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PubMed2026

Adolescents' Growing Sensitivity to Psychosocial Stressors: Evidence From Two Decades of Health Behaviour in School-aged Children (HBSC) Data in the Nordic Countries.

PURPOSE: We tested a perception-based explanation for rising psychosomatic complaints among adolescents in the Nordic countries. Specifically, we examined whether adolescents have become more sensitive to psychosocial stressors, reflected in stronger associations between stressors and psychosomatic complaints in 2022 than in 2002. METHODS: Data were drawn from the 2002 to 2022 waves of the Health Behaviour in School-aged Children survey among 15-year-olds in five Nordic countries (N = 7,263 in 2002 and 6,739 in 2022). Psychosomatic complaints were examined in relation to stressors in the following three domains: interpersonal relationships, school-related strain, and body- and activity-related factors. Moderated regression analyses tested whether associations between stressors and complaints differed between survey years. Sex and perceived family finances were included as covariates. RESULTS: Four of five psychosocial stressors showed stronger associations with psychosomatic complaints in 2022 than in 2002. Perceived poor family finances, although less prevalent in 2022, were more strongly related to complaints. Girls consistently reported higher levels of psychosomatic complaints, and the association between school pressure and complaints was stronger among girls. DISCUSSION: Although several psychosocial stressors declined in prevalence, their associations with psychosomatic complaints strengthened over time. These findings suggest that rising complaints may reflect changes in how psychosocial stressors are linked to adolescents' psychosomatic symptoms, rather than increases in exposure to those stressors. This shift highlights the importance of considering how adolescents interpret and respond to everyday stress when addressing population trends in mental health.

Humans↗
PubMed2026

Effects of carbohydrate mouth rinse on psychophysiological responses, kinematic variables and technical actions during small-sided soccer games.

BACKGROUND: This study investigated the effects of carbohydrate mouth rinsing (CHOMR) on various psychophysiological, kinematic, and technical actions during 4-a-side small-sided soccer games (SSGs). METHODS: In a randomized, crossover, double-blind design, 16 young male soccer players (age: 15&#x2009;&#xb1;&#x2009;1 years; height: 172.6&#x2009;&#xb1;&#x2009;7.0&#x2009;cm; body mass: 57.8&#x2009;&#xb1;&#x2009;7.9 kg) participated in two 4-a-side SSGs separated by one week following either CHOMR or placebo (PLA). During each SSGs, heart rate (HRmean, %HR, and HRmax), rating of perceived exertion (RPE), enjoyment, visual analogue scale (VAS) to perceived mental fatigue, mood states, total distance (TD), high-speed running distance (HSRD), average metabolic power (AMP), high metabolic load distance (HMLD), sprint distance (SD), acceleration (ACC), deceleration (DEC), and technical actions (e.g. passing, tackling, shooting, and interceptions) were assessed. RESULTS: Compared with PLA, CHOMR resulted in significantly higher RPE (p&#x2009;=&#x2009;0.025, g&#x2009;=&#x2009;0.86) and significantly lower VAS scores (p&#x2009;=&#x2009;0.010, g&#x2009;=&#x2009;-0.71). In addition, the CHOMR condition showed significantly higher values for interceptions, successful tackles, unsuccessful tackles, unsuccessful shots, and goals (p&#x2009;<&#x2009;0.05, g&#x2009;=&#x2009;0.96-2.02), whereas block values were significantly higher in the PLA condition. There were no statistically significant differences in HRmean, %HR, HRmax, enjoyment, TD, HSRD, AMP, HMLD, SD, ACC, DEC, successful passes, unsuccessful passes, successful shots, or mood states between the conditions (p&#x2009;>&#x2009;0.05). CONCLUSION: The current study findings suggest that CHOMR may enhance selected technical actions and lower VAS scores during 4-a-side SSGs, although it was also associated with higher RPE and did not alter the kinematic responses. In conclusion, CHOMR was associated with higher RPE, lower mental fatigue, and selective improvements in technical actions, with no significant effects on kinematic variables or HR.

