Studies show that many people report using cannabis to relieve anxiety as one of the novel ‘self-medication’ options, especially those with anxiety-related disorders [1-3]. Medical cannabis has potential anxiolytic effects through the modulation of functional activity of the limbic and paralimbic brain regions as well as the endocannabinoid systems [4-6]. Human experimental studies have shown that acute dosing of cannabidiol (CBD) is effective for treating multiple anxiety conditions, including social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder and obsessive-compulsive disorder [5,6].
We conducted a systematic review of randomized clinical trials (RCTs) evaluating the efficacy and safety of medical cannabis for relieving anxiety (Scoping the Evidence) by searching Ovid Medline, Embase, and PsychInfo databases. In this OE Original, we present results of a meta-analysis outlining the evidence from a total of 19 eligible RCTs with 462 participants that provided an anxiety outcome measured on a standardized scale [6-24]. Table 1 shows the characteristics of the various types of cannabis products identified in the included studies, by their routes of administration and specific formulations.
Table 1. Characteristics of Treatments in the Included Studies
Notes: THC = delta-9-tetrahydrocannabinol; THCV = Tetrahydrocannabivarin; CBD = cannabidiol.
* A synthetic form of THC
What Does the Evidence Show?
The outcome of anxiety was measured on a 0-100 visual analogue mood scale (VAMS) anxiety subscale, 0-10 visual analogue scale for anxiety, 20-80 Zung anxiety scale (ZAS) and the state trait anxiety inventory (STAI) anxiety subscale, 0-4 Hamilton anxiety scale, 0-36 profile of mood states (POMS) anxiety subscale, 0-24 Hopkins symptom checklist (HSCL) anxiety subscale, 0-21 hospital anxiety and depression scale (HADS) anxiety subscale and 0-63 Beck anxiety inventory. We converted the scores from different scales to the 0-100 numeric rating scale for level of anxiety (0 = no anxiety, 100 = highest level of anxiety). No statistically significant differences were detected between cannabis and control groups on the effect of anxiety relief by the separate meta-analyses for different durations of follow-up (Table 2).
Table 2. Effects of Medical Cannabinoids for Anxiety Relief
Mean difference: -2.42 [-9.65, 4.80]. Based on data from 8 trials.
Notes: CI = confidence interval.
Below we present the effects by the different types of cannabinoids, when possible, at the two follow-up durations (Tables 3-4). Compared to placebo, CBD demonstrated acute effects of anxiety relief (mean difference, -12.02; 95% CI, -18.34 to -5.70; low quality of evidence); tetrahydrocannabivarin (THVC) increased level of anxiety (mean difference, 18.50; 95% CI, 10.06 to 26.94; low quality of evidence) within 4 hours’ follow-up. Based on the recommended minimum important difference (MID) of 10mm on a 0-100mm anxiety measurement scale , the short-term point estimates of difference in our findings reached the threshold of MID for CBD and THCV (Table 3).
Table 3. Differences in Level of Anxiety Compared to Placebo Within 4 Hours
Mean difference [95% CI]
Quality of Evidence
Difference > 10 points
Notes: NS = not significant.
Table 4. Differences in Level of Anxiety Compared to Placebo (1 to 8 weeks)
Mean difference [95% CI]
Quality of Evidence
THC & CBD
-1.79 [-6.63, 3.05] based on data from 83 subjects in 2 trials.
3.11 [-6.64, 12.86] based on data from 32 subjects in 1 trial.
-6.51 [-19.20, 6.17] based on data from 114 subjects in 4 trials.
7.62 [-9.60, 24.84] based on data from 13 subjects in 1 trial.
Notes: NS = not significant.
There is a lack of evidence between acute examination and six days’ follow-up, and longer than two months’ follow-up. During a follow-up period of 1 to 8 weeks, no significant differences were found for any types of medical cannabis compared to placebo (Table 3). Unfortunately, there was insufficient data for us to conduct any other subgroup analyses by dose or patient condition.
Adverse event (AE) data were available from 5 trials. Overall, the risk ratio was 1.28 (95% CI, 1.00-1.63) for medical cannabis relative to placebo, with the medical cannabis group having 41 / 76 (53.9%) and the placebo group having 30 / 73 (41.1%) patients report an AE. In one study following patients 2.5 hours after taking a single dose of 300 mg CBD, no AEs were reported . The most commonly reported AEs after treatment with cannabis included dizziness (30%), dry mouth (9%), nausea (6%) and fatigue (6%). Most of these symptoms were mild or moderate and subsided over time after stopping medication.
What’s the Bottom Line?
Our analysis showed acute anxiolytic effects with a single dose of 300mg to 600mg oral CBD, one of the major compounds from the Cannabis sativa L. plant (12.0 points less anxiety than placebo with 95% CI of 18.3 less to 5.7 less points on a 0-100 anxiety measurement scale, within 4 hours’ follow-up). The size of effects reached the threshold of MID. The result is consistent with findings from previous studies in both animals and humans indicating that CBD has anxiolytic properties [4-6].
On the contrary, our analysis showed anxiogenic effects with a single dose of 10mg oral THCV (18.5 points more anxiety than placebo with 95% CI of 10.1 more to 26.9 more points, within 4 hours’ follow-up) based on data from 1 trial . THCV is similar to THC by its molecular structure but not as much studied as THC because of the low concentration of THCV in a cannabis plant [1,26]. It will require more laboratory and clinical studies to explore THCV’s effects on anxiety. In our analysis, no significant differences were found for THC at short or longer durations of follow-up. Previous non-randomized studies suggest that THC might have anxiolytic effects at lower doses but lead to anxiogenic effects at higher doses; however, the threshold of high and low doses for THC of such different dose-dependent “biphasic” effects was not clearly reported [1,5,6,26,27]. One three-arm trial that enrolled a total of 42 participants with current or past cannabis use showed non-significant increase in anxiety with a single dose of 7.5 mg oral THC and significant increase in anxiety with 12.5 mg THC at 2.5 hours follow-up, compared to placebo . Due to an insufficient number of studies, we were not able to conduct a subgroup analysis for THC by dose.
No significant differences in anxiety were detected for CBD and THC at longer duration of follow-up. For synthetic cannabis of nabilone and dronabinol, no significant differences were found at either short or long-time follow-up.
Hot Topic for Future Research
More high-quality trials are needed to answer the remaining questions including optimal dosing (e.g., lower than 300 mg single dose to minimize side effects) and route of administration (e.g., oromucosal spray or smoked) for CBD to play a role in reducing anxiety, and the dose threshold of THC for its anxiolytic or anxiogenic effects.
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