SMMGP Medicinal Cannabis Sponsored Clinical Update

Commentary:

Despite cannabis being the most commonly used illegal drug in the world, and the third most widely used psychoactive substance after alcohol and tobacco, there are currently no effective, licensed medications for the treatment of cannabis dependence. This well-designed RCT produced mixed results for the efficacy of dronabinol versus placebo for the treatment of cannabis dependence. Whilst no significant difference was found between treatment groups for the primary outcome of abstinence, dronabinol did display some of the characteristics of an effective agonist treatment, and certainly warrants further study.

One clear benefit of dronabinol was that it improved treatment retention, so perhaps dronabinol would be best utilised within a harm minimisation framework, similar to methadone and buprenorphine for opioid use disorder. A period of maintenance treatment with agonist pharmacotherapy may provide the stability that someone needs to engage with other aspects of treatment, such as psychosocial interventions.

Whilst abstinence is a worthy goal it is not necessarily the primary goal of treatment for everybody. Treatment with pharmacotherapy can achieve other therapeutic aims such as a reduction in withdrawal symptoms, and a reduction in the reinforcing effects of the illicit drug through the development of tolerance. These secondary benefits may help someone to reduce the amount of illicit drugs they take, if not stop completely, and this reduction may result in a marked improvement in their lives. It is important that these patient-centered outcomes are measured in addictions research, as abstinence alone can be a crude measure with limited real-world applicability.

The authors speculate that a longer maintenance treatment period with dronabinol may be required. They argue that many of the harms associated with cannabis dependence are often chronic and subtler than the immediate and dramatic socio-economic or psychosocial problems often seen with cocaine, heroin or alcohol dependence. Because negative consequences of cannabis use may be less apparent, motivation to quit may be low. Thus, the expectation that change would be initiated over a relatively short period of time may be unrealistic, and the treatment duration in the trial may therefore not have been sufficient to show a positive effect. In practice, as with opioid replacement therapies for opioid use disorder, the duration of cannabis agonist treatment would likely need to be flexible and tailored to the needs of the individual. Additionally, higher doses and flexibility in dosing schedules should be considered and studied in future research.

Dronabinol was more effective than placebo at reducing withdrawal symptoms, so perhaps it is also a candidate for managing acute withdrawal in patients who are making a quit attempt. Currently benzodiazepines (most commonly diazepam) tend to be used off-label for the short-term management of acute cannabis withdrawal. Future research could compare dronabinol with diazepam to evaluate the safety and efficacy of each medication for the management of acute cannabis withdrawal. The authors also suggest that future studies consider combining dronabinol with other medications with complimentary mechanisms, or more potent behavioural interventions.

Commentary:

The promising results of this small RCT showed that nabiximols is more effective than placebo at treating cannabis withdrawal and retaining patients in treatment, in a treatment-seeking cohort of adults with cannabis dependence. As opposed to dronabinol, which only contains THC, nabiximols is a combination medication containing the two primary cannabinoids found in the cannabis sativa plant – THC and CBD. Whilst THC produces the psychoactive effects of cannabis, CBD attenuates the paranoia and euphoria associated with THC. It might be prudent for future studies to compare different medicinal cannabis preparations (THC vs THC/CBD vs CBD) to demonstrate whether or not there is a benefit of one preparation over another for reducing withdrawal symptoms, according to the type of cannabis used by an individual.

Through the use of urinalysis in this study, the authors found that participants’ baseline CBD levels were negligible. This was consistent with reports that street cannabis in the local area contained very low levels of CBD. The efficacy of different medicinal cannabis formulations may differ depending on the ratio of THC and CBD in the cannabis used by the individual. If future research finds this is the case, pre-treatment urine drug screens or blood tests could be used to determine the concentration of THC and CBD in the cannabis used by an individual in order to guide treatment decisions regarding choice of medicinal cannabis therapy.

Unsurprisingly, nabiximols was no more effective than placebo in achieving long-term reduction in cannabis use at 28-day follow-up. As the authors wisely acknowledge, there is little precedence for medication-assisted withdrawal to affect long-term abstinence in the absence of ongoing support. As we know, the drivers for drug use for most people are multifactorial, and reduction of withdrawal symptoms is just one reason that people continue to use drugs. We should remember that whilst agonist replacement medication may be a useful component of treatment, either for medically-assisted withdrawal or ongoing maintenance therapy, it will not cure someone of their addiction. Indeed, agonist treatment may effectively treat withdrawal symptoms and subsequently reduce cravings, but it should be a part of a larger treatment plan utilising psychosocial interventions to address underlying issues. It is important that patients are aware of this so that they have clear expectations of pharmacological treatment.