Humans↗
PubMed2024

Emotional and Cognitive Processes Underlying Persuasion, Moderating Factors, and Physiological Reactions: A Systematic Review.

Persuasion is a type of social influence aiming to produce changes in others' attitudes or behaviors. This study explores the relationship between emotions and persuasion, principal moderating factors, and physiological reactions during persuasive attempts. Following PRISMA guidelines, 28 empirical articles were analyzed, addressing emotions, affective/cognitive orientations, framing effects, and psychophysiological reactions. Mixed findings emerged regarding emotions, with fear appeals being effective in health education, while more recent studies favor the use of positive persuasive messages to increase behavior intention. Principal moderating factors included personal relevance, need for cognition (NFC) and need for affect (NFA), thought confidence, vulnerability, and efficacy beliefs. Psychophysiological studies revealed distinct physiological arousal during persuasion processing compared to a rest state. In addition, a greater misalignment between current behavior and the persuasive attempt led to perceived freedom threat and psychological reactance. These insights enhance persuasive effectiveness and deepen understanding of persuasion processes, guiding future research directions.

Humans↗
PubMed2026

Targeting cortico-striatal-amygdalar networks via theta-band frontoparietal synchronization in opioid use disorder: a randomized tACS-fMRI Trial.

Theta-band oscillation is integral to fronto-parietal connectivity in the executive control network and its top-down regulation on subcortical areas. External frontoparietal synchronization using theta-frequency transcranial alternating current (tACS) is a technology to potentially engage this network. In this pre-registered, triple-blind, sham-controlled trial (NCT03907644), we tested this intervention targeting the right frontoparietal network in people with opioid use disorder (OUD) to measure network engagement and behavioral outcomes. Sixty male participants with OUD were randomized to receive 20&#x2009;min of active or sham 6&#x2009;Hz tACS (HD electrodes over F4 and P4). Structural, resting-state, task-based fMRI drug cue reactivity, and repeated cue-induced craving assessments were collected immediately before and after stimulation. Pre-registered outcome measures were analyzed using time&#x2009;&#xd7;&#x2009;group interaction models to examine (1) modulation of drug cue-related brain activity, (2) changes in craving, (3) alterations in functional connectivity, and (4) relationship between electric field, neural responses, and craving behavior. (1) A significant Time&#x2009;&#xd7;&#x2009;Group interaction revealed decreased post-stimulation opioid cue-related activity in the active group relative to sham, involving key nodes in reward processing (ventral striatum, amygdala and ventral tegmental area) (FWE corrected &#x3b1;&#x2009;=&#x2009;0.05) (2) subjective craving did not differ significantly between groups (3) Group by time generalized psychophysiological interaction analyses showed increased right frontoparietal network engagement (&#x3b2;&#x2009;=&#x2009;2.63, p=&#x2009;0.0308) following stimulation, and increased top-down inhibitory regulation of frontoparietal network on right ventral striatum (&#x3b2;&#x2009;=&#x2009;1.99, p=&#x2009;0.037) and left medial amygdala (&#x3b2;&#x2009;=&#x2009;1.97, p=&#x2009;0.039) (4) Electric field strength in the right frontal/parietal node predicted frontoparietal network engagement in the active group (r&#x2009;=&#x2009;0.43, p=&#x2009;0.02). Together, these findings demonstrate that theta-band frontoparietal tACS can modulate activity and task-dependent coupling within cortical-subcortical circuits in OUD, supporting network-targeted neuromodulation as a potential intervention for addiction.

Humans↗
PubMed2026

Modulation of heart rate and heart rate variability during animal-assisted treatment of patients in a minimally conscious state: A randomized controlled crossover study.

