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28 research focus cannabis patient care | vol. 2 no. 2 cannapatientcare.com in humans by THC, these are isolated occurrences with no cor- relation to dosage, timing of administration, etc." (18). Pharmacokinetics Both THC and CBD have been shown to inhibit cytochrome P-450 enzymes, that is, they interfere with the metabolization of other medications (1–4,6,8,11,14,16). In particular, CBD decreases the rate of metabolism of the common anti-seizure medica- tion, clobazam. However, simply decreasing doses of clobazam seems to alleviate the effects (8,15). Adverse Effects Clinical studies indicate that the use of cannabidiol for epilepsy generally involves adverse effects. The majority of study par- ticipants experience adverse effects, including somnolence, di- arrhea, decreased appetite, fatigue, lethargy, pyrexia, vomiting, and elevated liver enzymes (3,6,15). Adverse effects reportedly dissipated upon cessation of dos- ing. Moreover, several studies noted that adverse effects were alleviated either by lowering doses of cannabis (or clobazam) (6,15) or by administering cannabis in forms alternative to the standard oil tinctures, such as through transdermal or vapori- zation administration (3). Placebo Effect Several researchers noted that cannabis has been receiving a lot of media attention lately, where CBD has been touted for its dramatic benefits in treating children with epilepsy. These media reports have created high expectations for many parents about the potential of CBD. Since the placebo effect is intimately tied to patient expectations, researchers have suggested that expectations created by media attention may be responsible for significant positive responses of study participants who were given placebos, rather than cannabis medicine (1,3,4,8). In par ticular, a study performed in Colorado included sub- jects whose families had moved to Colorado to be able to ac- cess cannabis treatments, as well as subjects who had been native residents of Colorado. Results showed that study par- ticipants who had moved to the state repor ted positive re- sponses to the medication (>50% seizure reduction) three times more often than study par ticipants who had been long-time residents of the state. These differences in repor t- ed results could not be explained by differences in types of epilepsy, types of cannabis treatment administered, or oth- er factors examined. Other similar examples were provid- ed. Paradoxically, such a strong placebo effect makes it dif- ficult for researchers to establish a true benefit attributable to medical cannabis (4). Nevertheless, cannabis studies have observed statistical- ly significant decreases in seizure frequency for epileptic chil- dren, a clinically important finding (8). Forms of Cannabis Use Two big challenges associated with studies of medical cannabis efficacy involve the forms of cannabis used in studies. The first challenge is that cannabis formulations vary from study to study, which makes head-to-head comparisons across studies difficult. Preclinical studies tend to involve pharmaceutical grade or synthetic forms of CBD, THC, or oth- er substances that act on the endocannabinoid-system (1,4). Next, surveys and retrospective studies tend to involve re- spondents who have used "cannabis," without providing spe- cific information about cannabis formulations (for example, CBD only, THC only, CBD and THC combined, minor cannab- inoids and terpenes), form of use (such as smoking, vaping, tinctures, capsules) or dosing (for example, 5 mg/day, 50 mg/ day) (1,6). Finally, clinical trials tend to differ in the types of cannabinoids used: synthetics, pharmaceutical grade isolates, or plant extracts (1,6). Again, the variation in cannabinoid type makes it difficult to compare outcomes across studies. The second big challenge with studies of medical canna- bis efficacy is their use of isolates—purified CBD or THC—which may be less effective in generating therapeutic effects than whole plant extracts. More specifically, cannabis researchers have emphasized the benefits of using plant extracts contain- ing multiple compounds from the plant. Relative to using CBD or THC isolates, plant extracts enable patients to use lower doses that achieve better positive effects, with fewer negative effects (19). Studies that use cannabis isolates rather than ex- tracts, as do most of the clinical trials, run the risk of biasing study results towards findings of lower efficacy. Patient Versus Provider Safety Concerns When considering the benefits and risks of different therapies, physicians tend to have very different perspectives than patients do. In particular, physicians tend to be risk-averse and eschew potential therapies that offer potential benefits, but that come with the risk of making patients worse off than they currently are. Patients, on the other hand, tend to be less risk-averse than providers: Patients live with the day-to-day reductions in quality of life caused by their ill health, and many patients are quite willing to risk further harm with a new therapeutic, if it comes with enough of a chance at improvement in their current state. Roughly 30% of epileptic patients are treatment-resistant. As reported earlier, these patients suffer frequent seizures, together with severe cognitive and behavioral impairment, morbidity, and mortality. As seen by the relocation of many families with epileptic children to cannabis-friendly states, many of these treatment-resistant patients would willing- ly risk potential harms associated with using cannabis for the chance of reduction in seizures associated with cannabis use. Physicians should be aware of this difference in perspective. At the same time, a non-trivial portion of epileptic patients who have participated in cannabis research indicate that they