By Ellen Feldman, MD

Altru Health System, Grand Forks, ND

Dr. Feldman reports no financial relationships relevant to this field of study.

SYNOPSIS: In a review of 83 eligible studies, researchers found little evidence to support the efficacy of cannabinoids to treat depressive disorders, anxiety disorders, or several other mental health disorders.

SOURCE: Black N, Stockings E, Campbell G, et al. Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: A systematic review and meta-analysis. Lancet Psychiatry 2019;6:995-1010.

One of the most common reasons given for seeking medicinal cannabinoid use is for treatment of a mental health disorder. Medicinal cannabis is legal in 33 states; quality research regarding this substance is necessary to provide individuals with full clinical guidelines and risk profiles.1

Recognizing this need, Black et al conducted a meta-analysis of 83 eligible studies regarding medical cannabinoids and mental health disorders. The authors used “medicinal cannabinoids” to cover all plant-based and synthetic derivatives of the cannabis plant; “medicinal cannabis” refers to any part of the cannabis plant; “pharmaceutical cannabinoids” are extracts with defined tetrahydrocannabinol (THC) with or without cannabidiol (CBD); and “pharmaceutical CBD” refers to extractions of CBD alone.

Eligibility criteria included studies that used medicinal cannabinoids of any type and remission or change in symptoms in at least one of the following disorders: depression, anxiety, post-traumatic stress disorder (PTSD), attention-deficit/hyperactivity disorder (ADHD), Tourette syndrome, and psychosis. In all studies, the mental health disorder was either primary or secondary to another medical problem. Adverse effects and study withdrawals were included in the analysis.

Using standard tools the Cochrane risk-of-bias tool2 and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE)3 researchers put the evidence from the controlled trials into one of four categories, ranging from “very low quality” to “high quality.” Within the 83 eligible studies, there were 50 randomized, controlled trials (RCTs). The median sample size across all diagnoses for RCTs ranged from 10 to 39 participants. Median length of the trials was four to five weeks. The most common substance investigated was pharmaceutical THC; the next most common was pharmaceutical CBD. The eligible studies that were not RCTs were observational and included prospective studies, chart reviews, and case studies.

Pharmaceutical THC (with or without CBD) was used in all but one RCT involving depression. In all studies, depression was not a stand-alone diagnosis but was secondary to a chronic medical problem (mainly chronic noncancer pain or multiple sclerosis [MS]). The pooled standardized mean difference (SMD) for a change in depressive symptoms associated with the use of pharmaceutical THC with or without CBD was 0.00 to 0.05 (95% confidence interval [CI], -0.20 to 0.17). Black et al explained that an SMD of 0.2 represents a small effect, 0.5 represents a medium effect, and 0.8 represents a large effect, meaning that pharmaceutical THC with or without CBD did not affect users with depression very much at all. The one RCT that concerned medicinal cannabis revealed no change in depressive symptoms in patients with chronic noncancer pain when compared to treatment with placebo.

Pharmaceutical THC with CBD beat placebo in a significant lowering of anxiety symptoms in seven studies involving patients with either chronic noncancer pain or MS. The SMD was -0.25 (95% CI, -0.49 to -0.01). However, the evidence GRADE was very low because of several factors, including reporting bias, and none of the respondents had received a primary diagnosis of anxiety. Two studies concerned CBD alone vs. placebo in the treatment of social anxiety; there was no significant improvement in symptoms.

Symptoms of ADHD did not show a significant change in one RCT of pharmaceutical THC with CBD vs. placebo. Two small RCTs compared pharmaceutical THC with CBD to placebo in treatment of Tourette syndrome and showed no significant effect on symptoms. One small study of 10 individuals with PTSD revealed pharmaceutical THC with CBD vs. placebo was associated with improved global functioning and reduced nightmares (SMD = -1.3; 95% CI, -1.48 to -0.77). One RCT of 24 individuals showed no change in positive symptoms of psychosis (such as hallucinations) with the use of pharmaceutical THC with CBD vs. placebo, but a worsening of negative symptoms, such as social isolation and withdrawal (SMD 0.36; 95% CI, 0.10-0.62). The remaining five RCTs of psychosis used CBD vs. placebo. There was no significant improvement noted in any primary outcomes, but the authors of one study involving 86 individuals reported an improvement in global functioning with an SMD of -0.62 (95% CI, -1.14 to -0.09).

