Controlled Inhalation of Tetrahydrocannabinol-Predominant Cannabis Flos Mitigates Severity of Post-Traumatic Stress Disorder Symptoms and Improves Quality of Sleep and General Mood in Cannabis-Experienced UK Civilians: A Real-World, Observational Study

Introduction

Post-traumatic stress disorder (PTSD) is a persistent condition triggered by exposure to emotionally traumatic events, encompassing natural disasters, wartime experiences, or instances of sexual violence [1]. The global lifetime prevalence of PTSD is estimated at 3.9%, according to WHO World Mental Surveys, and notably peaks among veterans, reaching up to 20% in certain countries [2]. The economic burden of this disorder is substantial, accounting for an annual productivity loss of USD 3 billion in the USA alone [3]. The hallmarks of PTSD reside in four cognitive symptom clusters: (i) intrusive memories, flashbacks, and nightmares; (ii) avoidance of distressing triggers; (iii) intensified negative emotions encompassing guilt, anxiety, depression, impulsivity, and hyperarousal; and (iv) alterations in social behaviours across personal and interpersonal spheres [1]. Emerging preclinical evidence highlights the direct involvement of the endocannabinoid system in both the onset and severity of PTSD. Studies have firmly established that cannabinoid type-1 (CB1) receptors in the amygdala play a pivotal role in the hyper-consolidation of traumatic memories under stress-induced glucocorticoid influence [4]. Activation of these receptors by endogenous cannabinoids, namely, anandamide (AEA) and 2-arachidonoylglycerol (2-AG), facilitates fear extinction in animal models [5]. Chronic stress has been correlated with decreased levels of anandamide and altered patterns of CB1 expression in the brain [6]. Furthermore, cannabinoids exhibit a dual effect by boosting activity in the ventromedial prefrontal cortex while suppressing neuronal activity in the amygdala – directly counteracting the deficits observed in PTSD [7]. Clinical studies corroborate these findings, demonstrating reduced circulating levels of endocannabinoids and heightened CB1 expression in key brain regions among individuals diagnosed with PTSD, including the amygdala, hippocampus, and the anterior cingulate cortex [8]. Notably, specific genetic variants leading to CB1 receptor overexpression have been linked to an increased susceptibility to PTSD and anxiety disorders in humans [9, 10].

Existing therapeutic approaches for PTSD primarily revolve around psychological therapies, including trauma-focused interventions and eye movement desensitization and reprocessing, alongside medication targeted at symptomatic relief. Nonetheless, these treatments exhibit a high dropout rate, with a significant portion of patients – ranging between 60 and 72 percent – reporting persistent symptoms that qualify as PTSD [11]. While selective serotonin reuptake inhibitors like sertraline and paroxetine hold approval for treating PTSD in the UK, their efficacy often yields suboptimal responses [12]. Consequently, polypharmacy and off-label use of medications are commonplace in managing PTSD, exemplified by the prevalent prescription rates of benzodiazepines, reaching up to 74% in some studies, despite contraindications and potential exacerbation of the condition [13]. The challenges in effectively treating PTSD underscore a critical unmet need for safer and more efficacious alternatives to address its symptoms and manage the disorder itself. Several small-scale clinical trials exploring pharmacological interventions involving oral CB1 agonists, such as Δ9-tetrahydrocannabinol (THC) or nabilone, in chronic PTSD patients have revealed promising outcomes. These interventions improved overall symptom severity and sleep quality, concomitant with reduced occurrences of nightmares and hyperarousal symptoms [14–16]. Real-world evidence also indicates heightened self-medication tendencies with cannabis among individuals grappling with PTSD [17]. Countries facilitating legal access to medicinal cannabis, such as Israel and Canada, promote its use for managing PTSD symptoms [18, 19]. However, comprehensive medical research assessing the efficacy of vaporizing cannabis flowers to alleviate PTSD symptoms typically encounters significant obstacles in recruiting participants and conducting adequately blinded randomized clinical trials [20, 21]. To help bridge this gap, our group and others are reporting real-world data associated with the clinical use of cannabis-based medicinal products (CBMPs) to manage PTSD symptoms, despite the limitations inherent to this type of clinical evidence such as the potential selection bias and the lack of a control group [22, 23]. The present investigation focuses on analysing clinical outcome measures reported by a cohort of civilian patients diagnosed with PTSD in the UK, specifically prescribed a chemotype 1 (THC-predominant) cannabis flos intended for inhalation.