One of the limitations of this study is the relatively small sample size. Further research with larger cohorts is required, as well as trials comparing medicinal cannabis to other current pharmacological treatments for cannabis withdrawal such as diazepam. It is one thing to demonstrate the safety and efficacy of a medication compared to placebo, but studies demonstrating its effects in comparison to current best available treatments will allow us to make better evidence-based, patient-centred treatment decisions.

Commentary:

This study found that nabiximols treatment resulted in fewer days using illicit cannabis, but did not improve treatment retention compared to placebo. Conversely, the dronabinol study above (Levin, et al., 2011) found that treatment with dronabinol significantly increased treatment retention but did not reduce illicit cannabis use. It is uncertain why these studies found opposing results for nabiximols and dronabinol. The authors highlight that it remains unclear whether flexible dosing with nabiximols, its’ higher bioavailability and faster onset of action, and/or the combination of THC with CBD (which has anti-craving and neuroprotective properties in cannabis users) may convey advantages over dronabinol. Future studies comparing the two medications are needed to identify which patients may benefit from each medication, and why. Crossover studies comparing different medications within the same groups, with qualitative patient-centred outcome measures, may also help to answer these questions.    

This study clearly demonstrates that there are a proportion of patients wishing to reduce their illicit cannabis use who may benefit from long-term nabiximols treatment. However, whether or not a reduction in the number of days using illicit cannabis results in improved quality of life and longer-term health outcomes remains to be seen. As a harm reduction strategy, to reduce the harms arising from the route of administration (e.g. smoking), it stands to reason that fewer days smoking illicit cannabis (particularly when mixed with tobacco) would have some benefits to respiratory health. There may also be cost benefits for an individual taking a more affordable prescribed medication rather than purchasing illicit cannabis.

One potential limitation of this study was that the primary endpoint was a self-reported measure of cannabis use. Whilst the authors argue that the urine drug screen results in the placebo arm indicate adequate validity of self-report in this study, it was not possible to differentiate between illicit cannabis use and prescribed cannabis use in the nabiximols group using urine drug screens. This may present a difficulty in clinical practice where urine drug screens are often used to measure illicit drug use, and as a marker of treatment success.

Whilst the three studies above represent a big step forward in the search for truly efficacious pharmacotherapies for cannabis dependence, this research is preliminary and long-term open-label studies are required to assess the efficacy and safety of cannabis agonist treatment in real-world settings. Furthermore, qualitative studies are required to understand exactly how cannabis pharmacotherapy may benefit patients over time, and whether or not cannabis agonist treatment improves the chronic negative consequences of cannabis dependence.

Commentary:

Chronic non-cancer pain is a significant cause of disability globally, and can present a major challenge for both the patients living with it, and the treating clinicians. With wide-ranging causes for CNCP, treatment can be complex and challenging, and although there is a range of potential pharmacological interventions available, many patients fail to benefit. This in turn has likely contributed to the overprescribing of opioids for CNCP, and a corresponding increase in opioid-related harms, so it is understandable that there is a strong desire to find safe and effective alternative pharmacotherapies for CNCP.

Whilst previous reviews have reported conflicting conclusions on the effects of medicinal cannabis for the treatment of CNCP, this comprehensive review expanded its scope to include all types of study design, different CNCP conditions, potential differential effects of different cannabinoids, and safety considerations, in order to fully examine the evidence base. This review included studies evaluating many different types of cannabis - from synthetic THC formulations to plant-based cannabis - for the treatment of CNCP. Therefore, the conclusions are based more generally on the use of cannabis and cannabinoids for CNCP. Despite the broad scope of this review, nabiximols was the most commonly studied treatment, followed by plant-based cannabis, and the majority of studies investigated a pharmaceutical grade cannabis product (n=74).

This review found moderate evidence for a statistically non-significant reduction in pain for cannabinoids compared to placebo. Whilst this finding may be underwhelming, non-significance does not necessarily mean there is no clinical significance to the findings. This review helpfully calculated the number needed to treat to benefit (NNTB) to allow us to compare cannabis to other evidence-based treatments for CNCP. The number of patients needed to treat for one patient to experience a 30% reduction in pain was estimated to be 24. The authors acknowledge that whilst caution must be exercised when comparing NNTBs across studies that compare different groups and timeframes, this number is much higher than the NNTB of other analgesics for neuropathic pain (opioids 4.3; pregabalin 7.7; tricyclic antidepressants 3.6). Furthermore, the NNTB may actually be higher for cannabis than reported here as some studies did not report on the 30% and 50% pain reduction outcomes.

