Balancing risks and benefits of cannabis use: umbrella review of meta-analyses of randomised controlled trials and observational studies

Principal findings

This umbrella review grades the credibility and certainty of evidence on the effect of cannabinoid use, encompassing observational and interventional evidence.

Regarding harmful outcomes, among all meta-analytical associations supported by at least suggestive evidence in observational studies and moderate certainty in randomised controlled trials, converging evidence supports an increased risk of psychosis associated with cannabinoids in the general population. Specifically, cannabis use was associated with psychosis in adolescents (highly suggestive credibility, convincing certainty in main sensitivity analyses) and adults (suggestive credibility, suggestive certainty), and with psychosis relapse in people with a psychotic disorder (weak credibility, suggestive certainty). Use of cannabinoids in adult non-clinical and clinical populations was associated with positive (high certainty) and negative (moderate certainty) psychotic symptoms in randomised controlled trials.

Evidence from observational studies (weak credibility, suggestive certainty) and randomised controlled trials (high credibility, moderate certainty) show an association between cannabis and general psychiatric symptoms, including depression and mania, as well as detrimental effects on prospective memory, verbal delayed recall, verbal learning, and visual immediate recall (weak credibility, highly suggestive in observational evidence, moderate certainty in randomised controlled trials). Across different clinical and non-clinical populations, observational evidence suggests an association between cannabis use and motor vehicle accidents (weak credibility, convincing certainty). Additionally, evidence from randomised controlled trials shows an association with somnolence (cannabinoids (moderate certainty) and cannabidiol (high certainty)),103 and cannabis based medicines and visual impairment (high certainty), disorientation, dizziness, sedation, and vertigo (moderate certainty), among others.

These associations are of particular concern given the epidemiology and age pattern of cannabis use disorders, and the population attributable fraction of cannabis for schizophrenia, which is almost 10%.152 According to the Global Burden of Disease 2019, cannabis use disorders are associated with 690 000 (95% uncertainty interval 421 000-1 080 000) disability adjusted life years per 100 000 individuals globally.9 Prevalence and disability related to cannabis start to be measurable at ages 10-14 years (11 900 disability adjusted life years), peak at ages 20-24 years (163 000 disability adjusted life years), then gradually decrease.912153 The age pattern of cannabis use disorders coincide with the peak age at onset of mental health disorders. According to the largest meta-analysis on the age at onset of mental disorders published to date, which pooled 192 studies and 708 561 individuals, around 34.6% of mental health disorders have onset by age 14 years, 48.4% by 18 years, and 62.5% by 25 years; the age that any mental health disorder onset peaks is at 14.5 years.154 For cannabis use disorders, 66% of people will have onset by age 25 years, with age of peak onset 20.5 years. Of note, age at peak onset of schizophrenia spectrum disorders is also in the early 20s, with a slightly lower proportion of people with onset by 25 years (47.8%). In addition to the association between cannabis and psychosis, cannabis is also associated with a worse outcome after onset, including poorer cognition,87 lower adherence to antipsychotics,56 and higher risk of relapse.85 In other words, use of cannabis when no psychotic disorder has already occurred increases the risk of its onset, and using cannabis after its onset, worsens clinical outcomes. Mood disorders also have their peak of onset close to that for cannabis use, which is of concern given the associations shown in this work between cannabis and depression, mania, and suicide attempt. Moreover, high tetrahydrocannabinol content cannabis could serve as a so-called gateway to other substances, particularly in younger people: this effect has been shown in humans155 and animal models,156157 strengthening the recommendation to avoid cannabis use in adolescents and young adulthood.

