PTSD

Cannabinoids show hardly any evidence for improving depression, anxiety disorders, ADHD, Tourette syndrome, PTSD or psychosis; only very weak evidence for small improvement of anxiety symptoms in other conditions, but increased side effects.

Comprehensive SR + meta-analysis of medical cannabinoids (cannabis, pharmaceutical cannabinoids, THC, CBD) in mental disorders (depression, anxiety, ADHD, Tourette, PTSD, psychosis); databases 1980–2018. Primary outcomes: remission and symptom change. Evidence synthesis via random-effects meta-analyses (OR for remission/adverse events, SMD for symptom change). GRADE quality assessment. Included for PTSD as one of the indications examined.

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; PTSD was evaluated as an indication, but only in 1 RCT with n=10 (very low evidence, no significant effects). Main evidence for chronic pain, MS spasticity, chemotherapy-induced nausea. For PTSD: insufficient data.

Cannabis was associated with reduction of PTSD symptoms and improved quality of life, but some patients experienced worsening of PTSD symptoms; evidence is based mainly on low-quality studies with high risk of bias.

Systematic review specifically on cannabis for PTSD; analyzes RCTs and observational studies, shows indications of symptom reduction (nightmares, hyperarousal) amid heterogeneous data, methodologically sound evidence synthesis.

Trauma-focused treatments showed greater PTSD symptom reductions than non-trauma-focused treatments, independent of cannabis use at baseline.

IPD meta-analysis across k=4 RCTs from Project Harmony (subset n=410, 33.2% cannabis users) on trauma-focused (TF) vs. non-TF therapies in comorbid PTSD+SUD. TF treatment showed greater PTSD symptom reduction than non-TF — independent of cannabis use — but lower attendance rates. Alcohol and drug outcomes similar across all conditions.

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 across k=8 studies (n=316) on CBD in anxiety disorders (GAD, SAD, PTSD); significant effect of CBD on anxiety with Hedges' g=-0.92 (95% CI -1.80 to -0.04). Caution advised in interpretation due to limited sample size.

Cannabis and synthetic cannabinoids show potential therapeutic benefit for improving PTSD symptoms, but current evidence regarding safety and efficacy is limited.

Systematic review of medical cannabis and synthetic cannabinoids in PTSD (PRISMA-compliant, PubMed/Cochrane/Web of Science up to May 2019). Cannabis and synthetic cannabinoids show therapeutic potential for improving PTSD symptoms (anxiety reduction, modulation of memory-associated processes, sleep improvement) through action on the endocannabinoid system. Evidence on safety and efficacy is currently limited; further research is required.

The observational studies found that cannabis did not reduce PTSD symptoms compared to non-use.

Systematic review on plant-based cannabis for PTSD (up to March 2017); k=5 studies identified (2 SRs, 3 observational studies, 0 RCTs). Observational studies showed that cannabis did NOT reduce PTSD symptoms compared to non-use. Overall evidence rated as insufficient evidence for conclusions on benefit and harm; moderate to high risk of bias. 2 RCTs and 6 further studies underway (as of 2017).

Cannabinoids may possibly reduce PTSD symptomatology, particularly sleep disturbances and nightmares, but the quality of evidence is low.

Systematic review on cannabinoids in PTSD, k=10 studies (only 1 RCT, remainder observational studies/case reports). All identified studies had medium to high risk of bias and low quality. Cannabinoids may reduce PTSD symptomatology, particularly sleep disturbances and nightmares. Evidence insufficient for clinical practice recommendations; well-controlled RCTs urgently needed.

CBD showed anxiolytic effects in healthy and certain clinical populations without prominent effects on sleep, with an inverted U-shaped dose relationship and the CBD-to-THC ratio moderating the effects.

Systematic review on cannabinoids in anxiety disorders with particular focus on sleep disorders; includes PTSD-relevant data on anxiolytic effects and sleep quality, methodically robust systematic data extraction.

In PTSD without comorbid cannabinoid disorder, 5 of 10 studies showed benefit and 5 showed no effect or worsening; in comorbid disorder all 3 studies showed risks of symptom worsening; some benefits observed for cluster B and E symptoms.

