Medicinal cannabis for treating post-traumatic stress disorder and comorbid depression: real-world evidence

Evidence base for use in PTSD

Given the increasing adoption of CBMPs as a treatment for PTSD there have been surprisingly few clinical trials on the efficacy of CBMPs for this indication. Several comprehensive and influential systematic reviews¹³ have been able to identify only one randomised controlled trial (RCT) of CBMPs for PTSD and, although this showed promising effects of nabilone in improving global functioning and reducing nightmare frequency, it was based on only 10 (male) participants and did not include any assessment of PTSD symptomatology.¹⁴ Since then, one further RCT of smoked cannabis which employed a cross-over design reported that although different cannabis preparations were well tolerated and were associated with improvements in symptomatology, the level of improvement was no greater than that experienced when using placebo.¹⁵ Thus, there is little, if any evidence from clinical trials to support the use of CBMPs to treat PTSD.

Nonetheless, real-world studies capitalising on the widespread use of medicinal cannabis to treat PTSD have reported promising results: in our own Project Twenty21 registry study¹ we reported that, after 3 months, there had been a substantial reduction in symptoms of PTSD (estimated effect size, Cohen’s d = 0.69; 95% CI 0.42–0.95) assessed using the PTSD Checklist – Civilian Version (PCL-C).¹⁶ Similarly, Pillai et al¹⁷ reported reductions in PTSD symptomatology after commencing CBMP treatment, with effects sizes at 1, 3 and 6 months varying between 0.30 and 0.50 for the avoidance, intrusion and hyperarousal subscales of the Impact of Event Scale – Revised (IES-R), as well as for the total IES-R score.¹⁸ Nacasch et al¹⁹ also reported positive effects of CBMPs for people with PTSD, albeit in a smaller sample.

Given promising preliminary findings about the potential utility of CBMPs for PTSD and their growing use for this indication despite a relative lack of high-quality empirical research testing their efficacy and effectiveness, there is a need for more research, including both trials and real-world studies, of the effects of these drugs. Although RCTs are typically considered the gold standard of medical evidence²⁰ they are not without shortcomings:²¹ they can be prohibitively expensive and are typically based on relatively small sample sizes with brief periods of treatment. Further, they typically apply extensive exclusion criteria, an approach that may threaten the external validity of findings from these trials.²⁰ Specifically, it is common practice for trials focusing on a specific condition to exclude individuals with comorbid psychiatric or other health conditions.^22,23

However, epidemiological research has consistently shown that there are high levels of comorbidity between PTSD and major depressive disorder (among other disorders), with estimates typically suggesting that a minimum of half those with PTSD will also meet criteria for major depressive disorder, and these rates are likely to be even higher in treatment-seeking samples.²⁴ If future trials exclude patients with major depressive disorder they may inadvertently study a sample of people unrepresentative of those seeking treatment, with the consequence that their results may not be representative of treatment effects that would be obtained in the real world.

Recruitment strategy and consent

An individuals must have an established diagnosis and evidence of failure of at least two treatment approaches before being eligible to legally receive prescribed CBMPs in the UK. Only specialist medical practitioners can prescribe CBMPs but patients can self-refer to a prescribing physician.

Patients making an appointment at one of the clinics affiliated with T21 were invited to participate in the registry. There were no inclusion or exclusion criteria specifically for participation in the registry: decisions about the suitability of CBMPs for a specific individual were entirely the responsibility of the treating physician. All individuals agreeing to participate in the registry provided written consent.

Prescribers partnering with T21 have access to a formulary that contains a range of CBMPs, including oils and flower of differing CBD and THC concentrations. However, there are no restrictions on what products can be prescribed and products from outside the formulary are also prescribed.

Between the start of the project (August 2020) and 1 November 2023 a total of 4036 individuals had contributed data to T21. During the first phase of the project, patients were recruited only if they were seeking treatment for any of eight categories of primary condition: anxiety disorders, chronic pain, multiple sclerosis, PTSD, Tourette syndrome, epilepsy, substance use disorder and attention-deficit hyperactivity disorder. However, from February 2022 all patients receiving a prescription of CBMPs were eligible to participate in the registry, regardless of their primary condition. The most common primary conditions were chronic pain (49.4% of the sample), anxiety disorders (42.4%) and PTSD (5.9%).

