Anxiety Disorders

Moderate evidence for chronic pain and spasticity, low evidence for nausea/vomiting, weight gain and sleep disorders; increased risk of side effects.

Comprehensive SR across 79 RCTs (n=6.462) on medical cannabis; NO sufficient evidence for anxiety disorders as a primary outcome — moderate evidence only for pain and MS spasticity, anxiety only as a secondary/exploratory outcome in some studies.

Adolescent cannabis use is associated with increased risk for later anxiety disorders and anxiety symptoms (OR = 2.14).

SR + meta-analysis across k=18 longitudinal studies (n=33.380) on adolescent cannabis use and later anxiety outcomes; meta-analysis of k=6 studies shows increased risk for later anxiety disorders (OR=2.14, 95% CI: 1.37-3.36, p<0.01). Qualitative synthesis of k=12 further studies: 9 of 12 found a significant association between adolescent cannabis use and later anxiety symptoms.

CBD showed a significant effect on anxiety disorders with a large effect size (Hedges' g = -0,92, 95% CI -1,80 to -0,04).

Systematic review + meta-analysis of CBD in anxiety disorders (GAD, SAD, PTSD); k=8 RCTs, n=316 participants. Significant effect of CBD on anxiety with large effect size (Hedges' g=-0.92, 95% CI -1.80 to -0.04, p<0.05). Limitation: limited clinical sample size.

CBD shows limited but potential therapeutic effect in selected psychiatric disorders, particularly substance use, psychosis and anxiety.

Systematic review (PRISMA) on CBD in psychiatric disorders; k=27 RCTs included (initial n=1.301 hits); limited but existing evidence for therapeutic efficacy in anxiety disorders; further large-scale RCTs required.

Overall insufficient evidence for efficacy of CBD and THC in affective disorders, anxiety disorders or PTSD; partial worsening with anxiety and psychotic symptoms observed in depression.

Systematic review on cannabinoids in anxiety disorders; k=8 controlled studies identified. For anxiety disorders: 1 study with THC ≤3 mg/day over 1 month showed symptom reduction in DSM-II anxiety disorder (baseline symptoms very low); 1 study with low-dose THC in social phobia with no symptom change; 2 studies with single-dose CBD administration reduced anxiety in laboratory paradigms in social phobia; 1 study with daily CBD over 4 weeks in adolescents with social phobia showed moderate improvement. Conclusion: insufficient evidence for efficacy of CBD/THC in anxiety disorders; medical cannabis not recommended.

Cannabis use significantly increases the risk for anxiety disorders overall, but not for individual anxiety disorder diagnoses.

SR+MA of 24 longitudinal studies (10 with OR data); cannabis use significantly associated with increased probability of developing anxiety disorders (OR=1,25; 95% CI 1,01–1,54). No significant association with generalized anxiety disorder, panic disorder, or social phobia in isolation. Causality cannot be established due to methodological heterogeneity.

In most observations (70,3%), CBD had no effect on anxiety disorders; there was no identifiable relationship between anxiety outcomes and substance concentrations across species.

Systematic review on CBD in anxiety disorders (preclinical + clinical); k=87 studies (PK/PD data across species). 70.3% of observations showed NO effect on anxiety outcomes; no consistent concentration-effect relationship identifiable. Anxiety-reducing effects clustered in certain concentration ranges, but differed across species. Bias assessment: SYRCLE's RoB + Cochrane RoB 2.0.

Tobacco use associated with mood disorders (RR 1,39), cannabis use associated with psychotic disorders (RR 3,19), but no clear evidence for cannabis and anxiety/mood disorders.

Systematic review and meta-analysis on cannabis/tobacco and incident psychiatric disorders; k=75 longitudinal studies. Cannabis use showed NO clear association with anxiety disorders (k=7; RR: 1.10, 95% CI 0.99-1.22). Only 27% of studies rated as high quality; confounder matrices and E-values suggest possible overestimation of effects.

Small positive association between anxiety disorders and cannabis use (OR 1,24) as well as between anxiety disorders and cannabis use disorders (OR 1,68); baseline cannabis use was associated with anxiety disorders at follow-up (OR 1,28).