Evidence suggests detrimental effects on cognition, an association with motor vehicle accidents, together with the age pattern of cannabis use (disorder), and related burden, which raise two additional matters. Firstly, given the adverse effects of cannabis on verbal delayed recall, verbal learning, visual immediate recall, and mental health, negative effects on scholastic or academic performance are reasonably expected, particularly in people who heavily use. Secondly, psychiatric symptoms such as suicide ideation and attempt, mania, and poor cognition, among other adverse events (eg, somnolence, disorientation, dizziness, sedation, vertigo, and visual impairment) might mediate the association between cannabis and increased risk of motor vehicle accidents. According to the DRUID project (driving under the influence of drugs, alcohol, and medicines in Europe), tetrahydrocannabinol ((0.5-2.2), measured as tetrahydrocannabinol or carboxy-tetrahydrocannabinol, in oral fluid or blood) is the second most frequent compound detected in seriously injured drivers, after alcohol (14.1-30.2%), then cocaine and amphetamines.158

Numerous observational associations indicated harmful outcomes, but they were either isolated without converging evidence from different study designs, supported by weak evidence only, or downgraded to not significant. Downgrading applied to the association between cannabis and low birth weight, and preterm delivery,100 which might be mediated by smoking.

Regarding the therapeutic potential of cannabis-based medicines, cannabidiol was beneficial in reducing seizures in certain forms of epilepsy in children and adults, including Lennox-Gastaut syndrome, Dravet syndrome, or other types of epilepsy. Cannabis based medicines were beneficial for pain and spasticity in multiple sclerosis, as well as for chronic pain in various conditions, and in palliative care, yet not without adverse events. However, cannabidiol 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 events, as stated previously. These findings must be put into a clinical perspective to be fully appreciated and compared with available alternatives. Regarding epilepsy, established anticonvulsants are not free from adverse events, including sedation, weight gain, cognitive impairment, and psychiatric symptoms.159160161 Regarding chronic pain, excessive use of prescribed opioid medications has contributed to the opioid crisis, indicating the need for novel pharmacological and non-pharmacological treatment options for chronic pain162 to reduce prescribed opioid medications abuse. Regarding multiple sclerosis, botulinum toxin seems to be the only pharmacological alternative to cannabis based medicines for spasticity.110163 Finally, 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, cannabis-based medicines could be reasonable options for chronic pain in different conditions, muscle spasticity in multiple sclerosis, and for nausea and vomiting in mixed clinical populations, and for sleep in people with cancer. Importantly, in patients with chronic pain, evaluation of the clinical effects considering the whole clinical presentation (several of the included reviews question the clinical value), the effects of prolonged use of cannabinoids still needs to be tested because current findings only come from short term randomised controlled trials. Also, active comparisons between cannabidiol and available options for epilepsy, as well as between cannabis-based medicines and other pain medications, other treatments for muscle spasticity in multiple sclerosis, or treatments for sleep in persons with cancer are needed, with a focus on both efficacy and safety, to inform future guidelines.

Overall, a mismatch is manifest between the legislation ruling cannabinoids versus alcohol use, considering both the well-known harms of alcohol on physical and mental health, in any age group,164 and the epidemiological figures. According to Global Burden of Disease 2019, alcohol use disorders were associated with 17 000 000 (95% uncertainty interval 13 500 000-21 500 000) disability adjusted life years per 100 000 individuals,9 roughly 25 times higher than for cannabis. Also, disability related to cannabis was largely limited to individuals aged 10-24 years, whereas alcohol is associated with disability from early stages of life, increasing continuously to 2 120 000 disability adjusted life years at age 35-39 years, and very slowly decreasing to less than 200 000 disability adjusted life years only after age 80 years.9 If cannabis use prevalence increased in the younger portion of the population due to large scale legalisation, whether the gap described previously would diminish is unclear. Moreover, to the best of our knowledge alcohol has no role as a medical treatment, whereas our research shows that cannabinoids can have beneficial effects in specific clinical conditions. The (scientific) reasoning behind extreme or ideological legislative approaches, namely complete legalisation and commercialization of cannabis even in young adults versus complete prohibition, and the different legislative requirements between cannabis and alcohol in disclosing to consumers the associated risks remains unclear.9

Strengths and limitations

The main strength of this work is that we pool evidence from different sources of evidence and deliberately consider convergence of results from different study designs. Also, this umbrella review is the first to pool observational and interventional studies on the effects of cannabinoids on humans.