BACKGROUND: Animal-assisted treatment (AATx) is a promising and increasingly used approach in neurorehabilitation, yet its psychophysiological effects remain largely unexplored. Patients in a minimally conscious state (MCS) show severely altered consciousness with minimal but definite behavioral signs of awareness. Because behavioral assessment in this population is limited, psychophysiological measures such as heart rate (HR) and heart rate variability (HRV) may offer valuable insights into autonomic regulation during therapy. AIM: The present study investigated whether AATx influences HR and HRV compared to treatment as usual (TAU). METHODS: A randomized controlled crossover design with repeated measures was conducted. HR and HRV data were recorded using an Empatica E4 wristband, and linear mixed-effects models were fitted for each outcome variable. The analytic sample included twenty-one patients with MCS who completed at least one of the four sessions. RESULTS: We found a significant decrease in mean HR (estimate = -12.75, p&#x202f;=&#x202f;.041) and a significant increase in the standard deviation of normal-to-normal intervals (SDNN) (estimate = 15.76, p&#x202f;=&#x202f;.020) during AATx compared to TAU from the pretreatment to the posttreatment phase, indicating enhanced parasympathetic activation and greater autonomic flexibility. Other HRV parameters revealed no significant effects of AATx, though trends were consistent with the hypotheses. CONCLUSIONS: These findings provide preliminary physiological evidence that AATx can modulate autonomic activity in MCS patients. Despite limitations related to sample size and recording quality, the results highlight the potential of AATx as an emotionally engaging intervention in early neurorehabilitation.

Humans↗
PubMed2026

Dispositional optimism and open-label placebo responses in hair cortisol concentrations and psychological distress-A randomized controlled trial.

Open-label placebo (OLP) treatments show beneficial effects on various health-related outcomes, but studies investigating OLP effects on physiological measures remain scarce. This randomized controlled trial examined the effect of a 4-week OLP intervention on psychological distress and hair cortisol concentrations (HCC) in 202 healthy university students preparing for mandatory oral exams and whether dispositional optimism moderates the OLP effects. Participants were randomly assigned to an OLP or control group. Psychological distress was repeatedly assessed via negative affect, test anxiety, and subjective stress. HCC was measured before and within the intervention. Treatment expectations were additionally examined in interaction with optimism. Results show that OLPs significantly reduced psychological distress and HCC compared to the controls. Optimism moderated the OLP effect on HCC, with less optimistic individuals demonstrating the strongest reduction, independent of expectation. Optimism did not moderate OLP effects in psychological distress. However, the OLP effect on psychological distress depended on the three-way interaction of group, optimism, and expectation. The results suggest that OLPs alleviate the psychophysiological impact of a real-life stressor and indicate that optimism and expectation differently shape psychological and physiological OLP responses. These findings are discussed within the framework of the interactionist perspective.

Humans↗
PubMed2026

Short-term effects of foot reflexology on pain, anxiety, and physiological responses in women with shoulder and neck pain: A randomized controlled trial.

OBJECTIVES: Shoulder and neck pain (SNP) is a common musculoskeletal complaint among women and is often accompanied by heightened anxiety. Foot reflexology (FR) is a complementary therapy proposed to promote relaxation and short-term psychophysiological regulation. This study examined the short-term effects of a single session of FR on pain, anxiety, and physiological responses in women with SNP. METHODS: A single-blind randomized controlled trial was conducted with 80 women aged 20-64&#xa0;years in southern Taiwan. Participants were randomly allocated to one of three groups: FR, exercise, or passive rest control. Each group received a single 50-min session. Pain intensity and anxiety were assessed using the Numeric Rating Scale (NRS) and the State-Trait Anxiety Inventory (STAI), respectively. Heart rate and blood pressure were recorded as physiological indicators. Outcomes were measured at baseline, immediately post-intervention, and at 24-h follow-up. RESULTS: Baseline pain, anxiety, and physiological measures did not significantly differ among groups. Immediately after the intervention, both the FR and exercise groups demonstrated greater reductions in pain intensity compared with the passive rest control (P&#xa0;<&#xa0;0.001 and P&#xa0;=&#xa0;0.018, respectively). The FR group additionally showed greater reductions in anxiety and heart rate compared with the passive rest group (P&#xa0;=&#xa0;0.005 and P&#xa0;=&#xa0;0.001, respectively). Pain reduction in the FR group remained significant at the 24-h follow-up (P&#xa0;=&#xa0;0.013), whereas anxiety reductions were not sustained. No significant between-group differences were observed for systolic blood pressure. CONCLUSION: A single session of FR was associated with immediate and short-term reductions in pain, anxiety, and heart rate among women with SNP. Foot reflexology may serve as a supportive, non-pharmacological approach for short-term modulation, although sustained effects require further investigation.