Meta-analysis of k=31 studies (n≈112.000) on the association between anxiety disorders and cannabis use. Small positive association: anxiety↔cannabis use OR=1.24 (95% CI: 1.06-1.45, p=0.006), anxiety↔cannabis use disorder OR=1.68 (95% CI: 1.23-2.31, p=0.001). Prospective subgroup (k=5): baseline cannabis use predicts follow-up anxiety OR=1.28 (95% CI: 1.06-1.54, p=0.01). Adjusted for confounders.

Cannabinoids significantly reduced anxiety symptoms (SMD = -1.85), but after correction for publication bias the anxiolytic effect was no longer statistically significant.

Systematic review and meta-analysis on cannabinoids for anxiety disorders; k=14 RCTs (n=1.548, median age 33 years, 66% male). Cannabinoids reduced anxiety symptoms (SMD=-1,85, 95% CI [-2,61 to -1,09]) without significant side effects. Stronger efficacy in younger patients (p<0,01) and longer treatment duration (p<0,01). After correction for publication bias, the overall anxiolytic effect was no longer statistically significant.

70% of the highest-quality studies showed positive effects in GAD, SAD and PTSD, but 30% reported negative results in OCD, trichotillomania and test anxiety; long-term effects remain unclear.

Systematic review on medical cannabis in anxiety disorders; k=57 studies (40% cohort, 30% RCTs, 18% cross-sectional, 12% qualitative designs). Among the 13 highest-quality studies, 70% (n=9) showed positive improvements in GAD, SAD and PTSD; 30% (n=4) negative results in OCD, trichotillomania, test anxiety and SAD. Over 90% of all studies reported positive outcomes for CBD- and THC-based cannabis. MASTER score: 62,9/100 (high risk of bias due to insufficient reporting). 53% (n=30) of studies omitted or used self-reported data on form/dosage.

CBD and nabiximols show moderate to weak evidence depending on the psychiatric indication, with the strongest support for cannabis use disorder and schizophrenia.

Systematic review (k=23 studies) on CBD and nabiximols in psychiatric disorders; grade B recommendation for social anxiety disorder; grade C (weaker evidence) for generalized anxiety and bipolar disorder. CBD-containing compounds helped reduce symptoms of psychotic and cognitive disorders; moderate to weak evidence for anxiety disorders.

Early, mixed evidence with preliminary positive signals for CBD in social anxiety and schizophrenia, but insufficient data for a clinical recommendation.

Systematic review on cannabis/cannabinoids in psychiatric disorders (2019); tentative evidence for CBD in social anxiety disorder (positive single-study finding); mixed (predominantly positive) evidence for adjunctive use in schizophrenia; recommendation: caution with high-dose THC in anxiety disorders.

CBD showed improved clinical outcomes in several anxiety disorders, was well tolerated with minimal side effects, but evidence is limited and heterogeneous.

Systematic review on CBD in anxiety disorders; k=8 studies (6 small RCTs, 1 case series, 1 case report). Dose range 6-400 mg CBD oral/sublingual. CBD showed improvement on various anxiety assessment scales in healthy volunteers, generalized anxiety disorder, social phobia and the PTSD anxiety component. Well tolerated, minimal side effects. No studies on panic disorder, specific phobia, separation anxiety or obsessive-compulsive disorder identified.

CBD showed significant superiority over placebo in GAD-7 and HAM-A scores (p<0.0001) as well as in secondary endpoints (CGI-I, CGI-S, PHQ-9, PSQI) with good tolerability and without serious adverse events.

n=178, phase III RCT (double-blind, placebo-controlled, multicenter), nanodispersible CBD (150 mg/mL oral) vs. placebo over 15 weeks in mild to moderate anxiety disorder; primary endpoints GAD-7 (difference CBD vs. placebo: −7,02; 95% CI −7,52 to −6,52; p<0,0001) and HAM-A (difference: −11,9; 95% CI −12,6 to −11,3; p<0,0001) significantly improved; secondary outcomes (CGI-I, CGI-S, PHQ-9, PSQI) also positive; no serious adverse events.

