBD did not attenuate THC effects (and in some cases potentiated them); furthermore, they show that cannabis causes similar disruption to resting-state connecti
Cannabidiol blood metabolite levels after cannabidiol treatment are associated with broadband EEG changes and improvements in visuomotor and non-verbal cognitive abilities in boys with autism requiring higher levels of support.
Citation: Cazares Christian et al.. Cannabidiol blood metabolite levels after cannabidiol treatment are associated with broadband EEG changes and improvements in visuomotor and non-verbal cognitive abilities in boys with autism requiring higher levels of support.. Translational psychiatry. 2026. PMID: 41611664.
Abstract: Oral cannabidiol (CBD) treatment has been suggested to alleviate severe symptoms of autism spectrum disorder (ASD). While many CBD preparations have been studied in clinical trials involving ASD, none has used purified CBD preparations or preparations approved by the U.S. Food and Drug Administration, nor have they focused on children with ASD with higher support needs. Previous studies have identified several candidate electrophysiological biomarkers of cognitive and behavioral disabilities in ASD, with emerging biomarkers including periodic (oscillatory) and aperiodic measures of neural activity. We analyzed electroencephalography (EEG) recordings from 24 boys with ASD and higher support needs (aged 7-14 years) from a prior double-blind, placebo-controlled, crossover Phase II Clinical Trial (NCT04517799) that investigated whether 8 weeks of daily CBD treatment (up to 20 mg/kg/day) improved severe behavioral problems, measured at baseline, post-CBD, post-placebo, and post-washout. Using linear mixed effect models, we found that aperiodic EEG measures varied with CBD metabolite levels in blood, as evidenced by a larger aperiodic offset across the scalp and a decreased aperiodic exponent across occipital electrodes. Furthermore, CBD metabolite levels in blood had a positive association with receptive vocabulary, nonverbal intelligence and visuomotor coordination. Our data suggest that this daily CBD preparation and administration schedule produced mixed effects, with some children showing improvements in cognitive and behavioral abilities while others demonstrated limited changes. Our findings support the inclusion of aperiodic EEG measures alongside traditional oscillatory EEG measures as candidate biomarkers for tracking the variable clinical impact of purified CBD treatment in children with ASD.
Neurodevelopmental, Pharmacological and Substance Use Factors in the Association Between ADHD and First-Episode Non-Affective Psychosis: A Systematic Review.
Citation: Ricci Valerio et al.. Neurodevelopmental, Pharmacological and Substance Use Factors in the Association Between ADHD and First-Episode Non-Affective Psychosis: A Systematic Review.. Early intervention in psychiatry. 2026. PMID: 41496432.
Abstract: OBJECTIVE: This systematic review investigates the complex relationship between attention deficit hyperactivity disorder (ADHD) and first-episode non-affective psychosis (FEP), focusing on neurodevelopmental, pharmacological and substance use factors that may influence this association. METHODS: Following PRISMA guidelines, we conducted a comprehensive literature search across PubMed, Scopus, Web of Science and PsycINFO databases for studies published between January 2001 and June 2024. We included experimental and observational studies examining ADHD and FEP in participants aged ≥ 16 years. Quality assessment was performed using standardised tools specific to each study design. RESULTS: From 1243 initially identified records, 13 studies met inclusion criteria. Five studies addressing neurodevelopmental factors revealed shared neurobiological vulnerabilities between ADHD and psychosis, including impaired cortical inhibition, neurophysiological markers and cognitive deficits. Five pharmacological studies demonstrated that whilst stimulant-induced psychosis can occur, the absolute risk appears low, with amphetamines carrying a 1.65-fold higher risk than methylphenidate. Three studies on substance use patterns showed that ADHD patients with FEP had significantly higher rates of substance use disorders, particularly cannabis use, which was associated with earlier psychosis onset and poorer outcomes. CONCLUSIONS: Individuals with ADHD, particularly those with persistent symptoms from childhood and neurocognitive deficits, may have an elevated risk of developing FEP. Substance use appears to be an important mediating factor in this relationship. Regarding pharmacological treatment, recent epidemiological evidence provides a more nuanced perspective on stimulant safety, though the evidence remains mixed and requires further investigation. These findings highlight the importance of comprehensive assessment, substance use prevention and individualised risk stratification whe
Impact of Glucagon-like Peptide-1 Receptor Agonists on Mental Illness: Evidence from a Mendelian Randomization Study.
