A growing number of countries and jurisdictions now permit the use of cannabis for medicinal – and increasingly, recreational – purposes, with patients able to access cannabis-based medicines for a range of conditions and symptoms in many parts of the world. However, despite this improved access, debates around the risks and benefits of cannabis use remain rife. Potential negative implications of cannabis use – particularly in adolescents and young adults – remain an area of concern as cannabis use rates continue to rise.
In Europe, over the last decade, self-reported cannabis use within the past month increased by almost 25% among 15-34-year-olds and 80% among those aged 55-64. Furthermore, evidence shows that the potency of cannabis products has also been on the rise with average strengths in Europe increasing from 6.9% tetrahydrocannabinol (THC) to 10.6% THC between 2010 and 2019.
As cannabis continues to become more widely available, it is crucial that we understand the potential risks and benefits associated with its use. The authors of a recent study aimed to “systematically assess the credibility and certainty of associations between cannabis, cannabinoids, and cannabis-based medicines and human health, from observational studies and randomised controlled trials (RCTs).”
Design and Methods of the Study
Researchers conducted an umbrella review of meta-analyses of observational studies and randomised controlled trials that reported on any outcomes associated with cannabis and cannabinoids use in humans. When two or more meta-analyses examined the same association, only the one that included the largest number of studies was included for review. The primary outcomes were the safety and efficacy of cannabinoids on target symptoms in meta-analyses of randomised controlled trials. The secondary outcomes were any outcome reported in the meta-analyses of observational studies.
Findings of the Review
Following the exclusion stage, a total of 101 publications, published between 2008 and 2022, were included in the final review. Of these, 50 were meta-analyses of observational studies and 51 were meta-analyses of randomised controlled trials. Of note, one meta-analysis reported on both observational studies and randomised controlled trials. The quality of included meta-analyses, according to AMSTAR 2, was high in 20 meta-analyses, moderate in seven, low in 21, and critically low in four.
Cannabidiol was specifically evaluated in seven meta-analyses, while others considered different combinations of cannabis, cannabinoids, tetrahydrocannabinol, and cannabis-based medicines including nabiximols, dronabinol, nabilone, levonantradol, and CT3. Overall, 364 unique meta-analytical associations were identified reporting on acceptability or tolerability of physical adverse events (n = 213), psychiatric- or psychological-related outcomes (n = 54), pain-related outcomes (n = 39), cognitive-related (n = 20), euphoria or feeling high (n = 5), quality of life (n = 5), and other various outcomes (n = 28).
Potential Risks of Cannabis Use
Among all meta-analytical associations supported by at least suggestive evidence in observational studies and moderate certainty in RCTs, the researchers found evidence that cannabis use was associated with psychosis in adolescents and adults, and with psychosis relapse in people with psychotic disorder. Furthermore, the use of cannabinoids in adult non-clinical and clinical populations was associated with positive (high certainty) and negative (moderate certainty) psychotic symptoms in RCTs.
Evidence from randomised controlled trials and observational studies also show an association between cannabis use and general psychiatric symptoms, including depression and mania, as well as detrimental effects on prospective memory, verbal delayed recall, verbal learning, visual immediate recall (weak credibility, highly suggestive in observational evidence, moderate certainty in randomised controlled trials), and cognition. Evidence from RCTs indicates an association between somnolence and cannabidiol, cannabis-based medicines and visual impairment, disorientation, dizziness, sedation, and vertigo, among other adverse effects.
A number of observational associations indicate harmful outcomes from cannabis use; however, the authors note that these were either isolated without converging evidence from different study designs, supported by weak evidence only, or downgraded to “not significant”.
Therapeutic Potential of Cannabis Use
Regarding the therapeutic potential of cannabis, evidence indicated that cannabidiol reduced seizures in certain forms of epilepsy in children and adults. Cannabis-based medicines also demonstrated benefits for pain and spasticity in multiple sclerosis, for chronic pain in various conditions, and in palliative care. However, CBD and other cannabis-based medicines were associated with lower acceptability and tolerability than placebo in children and adults, and cannabis-based medicines were also associated with psychiatric adverse effects.
Such findings should be put into a clinical perspective and compared with the available alternatives. For example, established anticonvulsants are not free from adverse effects, including sedation, weight gain, cognitive impairment, and psychiatric symptoms. The use of opioids in the treatment of chronic pain has contributed to the opioid crisis highlighting a clear need for novel pharmacological and non-pharmacological treatment options for chronic pain.
The clinical populations included in eligible meta-analyses had treatment-resistant or chronic conditions or were being treated in the context of palliative care and ongoing chemotherapy, and other treatment options had not proven effective. Thus, the authors of the current review note that cannabis-based medicines could be reasonable options for chronic pain in different conditions, muscle spasticity in multiple sclerosis, nausea and vomiting in mixed clinical populations, and for sleep in people with cancer.
Conclusions
This umbrella review is the first to pool observational and interventional studies on the effects of cannabinoids in humans, allowing researchers to consider the convergence of results from different study designs. However, the authors note that these results should be interpreted with caution. Variations in the types of cannabis products available in the legal or illegal market of the included study – including the THC content – may mean the difference between harmful, neutral, or beneficial effects. Furthermore, studies from over a decade ago may not be indicative of the cannabis products available in legal and illegal markets today.
Based on the findings of this review, the authors conclude that “cannabis use should be avoided in adolescents and young adults (when neurodevelopment is still occurring), when most mental health disorders have onset and cognition is paramount for optimising academic performance and learning, as well as in pregnant women and drivers.” However, it is also noted that cannabis-based medical products may have benefits for a number of conditions, including treatment-resistant epilepsy, chronic pain, and multiple sclerosis, as well as nausea and vomiting in people with mixed conditions and for sleep in cancer.
Finally, the authors recommend that “law and public health policymakers and researchers should consider the evidence synthesis when making policy decisions on cannabinoids use regulations, and when planning a future epidemiological or experimental research agenda, with particular attention to the tetrahydrocannabinol content of cannabinoids.”