Humans↗
PubMed2026

Memantine Augmentation for Obsessive-Compulsive Symptoms in Bipolar Disorder: A Randomized, Double-Blind, Placebo-Controlled Trial.

BACKGROUND: Obsessive-compulsive symptoms are frequently observed in patients with bipolar disorder and present a significant therapeutic challenge. This study evaluated the efficacy and safety of memantine as an adjunctive therapy for obsessive-compulsive disorder in patients with bipolar disorder. METHODS: In this randomized, double-blind, placebo-controlled trial, 46 patients with bipolar disorder and obsessive-compulsive disorder, stabilized on quetiapine and lithium, were randomly assigned to receive either memantine (n = 23) or placebo (n = 23) for 6 weeks. RESULTS: The memantine group showed a significant reduction in Yale-Brown Obsessive-Compulsive Scale scores compared with the placebo group (Cohen d = 1.57 vs 0.42, P < 0.001). Nausea was the most common side effect, but overall adverse effects were minimal. CONCLUSION: Memantine appears to be a safe and effective adjunctive treatment for obsessive-compulsive disorder in patients with bipolar disorder, warranting further investigation.

Humans↗
PubMed2026

New Horizons in the Development of Treatments for Substance Use Disorders.

Substance use disorders (SUDs) are a major public health problem in the United States and cause substantial morbidity and mortality. There are meaningful gaps in the available SUD treatment options, and the development of new therapies is urgently needed. While medications with U.S. Food and Drug Administration approval are available for alcohol, nicotine, and opioid use disorders, there are no approved pharmacotherapies for cannabis, cocaine, or methamphetamine use disorders. Behavioral treatments for SUDs have significant limitations in effectiveness and accessibility, and there is a need for the development of both new behavioral treatment options and new models of treatment delivery. The next generation of treatments for SUDs will likely come from a diverse set of interventions, including new drug classes, new technologies, and new methods of delivery.

Humans↗
PubMed2026

Perioperative care for patients with opioid exposure and opioid use disorder: screening and treatment strategies.

PURPOSE OF REVIEW: The prevalence of opioid tolerance, dependence, and use disorder is increasing among patients presenting for surgical care, yet perioperative management strategies for these patients remain inconsistent. This review examines the impact of preoperative opioid exposure on surgical outcomes, the scope of untreated opioid use disorder (OUD) among surgical patients, and advances in clinical and systems-level approaches to perioperative care. RECENT FINDINGS: Preoperative opioid exposure independently predicts worse surgical outcomes, including higher opioid consumption, readmissions, complications, and mortality, in a dose-dependent manner. Perioperative opioid exposure predicts persistent opioid use after surgery, with the duration of exposure a stronger predictor of subsequent OUD than daily dose. Data-driven prescribing guidelines and structured opioid tapering reduce overprescribing without compromising pain control. Among surgical patients with diagnosed OUD, approximately two-thirds do not receive medications for opioid use disorder (MOUD), though treatment engagement and maintenance substantially improve outcomes. Evidence now clearly supports perioperative buprenorphine continuation over interruption. SUMMARY: Effective perioperative management of opioid-complex surgical patients requires systematic screening, evidence-based prescribing, MOUD continuation, and institutional infrastructure. The primary barrier is shifting from evidence generation to implementation.