Systematic review on cannabis/cannabinoids in PTSD (January 1990–February 2023); k=14 studies (3 in comorbid PTSD+CUD sample, 11 in non-CUD sample). Of 10 studies on overall PTSD symptoms (non-CUD): 5 reported benefit, 5 no effect or worsening. 4 studies showed benefit for cluster B and E symptoms. All 3 studies with comorbid CUD reported risks of symptom worsening. No substantial benefits for overall PTSD symptoms; some risks regarding suicidality and violent behaviour.

Oxytocin showed normalized brain connectivity and improved functions in emotional and cognitive regions; hydrocortisone had no effects; THC reduced amygdala activity, but the evidence is preliminary.

Systematic review on functional brain changes under alternative pharmacotherapies in PTSD; k=16 fMRI studies (11 oxytocin, 2 hydrocortisone, 3 THC). THC administration associated with amygdala reduction and increased medial prefrontal cortex activation; oxytocin normalized vmPFC-amygdala connectivity.

Pure CBD shows a moderate effect (SMD -0,61), delta9-THC shows a moderate significant effect (SMD -0,65), CBD/delta9-THC mixtures show no significant effect; overall limited and low evidence quality.

SR + meta-analysis of k=21 placebo-controlled RCTs on cannabinoids in anxiety disorders and related conditions, including 7 PTSD studies. For pure/enriched Δ9-THC preparations, moderate significant effect (SMD=-0.65, 95% CI: -1.06/-0.24) favoring THC-dominant formulations; pure CBD preparations SMD=-0.61 (95% CI: -1.15/-0.07). Substantial heterogeneity across outcomes (clinical symptoms, neuroimaging, tolerability).

Majority of studies (n=37 of 45) showed significant association between RCU and PTSD; direction of effects variable and possibly bidirectional.

Systematic review on recreational cannabis use and PTSD; k=45 studies, of which n=37 with significant association. Findings support both self-medication and high-risk models; association probably bidirectional. Methodological variability (particularly non-standardized cannabis assessments) complicates comparability.

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 studies n=23, 30% RCTs n=17, 18% cross-sectional n=10, 12% other n=7). MASTER score mean=62.9/100 (high risk of bias). Among the 13 studies of highest quality: 70% (n=9) positive improvement in GAD, SAD and PTSD; 30% (n=4) negative results in OCD, trichotillomania, test anxiety and SAD. Over 90% of all studies report positive outcomes for CBD- and THC-based cannabis; 53% (n=30) missing or self-reported data on form/dosage.

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 THC/CBD in affective disorders, anxiety disorders and PTSD; k=8 controlled studies identified. For PTSD: one crossover study (n=10) showed THC-associated reduction of self-reported nightmares in PTSD patients under standard pharmacotherapy. Conclusion: insufficient evidence for efficacy of cannabinoids in PTSD; medical cannabis not recommended.

No significant differences between active cannabis concentrations and placebo in the change in PTSD symptom severity after 3 weeks.

First randomized, placebo-controlled trial of smoked cannabis in PTSD; n=80 US veterans, cross-over design with 3 active concentrations (High THC ≈12%, High CBD ≈11%, THC+CBD ≈8%/8%) vs. placebo over 3 weeks. No significant difference in PTSD symptom reduction between active arms and placebo in Stage 1; all groups including placebo showed significant improvement (p<0.001 within groups). Good tolerability of all concentrations.

Cannabis use and drug use significantly increase dropout risk and worsen treatment outcomes in PTSD therapy.

n=200 PTSD patients (chronic PTSD, PE vs. sertraline): current cannabis use significantly predicted higher dropout risk from PTSD treatment (OR=3,38) and worse adherence to Prolonged Exposure (β=-0,22 to -0,29, p<0.05). Drug use severity predicted worse treatment outcome (β=-0,22). Cannabis/drug use = significant risk factor for treatment dropout and reduced PTSD symptom reduction.