Measures

As part of their clinical assessment, in addition to providing information on their medical history, including past and current treatments, patients complete structured assessments of symptomatology. The measures used in the current analyses are as follows.

Patient characteristics

Prescribed CBMPs

The medical record contained information on what CBMPs were prescribed for each individual. We report information on the number of products prescribed for each participant. Further, we report the total number of different products prescribed to all participants and classify these according to their form (oil or flower) and relative THC and CBD ratios (CBD dominant, balanced and THC dominant). The percentage of prescriptions falling into each of these six categories is reported.

Statistical analysis

First, we examined the prevalence of our probable diagnosis of major depressive disorder in the sample of people with a primary diagnosis of PTSD and compared severity of PTSD symptomatology, sociodemographic characteristics (age, gender) and measures of general well-being between the two groups. Differences in categorical values (e.g. gender) were assessed using the chi-squared (χ²) statistic, and differences in mean ratings (e.g. quality of life) were conducted using one-way analysis of variance (ANOVA). These analyses were conducted on all participants with PTSD as their primary condition who have data available at baseline.

We compared the total number of CBMPs prescribed to the two groups using one-way ANOVA and the percentage of participants in each group receiving the six categories of CBMP described above (CBD-dominant oil, balanced oil, THC-dominant oil, CBD-dominant flower, balanced flower, THC-dominant flower) using χ².

We then compared changes in the severity of PTSD symptomatology between starting treatment and 3-month follow-up for those with or without secondary depression. Repeated-measures general linear models were used to estimate the between-individuals factor of depression, the within-individual factor describing changes between baseline and follow-up and the interaction between these two factors. These analyses include age and gender as covariates.

All analyses were conducted in SPSS version 29.0.1 for Windows.²⁹

Comparisons between those with PTSD with and without depression

Table 1 compares the severity of PTSD symptomatology, measures of quality of life and sociodemographic characteristics between participants with PTSD with and without depression.

Participants with PTSD and comorbid depression reported substantially higher levels of PTSD symptomatology than those without depression (mean 67.8 v. 48.4; F_(1,236) = 118.5, P < 0.001). They also reported lower well-being across three indicators: quality of life (F_(1,238) = 22.0, P < 0.001), general health (F_(1,238) = 20.4, P < 0.001) and sleep (F_(1,238) = 82.3, P < 0.001). The prevalence of depression was higher among females (87.1%) than among males (71.7%, χ²₁ = 7.7, P < 0.01) but there were no age differences between the two groups.

Types of CBMPs by depression status

There were no differences between individuals with comorbid depression and remaining sample members in terms of the total number of CBMPs they were prescribed: those with depression received an average of 2.1 products whereas those without depression received an average of 2.0 products (F_(1,105) = 0.01; P > 0.70). The most commonly prescribed category of CBMP was THC-dominant flower, with 74.8% of our PTSD sample receiving a prescription for at least one of these products. However, there were no differences between those with or without comorbid depression in the percentages of people receiving specific types of product (all P > 0.10).

Differences between those retained and those lost to follow-up

Data on PTSD symptomatology were available at treatment entry and at 3 months for 114 individuals, representing 48.3% of those for whom baseline data were available. Missing data at 3 months occur as a function of two processes: withdrawal from the study (either because participants cease medicinal cannabis use or continue using medicinal cannabis but do not contribute data to the project) and analyses occurring before all enrolled individuals have been in the study for 3 months and have therefore not yet been eligible for follow-up. Those who contributed data at 3 months did not differ from those not contributing data on any measure of symptom severity, sociodemographic characteristics or quality of life and well-being at entry, as summarised in Table 2.

Interpretation of our findings and comparison with the literature

In this sample, treatment with CBMPs is associated with significant improvements in well-being and quality of life in PTSD after 3 months of treatment¹ and these improvements in well-being are maintained in patients with psychiatric disorders, including PTSD, or chronic pain for up to 12 months (unpublished results: further details available from M.T.L. on request). These results parallel previous findings for quality of life across a broad range of conditions³⁰ and for PTSD specifically¹⁷ and highlight the potential benefits of CBMPs for symptom reduction and improvements in well-being across a wide range of chronic conditions.