Conversely the NNTH (for one person to experience an adverse event) was 6, which is relatively low, and comparable to the NNTH for opioids (NNTH=5). Study participants receiving cannabinoids were twice as likely to withdraw from a trial for any reason, compared to patients receiving placebo, and had 3.47 times the odds of withdrawing due to adverse events (AEs). This is an important finding as cannabis is typically deemed to be safer than many other substances, including alcohol, tobacco, and opioids. Whilst it would be disingenuous, for example, to downplay the risks of opioid use, or to equate the most severe risks associated with opioids (overdose and death) to the more commonly reported cannabis AEs in this review (dizziness, cognitive disturbance, and confusion and disorientation), further research is required to examine the safety of long-term cannabis use and the acceptability of its side effects to patients.

The authors commented that the majority of higher-quality RCT evidence was for neuropathic and MS-related pain, and that evidence for more common types of CNCP like arthritides, back pain, and migraines, was scant. High-quality RCTs are needed to investigate the effects of cannabis for these types of CNCP.

The authors identified a number of limitations to the evidence included in this review. Most studies were of limited duration (median of 8 weeks), which considering that CNCP is by definition a chronic, long-term condition, seems insufficient to clarify the appropriateness of long-term cannabis use for CNCP. The authors also flag that the relatively short duration of the studies are likely insufficient to detect potential adverse effects of long-term cannabis use, such as the risk of psychosis and cannabis dependence. Most studies also had small sample sizes, with only 21 of the 104 included studies having at least 100 participants in the treatment arm. Given that effect estimates tend to be larger in smaller studies, caution must be exercised when interpreting their outcomes.

The authors also speculate that the effectiveness of cannabis for CNCP may diminish over time. They found that the largest reductions in pain intensity were found in 1-day studies, and that this effect was smaller or non-significant in studies of 13-week duration or longer. Although speculative at this point, it is possible that individuals will develop tolerance to the analgesic effects of cannabis and it may be most effective when utilised irregularly, as required, for breakthrough pain. Further research into the development of tolerance to cannabis is required, as this phenomenon is currently poorly understood.

It is important to note that the majority of studies included in this review used cannabis as an adjunct treatment, with participants otherwise receiving stable doses of analgesics, non-steroidal anti-inflammatory drugs, and anti-spasticity drugs. However, dosing regimen for both cannabis and other treatments were not consistently reported. It is therefore difficult to ascertain how much of the effect can be attributed to cannabis treatment, demonstrating that the clinical significance of these results is far from certain.

When thinking of the psychiatric correlates of CNCP – depression, anxiety, and substance use disorders – it would be useful to consider whether or not cannabis treatment is more effective for patients with specific comorbidities, where the cannabis may be providing therapeutic benefit for comorbid conditions leading to a subsequent improvement in pain. Again, further research is needed to understand how certain populations with CNCP and specific psychiatric comorbidities may benefit from cannabis treatment.

Despite the poor quality evidence, and limited treatment effects found in this review, medicinal cannabis may be suitable, as part of a multidisciplinary treatment approach  (perhaps as a second-line or adjunct therapy), for certain types of CNCP, for carefully selected patients. Specifically, moderate to high-grade evidence was found supporting the use of nabiximols as adjunct therapy to achieve modest reductions in MS-related pain. As when initiating any new pain medication, regular review and assessment is vital to ascertain treatment effectiveness, and to ensure that any risks or adverse effects are outweighed by the benefits.

It is clear from the analysis of the evidence base in this review that cannabis is unlikely to be effective for treating CNCP for most patients. Many of the studies included in this review were of low quality, and their conclusions must be viewed with a degree of caution. Currently, we simply do not have the high-quality evidence needed to draw any firm conclusions about the efficacy of cannabis for many types of CNCP.

Commentary:

The overwhelmingly positive findings of this study suggest that specific populations – namely, military and police veterans with PTSD who have failed to benefit from first-line pharmacotherapy and psychotherapy – may benefit from medical cannabis treatment. However, in the absence of a control group, it is not possible to draw any firm conclusions about the use of medical cannabis for the treatment of PTSD.