Citation: Xiang Longgang et al.. Impact of Glucagon-like Peptide-1 Receptor Agonists on Mental Illness: Evidence from a Mendelian Randomization Study.. International journal of molecular sciences. 2025. PMID: 40141382.
Abstract: Emerging evidence suggests that glucagon-like peptide-1 receptor (GLP1R) agonists may have potential benefits for mental illnesses. However, their exact effects remain unclear. This study investigated the causal relationship between glucagon-like peptide-1 receptor agonist (GLP1RA) and the risk of 10 common mental illnesses, including attention deficit and hyperactivity disorder, anorexia nervosa, anxiety disorder, autism spectrum disorder, bipolar disorder, major depressive disorder, post-traumatic stress disorder, schizophrenia, cannabis use disorder, and alcohol use disorder. We selected GLP1RA as the exposure and conducted a Mendelian randomization (MR) analysis. The cis-eQTLs of the drug target gene GLP1R, provided by eQTLGen, were used to simulate the pharmacological effects of GLP1RA. Type 2 diabetes and BMI were included as positive controls. Using data from both the Psychiatric Genomic Consortium and FinnGen, we conducted separate MR analyses for the same disease across these two independent databases. Meta-analysis was used to pool the results. We found genetic evidence suggesting a causal relationship between GLP1RA and a reduced risk of schizophrenia [OR (95% CI) = 0.84 (0.71-0.98), I2 = 0.0%, common effects model]. Further mediation analysis indicated that this effect might be unrelated to improvements in glycemic control but rather mediated by BMI. However, the findings of this study provide insufficient evidence to support a causal relationship between GLP1RA and other mental illnesses. Sensitivity analyses did not reveal any potential bias due to horizontal pleiotropy or heterogeneity in the above results (p > 0.05). This study suggests that genetically proxied activation of glucagon-like peptide-1 receptor is associated with a lower risk of schizophrenia. GLP1R is implicated in schizophrenia pathogenesis, and its agonists may exert potential benefits through weight management. Our study provides useful information for understanding the neuropsychiat
GPR3 in neuro-metabolic-immune-reproductive nexus – a potential therapeutic target for Multi-System diseases.
Citation: Feng Bi-Dan et al.. GPR3 in neuro-metabolic-immune-reproductive nexus – a potential therapeutic target for Multi-System diseases.. Annals of medicine. 2026. PMID: 41574602.
Abstract: BACKGROUND: GPR3(G-protein-coupled receptor 3), an orphan G-protein-coupled receptor (GPCR) with constitutive Gs activity, is expressed in the brain, liver, ovary, and other tissues, regulating cell proliferation, differentiation, and apoptosis across the nervous, reproductive, immune, and metabolic systems. This review synthesizes evidence on its integrated signaling and physiological functions to address the lack of a comprehensive multisystem pathophysiology overview. METHODS: A systematic literature search was conducted on PubMed and Web of Science, using keywords such as “GPR3”, “GPCR”, “neurodegeneration”, “metabolism”, “immune”, “reproduction”, “agonist”, “inhibitor”, and “therapeutic target”. This search identified GPR3’s roles in neurodegenerative diseases, immune inflammation, reproduction, and energy metabolism. The analysis focused on signaling pathways, ligand regulation, and therapeutic potential. RESULTS: The research indicates that GPR3 is involved in neuronal survival, synaptic plasticity, and microglial activity via the cAMP/PKA, PI3K/Akt, and β – arrestin pathways. It promotes amyloid – β formation in Alzheimer’s disease (AD), yet provides neuroprotection in Parkinson’s disease (PD) models. It may contribute to anxiety/depression – like states, maintain oocyte meiotic arrest in the ovary, and activate thermogenic genes in adipose tissue. GPR3 modulates immune responses. Using oleic acid (OA) and diphenyleneiodonium (DPI) as activators, and AF64394 and cannabidiol (CBD) as antagonists, it shows potential in disease models. CONCLUSION: GPR3 acts as a central molecular hub integrating neural, metabolic, immune, and reproductive signaling, highlighting its potential as a therapeutic target for chronic multisystem disorders. However, its dual roles in certain pathologies and translation challenges necessitate further research.