THC reduced threat-related amygdala reactivity, increased mPFC activation and enhanced mPFC-amygdala coupling in adults with PTSD.

n=71 (19 PTSD patients, 27 trauma-exposed controls without PTSD, 25 healthy controls); randomized, double-blind, placebo-controlled. Acute low dose of THC in PTSD patients: reduced threat-associated amygdala reactivity, increased mPFC activation during threat, enhanced mPFC-amygdala coupling (fMRI). THC modulates threat-associated processing in PTSD.

THC showed effects on neural activation (vmPFC and amygdala) in PTSD patients during extinction learning and fear renewal, but no significant effects on behavioral fear indicators.

RCT with n=71 (PTSD n=19, trauma-exposed controls n=26, healthy controls n=26); randomized to low-dose oral THC (n=34) vs. placebo (n=37) before extinction learning. PTSD patients under THC showed greater vmPFC activation during early extinction learning and greater amygdala activation during fear renewal (vs. placebo). No significant effects on behavioral fear indices.

CBD showed good tolerability but no superiority over placebo for drinking amount, craving, mood, anxiety or PTSD symptoms in both studies.

Two proof-of-concept RCTs (Study 1: n=27 AUD, Study 2: n=30 AUD+PTSD/subthreshold PTSD); CBD up to 1200 mg/day vs. placebo over 4–6 weeks. CBD well tolerated, but NO superiority vs. placebo for alcohol outcomes, craving, anxiety or PTSD symptomatology (both groups showed large drinks-per-day reductions, Cohen's dz >0.9). 22.6% of CBD participants experienced dose-limiting side effects.

THC reduced negative affect and normalized PTSD-associated differences in corticolimbic activation during emotional reappraisal.

Double-blind RCT (n=51 trauma-exposed individuals with/without PTSD). THC vs. placebo before cognitive reappraisal task in fMRI. THC reduced negative affect during reappraisal; THC normalized angular gyrus activation in the PTSD group to the level of the trauma control group (no longer a significant group difference under THC). Higher PCC/precuneus activation under THC associated with lower self-reported negative affect (p<0.05). THC effects on dmPFC and cerebellum also significant. First RCT evidence for THC as a pharmacological adjuvant to cognitive reappraisal therapy in PTSD.

CBD 300 mg did not significantly reduce anxiety, distress, or heart rate in response to trauma scripts compared to placebo, either acutely or after 1 week of repeated administration.

n=42 trauma-exposed adults with elevated stress, 300 mg CBD daily vs. placebo over 1 week; CBD did NOT significantly reduce anxiety (B=13.37, p=0.096, d=0.09, BF₁₀=0.54), distress (B=15.20, p=0.197, d=0.07, BF₁₀=0.51) or heart rate (B=-1.09, p=0.755, d=0.02, BF₁₀=0.29) following idiographic trauma script presentation compared to placebo — neither acutely nor after repeated administration.

5 mg THC showed increased brain activation in ACC and PFC during early fear renewal after 24 h; 10 mg THC showed increased hippocampal activation during extinction recall and PFC activation during fear renewal after one week – dose-dependent effects on fear memory processes.

RCT, n=36 adults with PTSD, randomized to placebo (n=11), 5 mg THC (n=11) or 10 mg THC (n=14) before extinction learning. 24h after THC administration: 5 mg THC → increased ACC and PFC activation during early fear renewal. One week later: 10 mg THC → increased hippocampal activation during extinction recall and PFC activation during fear renewal. Dose- and timing-dependent effects on fear memory processes.

CBD significantly reduced cognitive impairment on the VAMS scale with the effect still present 1 week after administration, but showed no significant differences from placebo in anxiety, alertness and discomfort as well as physiological parameters.

n=33 PTSD patients (SCID-5 diagnosis), CBD 300 mg vs. placebo before trauma recall. CBD significantly dampened the increase in the VAMS factor cognitive impairment during trauma exposure, effect persisted 7 days after single-dose administration. No significant differences in anxiety, alertness or physiological parameters (blood pressure, heart rate, cortisol).

CBD (300 mg) dampened anxiety and cognitive impairment during trauma recall only for non-sexual, but not for sexual trauma.

n=33 PTSD patients, randomised 1:1 to CBD 300 mg oral vs. placebo before trauma memory recall; in the non-sexual trauma group, CBD significantly dampened the anxiety-related increase (significant group differences for anxiety and cognitive impairment); in the sexual trauma group, the differences were not significant.