Importantly, our findings add to this emerging literature by indicating that the presence of comorbid depression is associated with a greater reduction in PTSD symptomatology. This finding is in sharp contrast to findings from a recent meta-analysis of trauma-focused psychotherapy for the treatment of PTSD which indicated that comorbid depression is associated with a reduced efficacy of this treatment.³¹ Although both anti-depressants, particularly SSRIs, and psychological therapies, including prolonged exposure and cognitive–behavioural therapy, have been shown to be effective for treating PTSD, many people do not respond to these treatments and there is a considerable unmet treatment need. The current results suggest CBMPs may have a role in addressing this unmet need, while there is parallel evidence indicating that psychedelics, including 3,4-methylenedioxymethamphetamine (MDMA), may also be effective in treating PTSD. Notably, Mitchell et al,³² who demonstrated high efficacy for MDMA, did not exclude people with major depression from their clinical trial and, in fact, reported a high prevalence (91.1%) in their sample.

The apparent increase in effectiveness of CBMPs for those with comorbid depression may reflect a number of processes. First, there may be a reciprocal or asymmetrical relationship between changes in depression symptoms and PTSD symptoms. Evidence suggests that the relationship between changes in depression and PTSD symptoms may be affected differently depending on treatment modalities.^33,34 Further, there is preliminary evidence suggesting that CBMPs may be effective in treating depression³⁵ and that reduced depressive symptomatology may be associated with a similar reduction in PTSD symptomatology. Similarly, there is some level of symptom overlap between PTSD and major depression³⁶ and it may be that those transdiagnostic symptoms are especially responsive to treatment with CBMPs. Indeed, the high degree of comorbidity and symptom overlap between PTSD and major depression has led to suggestions that the comorbid condition may be a distinct subtype of PTSD.³⁶ Alternatively, the greater improvement observed in those with comorbid depression may be a reflection of the greater severity of PTSD symptomatology at the start of treatment in this comorbid group.

Implications for future trials

Our findings have implications for the design of future trials of CBMPs in the treatment of PTSD and other conditions. Specifically, it is common (although not universal) for such trials to exclude people with comorbid major depression or other psychiatric or general health conditions.²¹ The current findings suggest that this approach risks potentially recruiting a sample who are unrepresentative of patients with a specific condition (e.g. less than a quarter of patients in this sample would be eligible for participation in a trial even if the only exclusion criteria was depression). Additionally, our finding that CBMPs were significantly more effective for those with depression suggests that the application of exclusion criteria may result in the recruitment of participants who are least likely to benefit from CBMPs. This possibility may help explain the apparent discrepancy between real-world studies and RCTs, in which results from observational studies have typically reported more promising effects of CBMPS.³⁷ For example, the meta-analysis reported by Black et al¹³ included trials of cannabinoids for the treatment not only of PTSD but also of a range of additional psychiatric disorders, including depression, anxiety, tic/Tourette syndrome, attention-deficit hyperactivity disorder and psychosis. They concluded that there was no evidence that pharmaceutical THC (with or without CBD) improved any psychiatric outcomes other than anxiety occurring within the context of other medical conditions, and one study suggested that it increased negative symptoms in psychosis. They also reported that pharmaceutical THC increased adverse events and withdrawals from treatment. However, medicinal cannabis prescriptions in the UK now are increasingly for whole-plant extracts that have other constituents that may also be functional via the entourage effect.³⁸

Risk of drug–drug interactions

There are concerns regarding the potential ability of CBMPs to engage in clinically significant drug–drug interactions (DDIs) with commonly prescribed medications, including antidepressants, owing to their involvement with the cytochrome P450 (CYP450) system.³⁹ This is of relevance in the context of PTSD and depression as patients often concurrently use other medications. Some studies suggest that CBD and THC may inhibit CYP450 isoenzymes,^39,41 which play crucial roles in the metabolism of many pharmaceutical drugs. This inhibition could lead to altered drug concentrations and potentially affect the efficacy and safety of concurrently used medications. Although the drug–drug interactions between cannabinoids and various drugs at the CYP level are reported in vitro, their clinical relevance remains unclear.⁴¹ Prescribers should carefully monitor patients using CBMPs in conjunction with drugs metabolised by the CYP450 pathway to mitigate the risk of adverse interactions. Real-world evidence can play a key role in understanding the clinical relevance of these interactions and contribute to the development of informed clinical guidelines for the concurrent use of CBMPs and other medications for depression/PTSD.

We thank participants for contributing and allowing us access to their data.