Pooled results from all RCTs indicate pharmaceutical THC with CBD was associated with significantly more adverse effects in 10 studies (odds ratio [OR], 1.99; 95% CI, 1.20-3.29) vs. placebo and significantly more study withdrawals in 11 studies vs. placebo (OR, 2.78; 95% CI, 1.59-4.86). Adverse events were not recorded in this meta-analysis, but are known (from other literature) to increase the occurrence of depression, anxiety, and psychotic symptoms. The evidence GRADE for these findings was low to moderate. There were fewer studies of adverse effects and study withdrawal when CBD (one study) or medicinal cannabis (three studies) was compared with placebo, but none of these resulted in a significant difference. The researchers also did not state whether cannabis was the only treatment participants were using for their conditions.

COMMENTARY

The most striking conclusion emerging from this comprehensive review and meta-analysis regarding cannabinoids for the treatment of mental health disorders is how little we know. Standing in contrast to the lack of quality medical studies regarding mental health disorders and medical cannabinoids are high-quality, rigorous investigations regarding the use of this agent for chronic pain, neuropathic pain, and nausea and vomiting associated with chemotherapy, and spasticity associated with MS.4

In 2017, the National Academies of Sciences, Engineering, and Medicine released a comprehensive report reviewing and summarizing research since 1999 regarding recreational and medicinal cannabis use. The report summarized the relevant medical literature and ranked evidence for efficacy as well as adverse effects when using medicinal cannabinoids for a specific medical condition. Regarding mental health, the authors concluded there is “no evidence to support or refute a statistical association between cannabis use and changes in the course or symptoms of depressive disorder,” and there is moderate evidence of increased social anxiety disorder associated with regular cannabis use.5 In addition, the report noted substantial evidence of development of schizophrenia with heavy cannabis use and moderate evidence of more suicidal thoughts and attempts associated with heavy cannabis use.5

The work of Black et al strongly supports the idea that there remains no strong evidence for medicinal cannabis to treat depression, anxiety, ADHD, Tourette syndrome, or psychosis. Of note, with the exception of PTSD and Tourette syndrome, most of these conditions are not on a list of conditions qualifying for medicinal cannabinoid use in any state. However, 23 states currently specify PTSD as an approved condition for medicinal cannabinoids, and only five specify Tourette syndrome. In addition, in what appears to be a growing trend, at least six states allow physicians to certify a need for a dispensary card at the “discretion” of the provider.6,7

Considering the strong probability patients looking for alternative treatments will ask providers about medicinal cannabinoid use, it is useful to be armed with facts. There is no evidence showing medicinal cannabinoid use helps mental health disorders, and there are concerns that heavy use can cause mental health problems. There is weak evidence showing medicinal cannabinoid use is associated with a decrease in anxiety associated with a chronic health condition. Many states have preemptively approved medicinal use of cannabinoids for specific diagnosis without waiting for rigorous studies or medical evidence to prove their efficacy.

Medicinal cannabinoid efficacy is well-studied and established for specific disorders, but there is no convincing evidence this works for treating mental health disorders. The downside to using medicinal cannabinoids for a mental health disorder may be considerable. The primary care provider is well-situated to aid patients in understanding the current state of knowledge regarding medicinal cannabinoid use in disorders of mental health. However, it is important to urge caution and patience until enough evidence is gathered to reach firm conclusions.

REFERENCES

  1. World Population Review. States with medical marijuana. 2020.
  2. Cochrane Methods Bias. RoB 2: A revised Cochrane risk-of-bias tool for randomized trials. 2020.
  3. BMJ Best Practice. What is GRADE? 2019.
  4. National Academies of Sciences, Engineering, and Medicine. Therapeutic Effects of Cannabis and Cannabinoids. In: The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press (US); 2017.
  5. National Academies of Sciences, Engineering, and Medicine. Mental Health. In: The Health Effects of Cannabis and Cannabinoids: The Current State of Evidence and Recommendations for Research. National Academies Press (US); 2017.
  6. Leafly. Qualifying conditions for marijuana by state. Updated Jan. 29, 2020.
  7. Richter N. Qualifying conditions for medical cannabis (2020 update). Marijuana Break. Updated April 9, 2020.