Nabilone reduced PTSD-associated nightmares significantly more than placebo.

n=10 male military personnel with PTSD and treatment-refractory trauma-related nightmares; nabilone 0,5–3,0 mg vs. placebo (7-week crossover); CAPS nightmare score: −3,6 ± 2,4 (nabilone) vs. −1,0 ± 2,1 (placebo; p=0,03); CGI-C: 1,9 vs. 3,2 (p=0,05); well-being score: +20,8 vs. −0,4 (p=0,04); 50% much improved under nabilone vs. 11% under placebo.

72% of patients experienced cessation or significant reduction in nightmare intensity under nabilone.

Open-label study on nabilone in treatment-resistant nightmares, n=47 PTSD patients (2004-2006). 72% of patients showed either complete cessation of nightmares or significant reduction in intensity. Subjective improvements in sleep duration, sleep quality as well as reduction of daytime flashbacks and nighttime sweating reported.

Open pilot study (no control arm, n=10 patients with chronic, treatment-resistant PTSD) with oral Δ9-THC (2x 5 mg/day) as add-on therapy. Significant improvement in global symptom severity, sleep quality, nightmare frequency and hyperarousal; only mild side effects in 3 patients, no discontinuations. Preliminary evidence: very small, uncontrolled sample, primarily a tolerability and safety endpoint.

Systematic review (PRISMA, GRADE assessment) on the efficacy of cannabis and cannabinoids in psychiatric indications, including PTSD, agitation in Alzheimer's dementia, and Tourette syndrome. Of 170 screened publications, 29 were qualitatively synthesized, of which 13 concerned efficacy in humans. Central finding: for none of the three indications were randomized controlled trials available; only qualitatively poor studies (observational studies, case reports) were available. The authors assess the strength of evidence for a therapeutic benefit as insufficient. Important caveat: negative or non-robust evidence picture, no statement on efficacy possible (literature status up to 2015).

Cannabis use was associated with significantly greater PTSD symptom reduction and a higher remission rate.

n=150 PTSD patients (73% male), prospective observation over 1 year: cannabis users (dispensary) vs. cannabis non-users. Cannabis group showed a greater reduction in PTSD symptom severity (group×time interaction=-0,32; 95% CI=-0,59 to -0,05; p=0,02). Cannabis users 2,57× more likely to be without a DSM-5 PTSD diagnosis at study end (95% CI=1,12–6,07; p=0,03).

Higher THC:CBD ratio significantly improves neuropathic pain, insomnia and depression, but not anorexia and PTSD flashbacks; anxiety benefits most from a 1:1 ratio.

Retrospective real-world study (n=2.431, 26.150 observations): Higher THC:CBD ratio not significantly associated with improvement of PTSD flashbacks OR=1,43 (95% CI 0,60–3,41; p=0,415). Negative finding: THC:CBD ratio without significant benefit for PTSD flashbacks compared to lower ratio.

Cannabis use was significantly associated with more severe PTSD symptoms, more violent behavior and higher alcohol/drug use; restarting use showed an effect size of +0,34 on PTSD symptoms.

Longitudinal observational study, n=2.276 veterans with DSM-III/-IV PTSD (1992–2011), assessments at admission and 4 months after discharge. Cannabis use significantly associated with worse outcomes: higher PTSD symptom severity (p<0.01), more violent behavior (p<0.01), more alcohol/drug use (p<0.01). Starter group (cannabis onset after treatment) had the highest rate of violence (p<0.0001); effect size for PTSD symptoms was Cohen d=+0.34 for starters, and d=−0.18 for stoppers vs. never-users.

Significant improvements in PTSD symptoms, anxiety, sleep quality and general quality of life at all follow-up time points up to 18 months (p < 0,001).

UK Medical Cannabis Registry, n=269 PTSD patients over 18 months. Significant improvements in IES-R (PTSD symptoms), GAD-7 (anxiety), SQS (sleep quality) and EQ-5D-5L (quality of life) at all follow-up time points (p<0.001). Male sex associated with reduced chance of IES-R improvement (OR=0.51, 95% CI 0.28–0.94, p=0.034). Adverse events in 70 patients (26.02%), most common: insomnia (15.61%), fatigue (14.87%).

