Medical Marijuana: Is the Cart Before the Horse?

There is apressingneed todevelopnewmedications formany debilitating conditions. Novel approaches based onmarijuana or its constituent cannabinoids, if proven, could be added to the armamentarium of available treatments. In this issue of JAMA, reviews byWhiting et al1 and Hill2 provide detailedassessmentof thepharmacology, indications, benefits,adverseeffects,andlaws related tomedicalmarijuanaand thecannabinoids, and the results andconclusionsare consistent.There is someevidence to support the use of marijuana for nausea and vomiting related tochemotherapy, specificpain syndromes, andspasticity from multiple sclerosis. However, for most other indications that qualifyby state lawforuseofmedicalmarijuana, suchashepatitis C, Crohn disease, Parkinson disease, or Tourette syndrome, the evidence supporting its use is of poor quality. State laws vary widely regarding conditions for which marijuana is approvedandthedispensable legal limit.Bothreviewsraise important issues worthy of further discussion. First, for most qualifying conditions, approval has relied on low-quality scientific evidence, anecdotal reports, individual testimonials, legislative initiatives, and public opinion. Imagine if other drugs were approved through a similar approach. The US Food and Drug Administration (FDA) requires evidence from at least 2 adequately powered randomized clinical trials before approving a drug for any specific indication. For most of the conditions that qualify for medical marijuanause, theevidence fails tomeetFDAstandards. It has beenargued that the lackof high-quality evidence reflects the difficulty inconductingmarijuanaresearch intheUnitedStates. If so, the federal and state governments should support and encourage such research so that high-quality evidence canbe generated to guidedecisions aboutmedicalmarijuanause for the conditions forwhich the existing evidence is either insufficient or of poor quality. Second, there are inconsistencies in how medical conditionsarequalified formedicalmarijuanausewithina stateand between states. For example, in Connecticut, psoriasis and sickle cell disease but not Tourette syndrome qualify, even though the supporting evidence for all 3 conditions is uniformly of very lowquality. Similarly, posttraumatic stress disorder (PTSD) is approvedas aqualifying condition in somebut not all US states. These differences reflect inconsistencies in evaluatingandapplyingcurrentevidencetowarddecisionmaking about qualifying indications for medical marijuana use. Third,unlikemostFDA-approveddrugs that typicallyhave 1or2activeconstituents,marijuanaisacomplexofmorethan400 compounds including flavonoids and terpenoids and approximately 70 cannabinoids other than Δ9-tetrahydrocannabinol (THC)3.Thesecannabinoidshaveindividual, interactive,andeven entourageeffects(effectsofacompoundthatareonlyappreciable inthepresenceofothercompounds)thatarenotfullyunderstood andthatcontributetotheneteffectofmarijuana.Althoughclinical trials forsomeof thequalifyingconditionsandstudies inanimalmodelsof thoseconditionshavebeenconductedwith individual cannabinoids (eg, THCor cannabidiol [CBD]), given that marijuanahas somanyconstituents, the results of studieswith individualcannabinoids(eg,THCorCBD)cannotbeextrapolated tomarijuana and vice versa. In addition, unlike FDA-approved medicationsthathavearelativelyuniformcomposition,thecompositionofcannabispreparationscanvarysubstantiallyinitscontent of THC andCBD, such that precise dosingmaybe difficult. Giventhevariablecomposition,patientswillhavetoexperiment with different strains and doses to achieve the desired effects, withoutmuch input or oversight by physicians. Fourth, some individual cannabinoids are already commercially available in the form of dronabinol and nabilone. Thesedrugs are administeredorally, and somepublisheddata are available to guide dosing. In contrast, there are few data on dosing smoked medical marijuana for many of the qualifying medical conditions for which it is used. Fifth,while theacuteadverseeffectsofmarijuanaarequite well known, the effects of repeated exposure, aswould occur withmedicalmarijuana, need further study. Approximately 1 in 10 adult users of marijuana develops addiction, and this number is evenhigher amongadolescents.4Tolerance anddependence with accompanying down-regulation and desensitization of type 1 cannabinoid receptors occur with repeated exposure.5 Based on this profile, marijuana dosing will have to be increased over time to achieve the same effect. A distinct withdrawal syndrome is also well recognized. There is also a small but definite risk of psychotic disorder associated with marijuana use, as well as a significant risk of symptom exacerbations and relapse in patients with an establishedpsychoticdisorder.6Thus,explicitcontraindicationssuch as schizophrenia, bipolar disorder, or substance dependence need tobe identifiedalongwithmeasures tominimize the likelihoodthatpersonswithcontraindicationswouldbeable toobtain medical marijuana. Perhaps US states should establish clinical follow-upprogramstomonitor long-termoutcomesprospectively, especiallynegativeoutcomes (eg,newcasesofpsychosis) in patients with contraindications. Author Audio Interview at jama.com