CBD as augmentation to exposure therapy showed no significant difference to the placebo control group in the Fear Questionnaire over the course of treatment and the follow-up phase.

Double-blind, randomized, placebo-controlled study on CBD augmentation (300 mg oral) of exposure therapy in treatment-refractory anxiety disorders (panic disorder with agoraphobia, social anxiety disorder); n=80 (CBD n=39, placebo n=41), 8 weekly exposure sessions. No differences in the Fear Questionnaire (FQ) between CBD and placebo over time (β=0,32, 95% CI [-0,60; 1,25]) or within diagnostic groups (β=-0,11, 95% CI [-1,62; 1,40]). CBD did not improve either early therapy response or extinction learning. Adverse event rate: CBD 10,3%, placebo 15,4%.

No effect on worry and acute anxiety, but reduced anxiety symptoms with repeated 300mg CBD administration over 2 weeks.

n=63 individuals with elevated trait worry, CBD 300mg vs. CBD 50mg vs. placebo; no acute effects on worry or anxiety symptoms. After 2-week administration, CBD 300mg reduced physical anxiety symptoms vs. placebo, but not cognitive symptoms (worry). CBD anxiolysis specific to physical aspects of anxiety.

CBD 300 mg significantly reduces acute anxiety during public speaking, whereas 100 mg and 900 mg do not, demonstrating an inverted U-shaped dose-response curve.

n=60 healthy volunteers (18–35 years); CBD 100/300/900 mg vs. placebo vs. clonazepam 1 mg in a simulated public speaking test (TPSRS). CBD 300 mg significantly reduced anxiety scores compared to placebo in the post-speech phase (p<0.05); inverted U-shaped dose-response curve confirmed — CBD 100 mg and 900 mg without significant anxiolysis. Clonazepam more sedating than CBD 300/900 mg.

CBD 300 mg significantly reduced anxiety, higher and lower doses showed no effect versus placebo (inverted U-curve).

n=57 healthy male subjects, CBD 150/300/600 mg vs. placebo in simulated public speaking anxiety test (SPST); only 300 mg CBD significantly reduced anxiety vs. placebo (VAMS p<0.05); 150 mg and 600 mg showed no significant difference versus placebo — inverted U-shaped dose-response curve.

ICART led to a higher abstinence rate post-treatment, but therapy type did not moderate the effect on frequency of use and associated problems.

Pilot RCT (n=55; 56.4% male, M(age)=23.2 years) on integrated CBT for comorbid cannabis use disorder and anxiety disorders (ICART) vs. MET-CBT alone. ICART patients attended significantly more sessions and showed higher post-treatment abstinence rates. Both treatments reduced cannabis use and problems; no moderator effect of therapy type on frequency of use.

300 mg CBD daily significantly reduced social anxiety symptoms in teenagers compared to placebo.

n=37 Japanese adolescents (18-19 years) with social anxiety disorder and avoidant personality disorder, double-blind randomized: 300 mg CBD daily (n=17) vs. placebo (n=20) over 4 weeks. CBD significantly reduced anxiety on the Fear of Negative Evaluation Questionnaire and the Liebowitz Social Anxiety Scale (p<0.05). CBD could be a useful option for treating social anxiety.

CBD at doses of 150, 300 or 600 mg showed no effect on self-reported test anxiety or general anxiety during a statistics exam.

n=32 college students with moderate to severe test anxiety, randomized to CBD single doses (150/300/600 mg) vs. placebo. No significant effect of CBD on self-reported test anxiety or generalized anxiety during experimental exam situation; experimental manipulation validated (test anxiety successfully induced).

CBD mitigates THC-induced state anxiety, particularly in individuals with low baseline anxiety level.

n=26 healthy cannabis users, randomized placebo-controlled (within-subjects), vaporized THC (13,75 mg), CBD (13,75 mg), THC/CBD (13,75 mg/13,75 mg) vs. placebo. THC and THC/CBD significantly increased self-reported anxiety vs. placebo (p<0.05); THC/CBD-induced anxiety was significantly lower than after pure THC. At low baseline anxiety CBD completely neutralized THC-induced anxiety; at high baseline anxiety CBD showed no anxiolytic counter-effect.