Methods

Results

Discussion

PTSD ranks as the third most common mental health condition for which patients seek treatment with CBMPs in the UK, preceded only by generalized anxiety and ADHD. Our analysis of patient-reported clinical outcome measures revealed a temporal correlation between the initiation of medically supervised treatment with chemotype-1 cannabis dried flowers for inhalation and significant symptomatic improvement at 3- and 6-month follow-ups among individuals diagnosed with PTSD. The observed effect, marked by a 13-point reduction in the PCL-C global symptom severity score at 3 months and a 16.8-point reduction at 6 months, surpasses the 10-point threshold recognized for clinical meaningfulness. This finding aligns with prior research documenting reductions in both clinician-assessed and patient-reported PTSD symptoms with the use of cannabis and cannabinoids [17–20, 22, 23, 30–32]. Patients also reported significant enhancements in general health, mood, and sleep quality. Notably, we found no significant differences in health-related quality of life measured by the EQ-5D questionnaire, perhaps due to PTSD symptoms not being perceived as disabling within this scale [33]. However, improvements in general health, reported on a Likert scale (0–100), were marked at 3 months and further increased at 6 months. Additionally, scores on the PHQ-9 questionnaire showed substantial improvement, indicating a general psychological enhancement associated with treatment. Similar results were recently reported by our group in a larger cohort of T21 participants, where patients diagnosed with anxiety disorders reported an improvement in general mood significantly larger than participants diagnosed with chronic painful conditions [25]. Quality of sleep, assessed by the PSQI, showed robust improvements at both 3 and 6 months. This is consistent with the results obtained from the PCL-C questionnaire, where improvement in sleep was the most prominent effect among the 17 PTSD symptoms assessed. This effect on sleep quality adds to the existing evidence indicating a beneficial association between THC and sleep quality, insomnia, and the occurrence of nightmares in patients suffering from PTSD [34–36]. This finding highlights the relevance that activation of central CB1 receptors may have in the clinical management of this patient population, considering that sleep quality has been identified both as a vulnerability factor for developing PTSD and a landmark symptom that impacts overall outcomes [37]. Another significant effect reported in the PCL-C by patients was related to what researchers have termed “the restored self” [38]. Treatment with THC-predominant cannabis flowers facilitates the individual’s ability to engage in previously enjoyed activities, to socialize and to make meaningful connections, which were, according to our results, the main two drivers of the patient-reported improvement in mood alterations secondary to PTSD. Current evidence from both healthy individuals and PTSD patients supports the ability of THC to suppress anxiety and aversive memories [16]. The role of central CB1 receptors as key regulators of positive affective memory consolidation and emotional memory biases in humans has been previously documented [39]. In comparison with placebo, pharmacological blockade of CB1 induced a negative bias on a memory recognition task without producing a change in subjective mood [40]. Therefore, when administered as an adjuvant, chemotype 1 cannabis flowers may act as a memory-influencing drug, thus improving the effectiveness of behavioural and psychological interventions in PTSD patients [41, 42]. However, human studies exploring the beneficial effects of cannabinoids on human psychophysiological extinction learning have attained conflicting results, thus indicating that this potential clinical application of cannabis requires further study [43].

This report offers two key contributions to the existing literature. First, we established selection criteria to limit the intrinsic polypharmacology of cannabis flower, which often leads to complex interactions due to the presence of multiple active compounds [44]. Unlike other similar observational studies, all participants in our study received the same cannabis variety, KHIRON HK 20/1, either alone or in combination with other chemotype 1 flowers. Hindu Kush, a well-established cannabis strain with a stable genetic background and a well-characterized chemical and pharmacological profile, was chosen for this study [25]. Its availability from multiple manufacturers and its potential suitability for inclusion in national public healthcare access programs targeting a broader population make it an interesting candidate for further research. Second, while most observational research on inhaled cannabis in PTSD patients focuses on military and veteran populations, our data derive from a civilian cohort. The unique psychosocial and warfare-related experiences of military personnel may result in different outcomes in symptom severity and violent behaviour when using cannabis compared to civilians with PTSD [45].