Humans↗
PubMed2026

Feasibility and effectiveness of the Bergen 4-Day Treatment for obsessive-compulsive disorder in Australia: A pilot comparison with 3-week inpatient obsessive-compulsive disorder treatment.

OBJECTIVES: Obsessive-compulsive disorder is a debilitating and chronic condition that, when untreated or unresponsive to treatment, imposes a significant health and economic burden on individuals and families. This prospective non-randomised inpatient study compared the acceptability and clinical outcomes of the Bergen 4-Day Treatment programme with those of a standard 3-week specialised treatment programme for obsessive-compulsive disorder in Australia. METHOD: Twenty-five participants diagnosed with obsessive-compulsive disorder were non-randomly assigned to Bergen 4-Day Treatment (n&#x2009;=&#x2009;12) or a 3-week standard (n&#x2009;=&#x2009;13) inpatient programme. Independent assessments were completed at pre-treatment, 10&#x2009;days post treatment and at 3-month follow-up. The Yale-Brown Obsessive-Compulsive Scale was rated to assess obsessive-compulsive disorder severity, while secondary measures of depression, anxiety, obsessive beliefs and wellbeing were self-rated by participants. RESULTS: Baseline characteristics of both groups were comparable, with obsessive-compulsive disorder symptom severity within the moderate to severe range. After treatment, obsessive-compulsive disorder symptoms as well as secondary depression and anxiety symptoms were reduced in both treatment groups. Participants receiving Bergen 4-Day Treatment had significantly lower Yale-Brown Obsessive-Compulsive Scale scores at 10&#x2009;days (M&#x2009;=&#x2009;13.46) and 3&#x2009;months (M&#x2009;=&#x2009;11.84), compared to standard treatment (M&#x2009;=&#x2009;19.04 and M&#x2009;=&#x2009;19.15, respectively). Response (91.9%) and remission (45.8%) rates for the Bergen 4-Day Treatment group were significantly higher at both post-treatment timepoints, compared to the standard treatment group. No dropouts occurred in the Bergen 4-Day Treatment group, and participant satisfaction was high. CONCLUSION: The findings of this pilot open-label study suggest that Bergen 4-Day Treatment shows promise as an acceptable, efficient and effective treatment for obsessive-compulsive disorder, warranting further investigation as a scalable alternative for improving access to specialised obsessive-compulsive disorder treatment in Australia.

Humans↗
PubMed2026

Atomoxetine Versus Placebo for Cognitive Deficits in Stimulant Use Disorder: A Systematic Review.

BACKGROUND: Stimulant use disorder (StUD), particularly involving cocaine and amphetamines, is associated with significant cognitive impairments that impede recovery and increase relapse risk. Atomoxetine, a selective norepinephrine reuptake inhibitor, has been proposed as a potential treatment given its role in enhancing executive function and its established efficacy in attention-deficit/hyperactivity disorder (ADHD). This systematic review aimed to evaluate the efficacy, cognitive, and mood effects of atomoxetine compared with placebo in individuals with StUD. METHODS: A comprehensive literature search of PubMed, Cochrane CENTRAL, and Embase databases was conducted to identify randomized controlled trials (RCTs) evaluating atomoxetine for StUD. Eligible studies compared atomoxetine with placebo and assessed outcomes related to cognition (attention and response inhibition), stimulant use or abstinence, mood symptoms, and safety. Data were extracted and synthesized qualitatively due to methodological heterogeneity across studies. RESULTS: Nine RCTs met the inclusion criteria. Findings on cognitive outcomes were inconsistent: Some studies reported improvements in attentional bias and inhibitory control, while others showed no significant effects. Atomoxetine did not significantly reduce stimulant use, craving, or sustain abstinence compared with placebo. Limited mood-related benefits were observed, particularly among male participants, although results were variable. Across studies, atomoxetine was well tolerated, with most adverse events mild and transient. CONCLUSION: Despite a compelling neurobiological rationale and evidence of modest cognitive and mood benefits, atomoxetine has not demonstrated consistent efficacy as a monotherapy for StUD. Its favorable safety profile may warrant further investigation in carefully defined populations, such as individuals with comorbid ADHD or in combination with behavioral interventions.