Nabilone reduced anxiety symptoms significantly more than placebo (p<0,001).

Placebo-controlled RCT (n=25 anxiety patients, 28 days): nabilone (synthetic cannabinoid) vs. placebo — dramatic improvement on the Hamilton Anxiety Scale under nabilone (p<0,001). Side effects: dry mouth, dry eyes, drowsiness; no psychotropic experience (no "high" reported).

CBD 600 mg significantly reduced situational anxiety, cognitive impairment and negative self-statements in SAD patients compared to placebo.

n=24 treatment-naïve patients with social anxiety disorder (SAD), CBD 600 mg vs. placebo before simulated public speaking test. CBD group showed significantly reduced anxiety, cognitive impairment and discomfort (VAMS, p-values not specified); SSPS-N scores in the CBD group nearly identical to healthy controls (n=12), while the placebo group showed markedly higher anxiety values. Premedication with CBD led to a stress response similar to that of healthy individuals.

Smoked cannabis (THC or CBD) had no significant acute effect on OCD symptoms and led to less anxiety reduction than placebo.

n=12 OCD patients (adults), randomized crossover laboratory RCT with THC-containing cannabis, CBD-containing cannabis and placebo. OCD symptoms did not differ significantly between the cannabis varieties. State anxiety was significantly lower immediately after placebo than after THC and CBD — cannabis showed no anxiety reduction compared to placebo. First placebo-controlled finding on cannabis in OCD.

CBD significantly reduced subjective anxiety compared with placebo and showed specific effects on limbic and paralimbic brain regions.

n=10 treatment-naive patients with generalized social anxiety disorder (SAD), CBD 400 mg oral vs. placebo (double-blind cross-over); rCBF measurement via 99mTc-ECD SPECT. CBD significantly reduced subjective anxiety (p<0.001); reduced ECD uptake in left parahippocampus, hippocampus, inferior temporal gyrus (p<0.001, uncorrected); increased uptake in right posterior cingulate (p<0.001, uncorrected).

CBD led to a significant reduction in anxiety severity of 42,6% (OASIS score from 10,8 to 6,3) as well as significant improvements in depressive symptoms, clinical global impression, and functioning.

n=31 treatment-resistant adolescents/young adults (12-25 years) with DSM-5 anxiety disorders, 12 weeks CBD add-on up to 800 mg/day. OASIS scores decreased from 10,8 (SD=3,8) to 6,3 (SD=4,5), corresponding to -42,6% (p<0,0001). Depressive symptoms (p<0,0001), CGI-Severity (p=0,0008) and functional level (p=0,04) improved significantly. Side effects in 80,6% (fatigue, mood dips, temperature sensations), no serious unexpected events.

Medical cannabis card led to improved self-reported insomnia symptoms, but to higher incidence and severity of cannabis use disorder and no significant improvement in pain, anxiety or depressive symptoms.

n=269 adults with medical cannabis card (Massachusetts), 12-month follow-up; significant reduction in anxiety symptoms (PROMIS Anxiety T-score reduction -3.4 points, p0.001); observational data without control group, real-world evidence for affective disorders.

Delta9-THC increased anxiety and intoxication, while CBD showed a trend toward anxiety reduction with differing effects on brain activation and autonomic responses.

n=15 healthy subjects, fMRI during emotional face recognition; THC increases amygdala activation in response to fear stimuli, CBD reduces it — differential neural effects on fear networks.

CBD blocks the anxiety provoked by Δ9-THC as well as cannabis-like effects and other subjective changes caused by Δ9-THC.

Small crossover RCT (n=8 healthy volunteers) on CBD vs. THC-induced anxiety; CBD 1 mg/kg blocked THC-induced anxiety (measured with anxiety scales), but also showed antagonism against other THC effects. Diazepam 10 mg as positive control. CBD showed independent effects opposite to THC.

Daily adolescent cannabis use is associated with increased risk of anxiety disorder at age 29 years, but not consistently with depression.