Therapeutic Potential for Cannabidiol on Alzheimer’s Disease-Related Neuroinflammation: A Systematic Review and Meta-Analysis.
Citation: Wu Shuo et al.. Therapeutic Potential for Cannabidiol on Alzheimer’s Disease-Related Neuroinflammation: A Systematic Review and Meta-Analysis.. International journal of molecular sciences. 2025. PMID: 41465389.
Abstract: Alzheimer’s disease (AD) is a pervasive neurodegenerative disorder characterized by chronic neuroinflammation; current interventions primarily offer symptomatic relief. Cannabidiol (CBD), a non-psychoactive phytocannabinoid, exhibits multi-target therapeutic potential due to its established anti-inflammatory and neuroprotective properties. While growing interest exists, the evidence regarding CBD’s effects on AD-related neuroinflammation has not been robustly consolidated in a quantitative meta-analysis. Therefore, this article reviews the current literature around CBD related to its potential in alleviating neuroinflammation, followed by a meta-analysis of preclinical and clinical studies using random-effects modeling to assess CBD efficacy on neuroinflammation and clinical outcomes in AD. In preclinical AD models, the meta-analysis demonstrated that CBD significantly and consistently reduced key markers of neuroinflammation and reactive gliosis, specifically glial fibrillary acidic protein (GFAP) (p < 0.0001), Interleukin-6 (IL-6), and inducible nitric oxide synthase (iNOS). Effects on other markers, such as tumor necrosis factor-alpha (TNF-α) and interleukin-1 beta (IL-1β), were non-significant and heterogeneous. Clinical evidence, though limited by small sample size and heterogeneity, showed a borderline significant benefit favoring CBD for overall behavioral symptoms (p = 0.05), agitation, and caregiver distress. Adverse events were typically mild. We conclude that CBD demonstrates biologically consistent anti-inflammatory efficacy in preclinical AD models. While current clinical data remains insufficient to substantiate efficacy, they suggest promising signals for behavioral control. Determining CBD’s full therapeutic potential in AD necessitates future rigorous, mechanism-driven trials with standardized preparations and biomarker-anchored endpoints.
The prevalence of benzodiazepines and other hypnotics and their impact on injury severity among older adults involved in motor vehicle collisions: a multicenter retrospective cohort study.
Citation: Benhamed Axel et al.. The prevalence of benzodiazepines and other hypnotics and their impact on injury severity among older adults involved in motor vehicle collisions: a multicenter retrospective cohort study.. Journal of safety research. 2025. PMID: 40930644.
Abstract: INTRODUCTION: Older adults are increasingly involved in motor vehicle collisions (MVCs). Hypnotics are known to impair driving ability. This study investigated the prevalence of hypnotics use among older adult drivers involved in MVCs and evaluated their impact on injury severity and co-prevalence with other central nervous system (CNS) depressants. METHODS: This study analyzed prospectively collected data from older drivers (≥65 years) involved in MVCs from 2018 to 2023 across 17 Canadian emergency departments. Blood samples were tested for benzodiazepines, non-benzodiazepine hypnotics, alcohol, opioids, cannabis, stimulants, and other CNS depressants. Need for hospital admission was used as an indicator of severe injury. Statistical analyses included Chi-square tests to assess group differences and estimation of marginal relative risks via G-computation, adjusting for potential confounders. RESULTS: Among 1459 older drivers involved in collisions, 11.8% (n = 172) tested positive for hypnotics (hypnotic+). The most frequently detected agents in this group were non-benzodiazepine hypnotics (41.3%), followed by long-acting (33.7%), intermediate-acting (27.3%), and short-acting benzodiazepines (5.8%). Co-detections were also common in patients tested positive for hypnotics, particularly with antidepressants (40.1%), opioids (18.6%), antihistamines (10.5%), and antipsychotics (8.7%). Hypnotic + patients were more frequently aged 65-74 years (56.4%) and male (57.0%). There was no significant difference in risk of hospital admission between hypnotic+ and hypnotic- groups (50.0% vs. 45.8%, p = 0.59). The adjusted relative risk of admission was 1.01 [95% CI: 0.87, 1.17, p = 0.91]. CONCLUSION: Hypnotic use among older drivers involved in MVCs is prevalent and associated with polypharmacy. However, it was not associated with an increased risk of severe trauma among patients receiving ED treatment following MVCs.
