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

Background

Cannabis-based medicinal products (CBMPs) are increasingly being used to treat post-traumatic stress disorder (PTSD), despite limited evidence of their efficacy. PTSD is often comorbid with major depression, and little is known about whether comorbid depression alters the effectiveness of CBMPs.

Aims

To document the prevalence of depression among individuals seeking CBMPs to treat PTSD and to examine whether the effectiveness of CBMPs varies by depression status.

Method

Data were available for 238 people with PTSD seeking CBMP treatment (5.9% of the treatment-seeking sample) and 3-month follow-up data were available for 116 of these. Self-reported PTSD symptoms were assessed at treatment entry and at 3-month follow-up using the PTSD Checklist – Civilian Version (PCL-C). The probable presence of comorbid depression at treatment entry was assessed using the nine-item Patient Health Questionnaire (PHQ-9). Additional data included sociodemographic characteristics and self-reported quality of life.

Results

In total, 77% met screening criteria for depression, which was associated with higher levels of PTSD symptomatology (mean 67.8 v. 48.4, F_(1,236) = 118.5, P < 0.001) and poorer general health, quality of life and sleep. PTSD symptomatology reduced substantially 3 months after commencing treatment (mean 58.0 v. 47.0, F_(1,112) = 14.5, P < 0.001), with a significant interaction (F_(1,112) = 6.2, P < 0.05) indicating greater improvement in those with depression (mean difference 15.3) than in those without (mean difference 7).

Discussion

In this sample of individuals seeking treatment with prescribed medicinal cannabis for PTSD, over three-quarters (77%) met screening criteria for probable depression. Meeting depression criteria was associated with more severe PTSD symptomatology and poorer quality of life (worse general health and quality of life assessed using the EQ-5D-5L and poorer sleep quality). Treatment with prescribed cannabis was associated with substantial reductions in the severity of PTSD symptomatology, with these improvements being more marked in individuals with depression.

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 treatment^{Reference Lynskey, Schlag, Athanasiou-Fragkouli, Badcock and Nutt1} 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 conditions^{Reference Arkell, Downey, Hayley and Roth30} and for PTSD specifically^{Reference Pillai, Erridge, Bapir, Nicholas, Dalavaye and Holvey17} 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.^{Reference Kline, Cooper, Rytwinski and Feeny31} 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,^{Reference Mitchell, Bogenschutz, Lilienstein, Harrison, Kleiman and Parker-Guilbert32} 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.^{Reference Aderka, Gillihan, McLean and Foa33,Reference Liverant, Suvak, Pineles and Resick34} Further, there is preliminary evidence suggesting that CBMPs may be effective in treating depression^{Reference Mangoo, Erridge, Holvey, Coomber, Barros and Bhoskar35} 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 depression^{Reference Flory and Yehuda36} 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.^{Reference Flory and Yehuda36} 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.^{Reference Schlag, Zafar, Lynskey, Athanasiou-Fragkouli, Phillips and Nutt21} 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.^{Reference Stockings, Campbell, Hall, Nielsen, Zagic and Rahman37} For example, the meta-analysis reported by Black et al^{Reference Black, Stockings, Campbell, Tran, Zagic and Hall13} 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.^{Reference Simei, Souza, Lisboa, Campos, Guimarães and Zuardi38}

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.^{Reference Smith and Gruber39} 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,^{Reference Smith and Gruber39,Reference Zendulka, Dovrtělová, Nosková, Turjap, Šulcová and Hanuš41} 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.^{Reference Zendulka, Dovrtělová, Nosková, Turjap, Šulcová and Hanuš41} 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.

Limitations

Results from our analyses should be interpreted in light of several potential limitations, including lack of a placebo control. Owing to the relatively small sample size, we were also unable to consider the broader range of chronic conditions that may be comorbid with PTSD and the extent to which the effectiveness of CBMPs may vary with multimorbidity and other specific comorbidities. Further, there was substantial attrition, consistent with other observational studies like this one. Nonetheless, our analyses indicated that the included sample did not differ from those lost to follow-up in terms of severity of PTSD symptomatology, well-being or sociodemographic characteristics.

There appears to be a surprising disconnect between the widespread use of medicinal cannabis to treat PTSD and a very limited number of trials that have examined its safety and efficacy for this indication. Although both clinical trials and real-world observational studies have strengths and limitations, randomised controlled trials continue to be considered the gold standard in medical research (although see^{Reference Szigeti, Phillips and Nutt42}). However, given widespread prescription of medicinal cannabis and an apparent reluctance of funding agencies and sponsors to fund rigorous trials of its safety and efficacy, there should be greater recognition of the advantages of real-world data for advancing knowledge in this area.

Conclusions

Depression is common among individuals seeking CBMPs to treat PTSD and is associated with greater symptom severity and poorer quality of life. Effectiveness of CBMPs for treating PTSD does not appear to be impaired in people with comorbid depression.

REFERENCE .https://www.cambridge.org/core/journals/bjpsych-open/volume/88C18D6FEF983DDC4C2CD26E3A3BBCCC