There are a number of methodological limitations to this study, and several factors contributing to an overall high risk of bias. There were more than four types of medical cannabis used in this study and not all were clearly named by the authors. Each type had varying THC and CBD concentrations, and patients were often simultaneously using multiple types of medical cannabis. Differences between outcomes for the different types of medical cannabis used were not presented or investigated, so it is not possible to attribute superiority of one type of cannabis over another. Dosing also varied widely, from less than 5g/day (5%) to more than 10g (8%), though the majority used 10g/day (67%). If we take the THC content of just one of the study medications (Luminarium, 25-28% THC), 10g would contain approximately 2,500mg – a dose far greater than the maximum daily Nabiximols dose investigated in studies for cannabis dependence (86.4mg).

Alarmingly, this study captured no safety data, so any adverse events, hospitalisations, or other physician visits were not recorded. Therefore, this study was unable to provide any evidence for the safety of medical cannabis. There is further potential for bias as several of the study authors were employed by the manufacturer of the medical cannabis used in the study. Although it is acknowledged that the study was conducted in collaboration with the manufacturer, the details of this collaboration are not explicit.           

Some of the limitations acknowledged by the authors are that a validated tool for the assessment of PTSD symptoms was not used, and information regarding patients’ history of cannabis use and duration of PTSD was not collected. Interestingly, patients were asked to rate how their PTSD affected their “drug and alcohol overuse”, and of the 66 patients who responded, a mean improvement of 82% was found. This suggests that drug and alcohol overuse, though not a clearly defined term, was prevalent for a number of study participants, at least at baseline. In their critique of another retrospective chart review, where patients were pre-screened as having already used cannabis, the authors stated that “cannabis-withdrawal syndrome may have exacerbated their PTSD symptoms when they were not on cannabis, possibly contributing to their positive findings”. In the absence of any information about the types of substances used, or overused, by participants this critique could equally apply to this present study.

In light of the numerous limitations mentioned above, it is difficult to place much confidence in the findings presented in this study. Whilst theoretically medical cannabis might alleviate several of the symptoms of PTSD, future high-quality RCTs are needed with larger sample sizes to determine the efficacy and safety of medical cannabis for the treatment of PTSD.

Commentary:

This paper provides a useful overview of the role of the endocannabinoid system in PTSD, and the potential therapeutic value of treatment with medical cannabis. However, perhaps due to the extreme heterogeneity of methodological strategies used in the studies included in this review, no meta-analysis was performed, and the authors were unable to provide any broad conclusions about the efficacy or safety of medical cannabis for the treatment of PTSD.

The authors found no randomised, controlled clinical trials for inclusion in this review, and although no grading of the quality of the evidence was presented, the studies that were included appear to be of questionable quality. For many of the studies, limited detail is provided regarding the type of cannabis used, the dosing regimen, and the route of administration. Furthermore, 50% of the studies had no control group, and no information is given regarding concurrent psychosocial interventions. Thus, the evidence base is currently lacking in high-quality studies demonstrating the efficacy and safety of medical cannabis for PTSD.

One observational study found at follow-up that participants who had never used cannabis, or had stopped using, had the lowest levels of PTSD symptomology compared to participants who continued or commenced use. It is possible that participants with long-term cannabis use had more severe PTSD symptoms to begin with, and were self-medicating with cannabis. It is also possible that participants who are using cannabis at a dependent level may also be experiencing withdrawal symptoms that mimic or exacerbate their PTSD symptoms. It is important that any patients being considered for treatment with medicinal cannabis have a thorough assessment of their substance use, so that the individual risks and treatment aims are clear.

Although the current evidence base is lacking, and the efficacy and safety of medical cannabis for PTSD has not yet been demonstrated, the theoretical evidence is promising, and suggests that medical cannabis may be of use in treating some symptoms of PTSD for some people. The most commonly reported motivations for cannabis use in patients with PTSD are reduced anxiety and tension. The authors suggest that PTSD subjects may use cannabis and cannabis-related compounds primarily for their anxiolytic, sedative, hypnotic, dream recall suppressor, and antipsychotic activities.

Further research should explore which specific cannabis types may be most effective, and whether or not different THC/CBD concentrations may treat different symptoms of PTSD. Randomised, controlled trials with adequate participant numbers are needed, and validated PTSD symptom checklists should be used to measure outcomes. Long-term follow-up is also needed to evaluate the safety of long-term medical cannabis use, and to determine if tolerance to the potentially beneficial effects of cannabis develops.