Given just how common it is for cannabis patients to try different types of products and methods of administration23,24, it is surprising how few previous investigations have examined which fundamental characteristics of the products consumed in vivo by millions of people daily are associated with real-time patient outcomes and experienced side effects. While RCTs may be the ‘gold standard’ for measuring the pharmacodynamics of synthetic, standardized (usually particular symptom focused) medications, they are poorly suited for understanding the effects of a medication with substantial heterogeneity in product characteristics and consumption methods across the estimated 2.2 million state-legal medical cannabis patients in the United States25. Our observational study using mobile app technology was designed to measure these effects in real-time among a large sample of patients using cannabis for treating their medical symptoms under naturalistic conditions. On average, responders experienced significant improvements across the 27 health symptom categories measured. Dried, whole natural flower was associated with greater symptom relief than the use of other types of products (i.e., concentrates, edibles, tinctures, and topicals). However, and despite the fact that different routes of administration deliver variable amounts of cannabinoid contents and have different metabolomics26,27,28,29,30,31, we did not find variation in symptom relief with use of pipes, joints, or vaporization combustion devices. Products made from pure C. indica strains were more effective than products made from C. sativa, matching patient-reported preferences for the former for treating conditions such as pain and insomnia32,33. However, once we controlled for cannabinoid contents, none of the other product characteristics predicted variability in symptom levels. Only THC potency levels showed independent associations with symptom relief and experiences of both positive and negative side effects, with higher levels resulting in larger effects. In contrast, we did not observe an independent link between CBD levels and any of the omnibus symptom effects measured in the current study across nearly 20,000 user sessions.

Variability in cannabinoid profiles may partially explain inconsistent findings in the literature on, for example, the benefits of using cannabis for treating chronic neuropathic pain, with effectiveness observed in some studies4,34, but not others35. Similarly, while many patient groups (e.g., sleep–disturbed medical cannabis users) have reported a preference for high CBD concentrates36, we did not observe any patient outcomes varying by CBD potency levels alone. One possibility is that many of the CBD potency levels displayed on labels of the products consumed in the study were inaccurate (e.g., inflated), as is currently common in the medical cannabis industry37. Alternatively, it is possible that CBD has more latent effects than THC (e.g., expanding beyond the 90 minute observation window), has an impact on symptoms infrequently reported in our data, or that CBD’s effects may not lend themselves to perceptual detection and subjective reporting. The phytocannabinoid family of CBDs are known to differ from other cannabinoids such as THC in several ways, including having no affinity to CB1 receptors, serving as an antagonist to GPR55 receptors and as an inverse modulator of the effects of THC and perhaps the endocannabinoid system more generally, as well as functioning as an immuno-suppressant and anti-inflammatory agent38,39. Thus, it is possible that while CBD may operate inconspicuously to improve certain health outcomes, the adjunctive consumption of THC is needed to consciously experience or be aware of such effects.

Notwithstanding the innovative nature and potential implications of the study’s findings, our observational, quasi-field experiment had unavoidable limitations, including the lack of a control group, e.g., non-cannabis users with similar symptoms, salient characteristics, past experiences, and voluntary reporting, which could lead to either: a) overestimation of the effectiveness of product characteristics if users who have negative experiences with cannabis are more likely to drop out of the sample by choosing not to use the ReleafApp; or b) underestimation of cannabis’ effectiveness if users fail to use the ReleafApp due to already being satisfied with their product choices and their effects. It is also important to note that the patient-reported outcomes were not cross-referenced with clinical assessments. As with any observational study there is the potential confound of a placebo effect, and given that cannabis products advertised as containing higher THC contents are generally more expensive to consumers, they may be subject to a buyer’s justification effect (magnified appreciation to justify an added expense of purchase). Another limitation is that the ReleafApp may be better suited to tracking the more immediate responses of users of concentrates, flower, and to some extent, tinctures versus the longer to peak effects of edibles and topicals. It is also possible that people who choose not to use the ReleafApp have different experiences with product characteristics than those who do use the app. Another limitation was the inability to distinguish subtleties across product types, such as pipes, which can vary in material construction and potential chemical reactions (e.g., hydrolysis via water pipes). Finally, we anticipate that greater nuances exist in the effects of product characteristics, and particularly, cannabinoid contents across symptom categories, but the current study is limited by our sample size within each respondent subgroup. Future research will capitalize on our ever increasing sample size to analyze the pharmacodynamic interactions of major cannabinoids and other organic compounds including terpenoids, as well as the harm of cannabis production practices. For example, the use of solvents to extract cannabinoids for making concentrates used in making non-flower products (e.g., edibles, tinctures) may place patients at risk for respiratory and cardiovascular problems40 and be a cause of increased emergency cases of Cannabinoid Hyperemesis Syndrome41.

In conclusion, rapid increases in the popularity of medical cannabis and the associated increase in the number of patients highlight the urgency of investigating and directing effective usage. Cannabis use carries the risk of addiction and short-term impairments in cognitive and behavioral functioning, including the potential for safety issues in the workplace or while driving. However, with preliminary evidence that cannabis may treat an even wider range of conditions than those tracked in this study, including cancer42,43, it is imperative that the scientific community develop innovative strategies such as the use of mobile technology for measuring the multidimensional relationships among cannabis product characteristics, patient health conditions, perceived symptom relief, and side effect manifestation.