Clinical Considerations of Cannabinoid Medicines

Behavioral research has established that most patients have already experimented with using cannabis therapeutically before asking their physicians about it—if they ask at all.1 The concern patients have for how their doctor perceives them, coupled with a fear of being stigmatized as a marijuana user, indicates that patients using cannabis medicinally often fail to disclose that use to their doctors.50 The robust market in cannabis makes independent experimental use possible in ways that are not seen using conventional medications. As a result, it behooves clinicians to not just be prepared for such questions, but to be assertive about broaching it with patients for whom cannabis may be a legitimate treatment option.

While some individuals may hide their therapeutic use of a stigmatized drug, others may ask physicians for medications outside the bounds of accepted treatment. Research indicates that 20% of individuals who present themselves in emergency room visits as having acute pain are seeking opioid medication for questionable or non-therapeutic reasons.51 Clinical guidelines for managing addiction liability include continuity of care and use of signed treatment agreements to describe and minimize risks, an approach that has been recommended for medical cannabis.52

Dosing Guidance

Clinicians are rightfully concerned with providing accurate medication dosing directions for their patients. Though plants have been the source of treatments throughout most of human history, botanical medicines pose a challenge for accurate dosing because of the difficulty in obtaining reliably standardized products. The complexity and variability of botanical medicines contributed to the 20th century’s turn away from plant remedies to pharmaceuticals based on isolated active ingredients that can be synthetically manufactured with consistency.

This complexity and variability are particularly true of medicinal cannabis products and of the plant itself, all of which are highly variable in their chemical components. Even carefully cultivated cannabis plants of the same varietals, including clones from the same parent plant, may result in end-product variability with differing cannabinoid and terpene profiles. This is multifactorial and can depend on a given plant flower’s chemical variability, how and where it was grown, when it was harvested, and how it was dried and cured. Additionally, non-standardized chemical testing reports can vary significantly in assessing products, further complicating the matter (Figure 4.12).

As with most medications, “start low and go slow” is a sound strategy for cannabinoid medicine therapies in most conditions. The variability of commonly available cannabis products is

Summary of current cannabinoid medicines with their available component doses, research trial dose ranges, and Drug Enforcement Administration schedule (Jeffrey S. Block, MD)

FIGURE 4.12 Summary of current cannabinoid medicines with their available component doses, research trial dose ranges, and Drug Enforcement Administration schedule (Jeffrey S. Block, MD).

compounded and confounded by considerable variance in patient experiences based on inconsistent product types and routes of administration, use timing and routines, and physiologic set points. What counts as a sub-optimal dose in one individual may be a robust effective treatment in another, and this often changes with individuals over time. Some of those differences may be associated with developed tolerance via receptor downregulation, but changes in sensitivity can affect some long-time users such that they report decreasing their dosing over time with comparable results. What serves as a low or high dose will vary between individuals based on that person’s experience with cannabis use, their physiology, and the route of administration. Many state regulatory agencies have set dosing standards or “serving sizes” at 10 mg THC, but doses as low as the clinical threshold of 2.5 mg THC or 2.5 mg of balanced ratio THC:CBD products are commonly manufactured and used effectively by cannabis-naive patients. CBD dosing should be carefully integrated as part of a patient’s overall pharmaceutical management because it can induce some cytochrome p450 enzymes, suggesting that it has clinical relevance concerning the breakdown of other medications, including blood-thinners and other anxiolytics.

Paradoxical Dose-Dependent Effects on Pain

For pain patients, care with dosing is especially important, as THC and whole-plant preparations have been shown to exhibit dose-dependent effects that are paradoxically biphasic. Relatively low doses typically produce effective mild to moderate analgesia, but high doses can actually intensify pain sensations. This dose-dependent characteristic features a narrow window of effective dosing (ED) that may explain early clinical studies of cannabinoid analgesia that produced inconclusive results. The doses of THC vary between clinical trials, and the studies included in the NASEM report produced some indication of dose-dependent effects. The importance of dose was also seen in studies of vaporized cannabis involving acute pain,53 54 but a similar study found analgesic effects to not be dose-dependent.55 Anecdotal reports of pain intensification typically entailed relatively large doses. Escalation in dosing can occur when a patient believes the amount taken was insufficient, and subsequently takes more. That can happen when the time to onset of effect is underestimated, as is more common with edible cannabis product’s slower GI absorption. Failure to achieve the desired level of analgesia can also contribute to a cannabis user surpassing the effective dose range as more and more is taken in hopes of achieving more relief.

Increasing cannabinoid dosing may cause increasing side effects, hence diminishing its overall therapeutic value. This is most profound with synthetic cannabinoids. When comparing synthetic cannabinoid medications such as dronabinol and nabilone, many patients prefer the whole plant’s balanced chemicals, critically describing the THC isolates as having "all of the side effects without all of the benefits." At high doses, the effects of THC alone may be not just hyperalgesia but acute anxiety and dysphoria. As mentioned earlier, CBD modulates these concerning effects of THC through direct and indirect mechanisms.

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