Atomoxetine Hydrochloride↗
PubMed2026

Shared Medical Appointments for Substance Use Disorders: A Systematic Review.

BACKGROUND: Shared medical appointments (SMAs) integrate group-based clinical care with individual medical management and are increasingly used in the treatment of substance use disorders (SUDs) to improve access, engagement, and care coordination. However, their use, outcomes, and implementation in SUD care have not been systematically synthesized. METHODS: We conducted a systematic review registered with PROSPERO (CRD42025639504). MEDLINE, Embase, PsycINFO, Scopus, and Cochrane Central were searched from database inception through September 2025. Randomized controlled trials, observational studies, and qualitative studies examining SMAs among adults with SUDs were included. Outcomes of interest included treatment engagement and retention, substance use outcomes, mental health and patient-reported outcomes, and implementation characteristics. Study quality was assessed across quantitative and qualitative designs, and findings were synthesized descriptively. RESULTS: Fourteen studies, representing approximately 578 participants, met inclusion criteria. Twelve studies focused exclusively on opioid use disorder, 1 included both alcohol and opioid use disorders, and 1 did not specify substance type. Treatment retention was reported in 6 studies, with a median 6-month retention of 72.9%. Three studies reported reductions in substance use outcomes, and 2 reported improvements in depression or anxiety. Qualitative studies consistently described high patient satisfaction, peer support, and shared accountability. Implementation studies demonstrated feasibility across diverse outpatient settings, with substantial heterogeneity across study designs and outcomes. CONCLUSIONS: SMAs appear feasible and acceptable for addiction care and may support treatment retention and patient experience. Evidence remains heterogeneous and largely observational, highlighting the need for rigorous comparative studies to better define effectiveness and implementation.

Humans↗
PubMed2026

Clinical and psychological characteristics of adolescents at risk of mood disorders compared with adolescents with suicidal behavior.

Suicide is one of the leading causes of death among adolescents, yet little is understood about the biopsychosocial factors related to suicidality. The demographic, clinical, and biological characteristics of adolescents with and without psychiatric histories may help inform mechanistic approaches to treatment of mood disorders and suicidality. The 'characterizing the inflammatory profile and suicidal behavior in adolescents' and 'RAD arm of the Texas Resilience Against Depression' studies aimed to characterize the clinical and biological profiles of youth with suicidal behavior and youth at risk for mood disorders, compared to healthy adolescents (n&#xa0;=&#xa0;75 in each group). Here, we report the descriptive baseline clinical and psychological characteristics of adolescents at risk of mood disorders and those with suicidal behavior. The adolescents with suicidal behavior reported 3.53 lifetime suicidal events on average, predominantly reported moderate to very severe depression (34.7%, 24%, to 9.3%), moderate to severe anxiety (58.6%), low optimism (91.9%), and mild (39.2%) to moderate (28.4%) degree of hopelessness. The at-risk adolescents predominantly reported no depression (60%) or anxiety (68.9%), moderate optimism (50%), and a positive outlook (85.7%). Healthy adolescents predominantly reported no depression (88.3%) or anxiety (93.2%), moderate optimism (59%), and a positive outlook (87%). The adolescents with suicidal behavior and those at risk of mood disorders exhibited significantly higher irritability and borderline personality disorder features (uncorrected p&#xa0;=&#xa0;0.02 to p&#xa0;<&#xa0;0.001) and lower resilience compared to healthy adolescents. Ongoing investigations using the longitudinal clinical and biological data will help identify the immune biosignatures of suicidality in youth.