Examination of Correlates of OUD Outcomes in Young Adults: Secondary Analysis From the XBOT Trial.
Citation: Fishman Marc et al.. Examination of Correlates of OUD Outcomes in Young Adults: Secondary Analysis From the XBOT Trial.. The American journal on addictions. 2021. PMID: 34075644.
Abstract: BACKGROUND AND OBJECTIVES: Opioid use disorder (OUD) treatment outcomes are poorer for young adults than older adults. Developmental differences are broadly implicated, but particular vulnerability factor interactions are poorly understood. This study sought to identify moderators of OUD relapse between age groups. METHODS: This secondary analysis compared young adults (18-25) to older adults (26+) from a comparative effectiveness trial (“XBOT”) that randomized (N = 570) participants to extended-release naltrexone or sublingual buprenorphine-naloxone. We explored the relationship between 25 prespecified patient baseline characteristics and relapse to regular opioid use by age group and treatment condition, using logistic regression. RESULTS: Young adults (n = 111) had higher rates of 24-week relapse than older adults (n = 459) (70.3% vs 58.8%) and differed on a number of specific characteristics, including more smokers, more intravenous opioid use, and more cannabis use. No significant moderators predicted relapse, in either three-way or two-way interactions. CONCLUSIONS AND SCIENTIFIC SIGNIFICANCE: No baseline factors were identified as moderating the relationship between age group and opioid relapse, nor any interactions between baseline characteristics, age group, and treatment condition to predict opioid relapse. Poorer treatment outcomes for young adults are likely associated with multiple developmental vulnerabilities rather than any single predominant factor. Although not reaching significance, several characteristics (using heroin, smoking tobacco, high levels of depression/anxiety, or treatment because of family/friends) showed higher odds ratio point estimates for relapse in young adults than older adults. This is the first study to explore moderators of worse OUD treatment outcomes in young adults, highlighting the need to identify predictor variables that could inform treatment enhancements. (Am J Addict 2021;00:1-12).
Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis.
Citation: Velayudhan Latha et al.. Safety and tolerability of natural and synthetic cannabinoids in adults aged over 50 years: A systematic review and meta-analysis.. PLoS medicine. 2021. PMID: 33780450.
Abstract: BACKGROUND: Cannabinoid-based medicines (CBMs) are being used widely in the elderly. However, their safety and tolerability in older adults remains unclear. We aimed to conduct a systematic review and meta-analysis of safety and tolerability of CBMs in adults of age ≥50 years. METHODS AND FINDINGS: A systematic search was performed using MEDLINE, PubMed, EMBASE, CINAHL PsychInfo, Cochrane Library, and ClinicalTrials.gov (1 January 1990 to 3 October 2020). Randomised clinical trials (RCTs) of CBMs in those with mean age of ≥50 years for all indications, evaluating the safety/tolerability of CBMs where adverse events have been quantified, were included. Study quality was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) criteria and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) guidelines were followed. Two reviewers conducted all review stages independently. Where possible, data were pooled using random-effects meta-analysis. Effect sizes were calculated as incident rate ratio (IRR) for outcome data such as adverse events (AEs), serious AEs (SAEs), and death and risk ratio (RR) for withdrawal from study and reported separately for studies using tetrahydrocannabinol (THC), THC:cannabidiol (CBD) combination, and CBD. A total of 46 RCTs were identified as suitable for inclusion of which 31 (67%) were conducted in the United Kingdom and Europe. There were 6,216 patients (mean age 58.6 ± 7.5 years; 51% male) included in the analysis, with 3,469 receiving CBMs. Compared with controls, delta-9-tetrahydrocannabinol (THC)-containing CBMs significantly increased the incidence of all-cause and treatment-related AEs: THC alone (IRR: 1.42 [95% CI, 1.12 to 1.78]) and (IRR: 1.60 [95% CI, 1.26 to 2.04]); THC:CBD combination (IRR: 1.58 [95% CI,1.26 to 1.98]) and (IRR: 1.70 [95% CI,1.24 to 2.33]), respectively. IRRs of SAEs and deaths were not significantly greater under CBMs containing THC with or without CBD.
This digest is generated by the CED Clinic automated research pipeline. All articles are drawn from PubMed-indexed peer-reviewed literature. Scoring reflects study design quality, recency, and clinical relevance to cannabis medicine practice. This content is for educational purposes and does not constitute clinical advice.