15-year cohort study (n=1943): Daily cannabis use associated with anxiety disorder at age 29 years (OR=2,5; 95%-CI 1,2–5,2); cannabis dependence: OR=2,2 (95%-CI 1,1–4,4). Among weekly adolescent users who used daily by age 29: OR=3,2 (95%-CI 1,1–9,2). Association holds even after cessation of use (no protection through abstinence).

Cannabis use was prospectively associated with panic disorder, but this association was eliminated after controlling for daily cigarette smoking.

Prospective longitudinal study (n=1.709 adolescents, baseline age 16,6 years), follow-up into adulthood (mean 24,2 years); cannabis use and dependence significantly prospectively associated with increased odds for panic attacks and panic disorder. After controlling for daily cigarette smoking, no incremental effect demonstrable — no isolated proof of causality for cannabis.

Frequent cannabis use during adolescence significantly increases the risk of depression and anxiety disorders in young adulthood, especially with daily use in girls.

Prospective cohort study (n=1601, age 14–20 years): Daily cannabis use in young women associated with OR=5,6 (95%-KI 2,6–12,0) for anxiety disorder and depression in young adulthood (combined outcome). Weekly use: OR≈1,9 (95%-KI 1,1–3,3). Prior anxiety did not predict later cannabis use (no reverse causation).

Cannabis use shows only weak association with depression after adjustment; association with anxiety disappears after confounder control.

ALSPAC cohort study (n=4.561); cannabis use at 16 years showed after adjustment for confounders (including precursor anxiety, substance use) no significant association with anxiety disorders at 18 years. Negative finding with numerical confirmation (adjusted OR not >1 for anxiety).

CBMPs were associated with significant improvements in anxiety, sleep quality and health-related quality of life, particularly under dried flowers.

UK Medical Cannabis Registry: n=1378 patients with prescribed CBMPs, improvements in GAD-7 (anxiety) at all time points (1, 3, 6, 12 months; p<0.010); dried flowers or combination showed stronger improvements than oil alone (p<0.050); 21,55% of patients reported adverse events.

CBMPs were associated with significant improvements in anxiety symptoms and quality of life, but without a comparison group and with a relevant rate of adverse events.

UK Medical Cannabis Registry: n=67 patients with generalized anxiety disorder (GAD); significant improvements in GAD-7, EQ-5D-5L and Sleep Quality Scale at month 1, 3 and 6 (all p<0.050); 39.1% reported adverse events; no comparator — real-world data with limited causal inference.

Initiation of medical cannabis was associated with significantly reduced anxiety and depression symptoms.

n=368 medical cannabis users observed prospectively over 4 months; significant reduction in anxiety (GAD-7: −4.2 points, p<0.001) and depression (PHQ-9: −4.8 points, p<0.001); real-world data without placebo control.

45,2% of patients successfully discontinued benzodiazepines, with a stable abstinence rate over an average of 6 months.

n=146 medical cannabis patients (Ø 47 years, 61% female) with prior benzodiazepine medication. After an average of 2 months of cannabis therapy, 30,1% had discontinued benzodiazepines; after three prescription cycles (Ø 6 months) a total of 45,2% (n=66) had permanently discontinued. Indirect evidence for anxiolytic effect via benzodiazepine substitution.

Anxiety disorders showed marked improvement (79,2% persisting in the first month), while sleep quality was initially improved in 66,7% but fluctuated over time.

n=72 adults with primary anxiety (n=47) or sleep complaints (n=25), CBD as adjuvant to standard therapy. Anxiety scores decreased in the first month in 79,2% (n=57) and remained reduced over the study duration. Sleep scores improved initially in 66,7% (n=48), but fluctuated over the course. CBD well tolerated except in 3 patients. Validated instruments used, but no placebo control.

Preclinical evidence strongly supports CBD for several anxiety disorders with acute administration; clinical evidence is limited and restricted to acute dosing.

Narrative review on CBD in anxiety disorders; preclinical evidence strongly supports efficacy in generalized anxiety disorder, panic disorder, social anxiety disorder, obsessive-compulsive disorder and PTSD with acute administration. Human data confirm anxiolytic effect, though limited to acute dosing. Chronic dosing and clinical populations have so far been insufficiently studied. Conclusion: considerable potential, further controlled studies required.