Medicinal cannabis users showed more PTSD symptoms and arousal following trauma cue as well as higher cannabis use, but less alcohol use than recreational users.

Online survey of n=1.971 veterans with cannabis use history; medical cannabis users (vs. recreational users) reported greater combat exposure (d=0.56), higher PTSD symptoms (d=1.02), increased subjective arousal upon cue exposure (d=0.25), higher cannabis use (d=0.40–0.42), but lower alcohol use (d=0.28).

n=404 medical cannabis users with self-identified PTSD, 11.797 symptom trackings over 31 months via Strainprint® app. Acute inhalation reduced all PTSD symptoms (intrusive thoughts, flashbacks, irritability, anxiety) by >50% immediately after use. Higher doses predicted greater reductions in intrusions and anxiety. Long-term analysis: baseline symptomatology remained constant over time, anxiety dosing increased over time (tolerance development). Limitations: self-selection, no PTSD diagnosis validation, no placebo control.

Baseline cannabis use was significantly positively associated with increased trauma-related intrusion symptoms after 6 months (beta=0,46); PTSD showed a significant prospective effect on cannabis use disorder after 12 months (beta=0,15).

n=361 post-9/11 veterans, prospective longitudinal study (baseline, 6 months, 12 months); cross-lagged panel model analysis. Baseline cannabis use significantly positively associated with 6-month intrusion symptoms (β=0.46, 95% CI 0.155–0.765); reverse association weaker (β=0.22, 95% CI -0.003–0.444). Baseline PTSD significantly associated with 12-month CUD (β=0.15, 95% CI 0.028–0.272). Cannabis use prospectively linked to higher severity of trauma-associated intrusion symptoms over time.

Patients with high PTSD scores used cannabis more often to improve sleep and for coping; the study examined associations, not the health consequences of this use.

Observational study on cannabis self-medication for sleep disturbances; shows increased usage frequency among PTSD patients for sleep improvement, correlative data without causal intervention.

Nabilone showed significant improvements in PTSD-associated insomnia, nightmares, PTSD symptoms and Global Assessment of Functioning as well as subjective pain improvement; enabled reduction of riskier medications without abuse evidence in the prison population.

Retrospective analysis of n=104 male prisoners with severe mental illnesses and PTSD under nabilone (mean 4,0 mg/day). Significant improvements in PTSD-associated insomnia, nightmares, PTSD symptoms and Global Assessment of Functioning (p-values not reported). Nabilone targeted on average 3,5 indications per patient. No evidence of abuse in this high-risk population.

Cannabis use was not associated with lower PTSD symptom severity; PCL-C values did not differ between users and non-users.

n=94 cannabis users vs. n=94 age- and gender-matched non-users among veterans with probable PTSD; mean PCL-C scores: users 59,2 vs. non-users 59,1 (no significant difference); no association between PTSD score and cannabis use frequency; result argues against the hypothesis that cannabis use is associated with lower PTSD symptom severity.

Cannabis was associated with a more than 75% reduction in PTSD symptom severity according to CAPS.

n=80 PTSD patients (New Mexico Medical Cannabis Program, 2009–2011); CAPS score comparison with cannabis vs. without cannabis: >75% reduction in PTSD symptom scores with cannabis use. Retrospective, uncontrolled survey; prospective RCTs pending.

Oral CBD was associated with a 28% reduction in mean PCL-5 score and symptom improvement in 91% of patients.

Retrospective case series (n=11 PTSD patients); oral CBD for 8 weeks; 91% (n=10) showed a decrease in total PCL-5 score; mean PCL-5 score decreased by 28% (from 51,82 to 37,14); no treatment discontinuation due to side effects.

Case report (n=1): A 10-year-old girl with post-traumatic stress disorder and resulting anxiety and sleep disturbance received cannabidiol oil. Under treatment, a sustained decrease in anxiety was observed as well as a steady improvement in sleep quality and duration, after classic medications had only partially worked and with considerable side effects. Very weak level of evidence: uncontrolled single case without comparison group.