Our results should be interpreted with caution. Firstly, the evidence from observational studies has ecological validity with regards to the type of cannabis available in the legal or illegal market on a large scale. However, tetrahydrocannabinol content and other cannabinoids on which no meta-analytical evidence was included can vary considerably among legal and illegally sold products. At the individual level, this variation can mean the difference between harmful or neutral or beneficial effects. Moreover, evidence from more than a decade ago, might not be representative of the cannabis that can be purchased nowadays illegally and legally, which is rich in tetrahydrocannabinol. This means that findings of this work might be underestimating harmful effects of cannabis. Also, the clinical effect of tetrahydrocannabinol on GABA and glutamate signalling via partial agonism on CB1 receptors depends on the concentration and distribution of CB1 receptors in the brain of each individual.10 As such, not all individuals will experience the same effects of cannabis on their mental health and cognition. Nonetheless, a crossover trial of 64 volunteers found that short term detrimental effects of 10 mg of inhaled tetrahydrocannabinol on psychological measures and cognition was not influenced by the co-administration of up to 30 mg of cannabidiol, potentially mitigating potential concerns with a role of tetrahydrocannabinol or cannabidiol ratio as a confounder of findings of this work.165 However, this trial was limited by a very short follow-up (90 min) and high loss to follow-up (28%). Furthermore, cannabidiol products that contain either no tetrahydrocannabinol, or subclinical amounts, are unlikely to result in psychological or cognitive impairment. Similarly, cannabis use disorder seems to have similar rates of people who use recreationally versus medically.166 Secondly, another reason to be cautious is that umbrella reviews neglect evidence from individual cohort studies or randomised controlled trials that have not been previously pooled in meta-analyses. However, individual studies need replication, are frequently exploratory, and need to be pooled in systematic reviews (and ideally meta-analyses) so that a comprehensive understanding of a given association or intervention can be appraised. Hence, any evidence that was not included in this umbrella review, even if potentially relevant, could be exploratory or preliminary. Thirdly, confounding factors could drive associations in observational evidence. However, we have applied stringent criteria, as confirmed by downgrading convincing evidence to non-significant on the association between cannabis and pregnancy outcomes. The quantitative criteria we applied to grade evidence from observational evidence accounted for selection and publication bias, excess of significance driven by small studies with larger effect sizes than the largest study in the meta-analysis, or marginal statistical significance driven by large sample sizes. Also, we have discussed findings from observational evidence in the context of converging evidence from different sources of evidence. For instance, observational studies might be affected by confounding factors, whereas randomised controlled trials might not be representative of the real-world population and affected by selection bias instead. We believe that converging evidence from these two study designs strengthens the ecological and methodological credibility of our findings. Fourthly, excess of significance bias testing might have been underpowered in meta-analyses with few studies, which could arguably apply to all meta-analyses included in this umbrella review, yet, a specific threshold of number of studies to set adequate power of excess of significance bias has not been established. Fifthly, we could have included meta-analyses based on their quality instead of the number of studies. However, that would have introduced a selection bias, leaving out a large portion of evidence. Sixthly, to harmonise effect sizes, we calculated the equivalent odds ratio as a measure of strength of the association. Yet, the harmonisation comes at the cost of losing information on time-to-event analyses and of course any association should be considered more in depth considering the frequency of each outcome, and the follow-up duration and time to event occurrence in each of the included studies. Additionally, the number of cases over the overall population of included studies does not reflect the prevalence of outcomes of interest. For instance, the global prevalence of preterm birth is 11.3%167 versus 9.9% reported in this work and varies across regions and countries’ income levels. The global prevalence of small for gestational age is 27%167 versus 9.1% reported here, with large variations across regions. The prevalence of testicular cancer is 0.04% versus 29.5% reported in the included meta-analysis of case-control studies. Lastly, and most importantly, the results of this work aim to inform future guidelines. These guidelines should account for additional aspects such as cost-effectiveness considerations, clinical relevancies (eg, numbers needed to treat for benefit), long term effects of cannabinoids on which evidence is lacking, and stakeholders, including patients and family members perspectives.

Future research assessing use of cannabis should clearly report what type of cannabis that patients used, how cannabis was administered, the content of tetrahydrocannabinol and cannabidiol, and the amount of cannabis consumed. The dose of exposure to different cannabinoids is needed to infer any causal relation between cannabis and outcomes.

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