Humans↗
PubMed2026

Causal Relationship of Polyunsaturated Fatty Acids With Mental Disorders: A Systematic Review and Meta-analysis.

CONTEXT: Mental disorders (MDs) pose a important global health challenge, with a complex pathogenesis complicating treatment development. Nutritional interventions, particularly polyunsaturated fatty acids (PUFAs), have gained attention as potential therapeutic options. OBJECTIVE: This Mendelian randomization (MR) meta-analysis aimed to evaluate the potential causal relationship between PUFAs and MDs. DATA SOURCES: Genome-wide association study data were utilized to analyze the association between PUFAs (including omega-3, omega-3 percentage [omega-3%], omega-6, omega-6 percentage [omega-6%], and omega-6 to omega-3 ratio) and 12 major MDs. DATA EXTRACTION: Two-sample MR technology was used to assess the role of PUFAs in MDs. DATA ANALYSIS: The MR analysis revealed that genetically predicted omega-3 was causally linked to MDs, such as obsessive-compulsive disorder, bipolar disorder, schizophrenia, and major depressive disorder. Omega-3% exhibited protective effects against emotional personality disorder. Conversely, omega-6 was inversely correlated with attention-deficit/hyperactivity disorder risk, while a high omega-6 to omega-3 ratio was associated with an increased risk of depression and other mood disorders. CONCLUSION: High omega-3 levels and omega-3% may reduce the risk of MDs, whereas a high omega-6:omega-3 ratio may elevate the risk. These findings highlight the potential of PUFAs, particularly omega-3, in MD prevention and treatment, while underscoring the need for further research into the complex interactions between omega-3 and omega-6. The study provides a scientific foundation for future clinical trials and dietary intervention strategies. SYSTEMATIC REVIEW REGISTRATION: PROSPERO no. CRD42024598472.

Humans↗
PubMed2026

Cannabis and cannabinoids for the treatment of mental and substance use disorders and symptoms: A systematic review and meta-analysis of experimental and observational studies.

BACKGROUND: Interest in cannabinoids for mental and substance use disorders is increasing. We examined experimental and observational evidence for treating these disorders and their symptoms. METHODS: Systematic review and meta-analysis (PROSPERO CRD42023467536). We searched CENTRAL, MEDLINE, Embase and PsycINFO to May 2025 for studies of cannabinoids in adults (&#x2265;18 years) with ADHD, anxiety, depression, PTSD, psychosis or Tourette syndrome, or alcohol, cannabis, opioid or tobacco use disorders. Two reviewers screened, extracted and assessed quality using a risk-of-bias tool and GRADE. RESULTS: We included 82 experimental and 118 observational studies. In RCTs, cannabinoids reduced anxiety symptoms (SMD=-0.40; 95% CI: -0.57, -0.23; I&#xb2;=90%) and, in one small trial, PTSD symptoms (SMD=-2.60; 95% CI: -4.58, -0.62; n=20), with trivial-to-no effect on depression (SMD=-0.20; 95% CI: -0.43, 0.04; I&#xb2;=91.6%), ADHD, psychosis and Tourette syndrome. Much anxiety and depression evidence came from symptoms measured as secondary outcomes in other primary conditions. Cannabinoids worsened cannabis use disorder severity in one RCT (SMD=2.35; 95% CI: 1.49, 3.21), with no effect on craving or withdrawal; evidence for alcohol, opioid and tobacco use disorders was very limited. Observational studies suggested improvements but had high risk of bias. The only significant safety finding was increased withdrawals due to adverse events with THC (OR=2.78; 95% CI: 1.66, 4.65). Certainty was predominantly very low. DISCUSSION: The evidence base shows very low certainty, high heterogeneity and methodological limitations, and is insufficient to support cannabinoids as first-line treatment. Signals for anxiety and PTSD are limited by indirectness and low certainty; no benefit was evident for depression; THC-related safety signals warrant careful consideration.

Humans↗