Despite these potentially valuable clinical insights, our investigation has several significant limitations, which warrant a careful interpretation of these findings. Firstly, the study population is composed almost entirely (96.6%) of individuals who had previously tried cannabis and had a positive response, potentially introducing selection bias favouring reporting of benefits over side effects, compared to the general population [46]. The pre-selection of participants as cannabis responders underscores the importance for clinicians of questioning about cannabis self-medication in the initial assessment of PTSD in new patients. It remains unclear how these results would apply to cannabis-naive patients as the two naive participants in our study, while presenting similar results to the overall cohort, are not fully representative. A slightly lower proportion of participants who were current or previous cannabis users at baseline (88.9%) was reported in a PTSD cohort within the UK Medical Cannabis Registry, a single-centre patient registry run by Sapphire Clinic [23]. Sub-group analysis revealed that cannabis responders continued to report improved outcomes compared to baseline (p < 0.050). This is in agreement with our previous observations suggesting that patients who are cannabis users still find additional benefits from CBMPs beyond illicitly obtained cannabis and that these effects persist despite potential pharmacological tolerance [25]. Second, a key limitation of this study is the absence of a placebo control group, a factor that is often incompatible with real-world settings. The only randomized controlled trial conducted to date on the efficacy of inhaling cannabis flowers in PTSD patients suggests the presence of a significant placebo effect [20]. However, in that trial, participants treated with chemotype 1 flowers demonstrated a substantially greater improvement in PTSD symptom severity, as measured by the CAPS-5 scale (t = −6.19; p < 0.0001), compared to those receiving chemotype 2 (t = −2.57; p < 0.0143) or chemotype 3 cannabis flowers (t = −2.47; p < 0.0181). These findings indirectly support the pharmacological potential of CB1 modulation, as described in this report, although well-controlled, adequately powered studies will be necessary to determine whether inhaled cannabis effectively alleviates PTSD symptoms. A third limitation is that the dosing regimen utilized in our study remains unknown; however, it is noteworthy that most patients reported using cannabis only once a day, most likely at night-time before going to bed. This practice aligns with a concept previously characterized for the acute physiological effect following the inhalation of THC-predominant cannabis flowers termed “the sight of relief” [38]. However, data from T21 and the UK medical cannabis registry suggest that PTSD patients present an average daily consumption ranging between 0.5 and 1 g of dried cannabis flower, containing 100 and 200 mg of THC, respectively [23, 47]. This is coherent with “ad libitum” doses self-administered by military veterans diagnosed with PTSD over the course of 3 weeks in the only randomized controlled trial conducted with cannabis flowers [20]. Previous pharmacokinetic studies have revealed the existence of a “ceiling effect” for the pulmonary absorption of THC, suggesting that plasmatic levels achieved by inhaling either 100 or 200 mg of THC in flower format are indeed identical [48]. Therefore, it is essential to educate both patients and prescribers on the optimal dosing size and regime, particularly for heavy consumers, and consider spacing doses and reducing daily amounts to mitigate potential risks of addiction and related mental health issues in an already sensitive population. Further, some studies have reported short-term reductions in PTSD symptoms with THC-predominant cannabis flowers but no sustained long-term benefit despite increasing quantities of cannabis being administered, suggesting the appearance of tolerance [19]. Our data collection spans only 6 months, which underscores the need for further investigation into the long-term efficacy and safety of CBMPs in managing PTSD. Finally, a recurrent limitation when working with data stemming from the T21 patient registry is the low rate of reporting associated with AEs. While other cohorts of patients treated with CBMPs typically present an incidence of mild AEs associated with the treatment ranging from 20% to 30% [23, 49, 50], T21 participants failed to report any AEs. We interpret this result to indicate that cannabis responders will likely be less affected by potential side effects associated with treatment using THC-predominant cannabis flowers than cannabis-naïve individuals. However, precaution is advised when starting treatment with cannabis flowers, and a conservative dosing titration regime has been suggested to minimize the incidence of AEs in naïve patients, which could potentially lead to treatment discontinuation [25].

Conclusion

Results from this observational study suggest an association between treatment with THC-predominant cannabis flowers and symptomatic improvement for up to 6 months in a cohort of UK civilians diagnosed with PTSD. The treatment was safe and well tolerated and characterized by marked effects on quality of sleep, general mood, and severity of PTSD-associated symptoms. Despite previous exposure to cannabis, participants continued to report benefits after initiating treatment with THC-predominant cannabis flowers. Yet our results need to be interpreted carefully owing to the intrinsic limitations of the study design and data collection disclosed in the manuscript. However, considering the challenges of conducting properly designed and controlled clinical trials using cannabis flowers for inhalation, this study could inform current clinical practice with CBMPs so that both prescribing psychiatrists and patients suffering from PTSD could benefit from additional therapeutical options to tackle this debilitating condition.

Acknowledgments

The contribution of Sofia Antonopoulou and Alkyoni Athanasiou-Fragkouli is gratefully acknowledged.

Statement of Ethics

The work was conducted in accordance with the Declaration of Helsinki. At the time of enrolment, all T21 participants give written informed consent for their data to be used for research purposes. Based on the Medical Research Council decision tools, Research Ethics Committee review and approval is not required.

Conflict of Interest Statement

G.M.-S. is an employee of Khiron Life Sciences Corp, a global cannabis company that commercializes CBPMs. A.M. and W.S. are employed by Zerenia Clinics, a subsidiary of Khiron Life Sciences. No other Khiron employee or executive was involved in the design of the work; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. The authors declare no other conflict of interest.

Funding Sources

This study received no external funding.

Author Contributions

Conceptualization: W.S. and G.M.-S.; methodology, writing – original draft preparation, visualization, and supervision: G.M.-S.; data curation: A.M. and G.M.-S.; and writing – review and editing: W.S., A.M., and G.M.-S. All authors have read and agreed to the published version of the manuscript.

Funding Statement

This study received no external funding.

Data Availability Statement

The data presented in this work are available on request from the corresponding author. The data are not publicly available due to privacy and ethical reasons.

Supplementary Material.