with minimal changes in opiate metabolism and toxicity. THC appears to synergize most with the painkilling effect of opiates, while CBD is most promising for reducing withdrawal and dependence. Hence, cannabinoids are likely to potentiate opiates, decreasing pain while minimizing risks associated with tolerance, dependence and overdose. Not all interactions will be positive, but the potential is there, and dramatic problems appear unlikely.
which activation of CB1 is important). But if the former effect of cholesterolinhibiting CB1 is dominant, then statins may amplify the effect of cannabinoids, resulting in increased side effects like anxiety. These changes will be particularly relevant in patients taking THC, which directly activates CB1 receptors. Cannabinoids also exert effects through changes in membrane fluidity and permeability, which will certainly be altered if cholesterol levels are decreased. Patients taking cannaMetabolic Syndromes binoids who begin treatment with statins Insulin: There is strong preclinical should be warned that the effective dose evidence that cannabinoids inf luence of cannabinoids will likely change. (Note glucose and insulin sensitivity, which could that there is no established “normal” dose have a serious impact on of cannabinoids. Doses of patients with type 1 or THC range from roughly 1 type 2 diabetes, though to 50 mg, and are depenthe effect will depend on dent on a patient’s condiwhich cannabinoids are tion, tolerance, experience taken. 34 Insulin sensitiva nd com for t w it h t he ity will likely be impaired psychoactivity of THC. by psychoactive constituIf a patient has found an ents of cannabis like THC, effective dose of cannawhile cannabinoids includbinoids, stat ins cou ld ing CBD and tetrahydroshift this dose in either ca nnabivarin (T HC V ) direction.) may increase sensitivity Warfarin: Warfarin is to insulin. CB1 activaone of the most widely tion is part of a feedback used blood thinners and mechanism that reduces is primarily inactivated the body ’s response to by C Y P 2C9. Com mon glucose and insulin. 35-36 mutat ions in C Y P2C9 Gel caps being formulated with specific concentrations of THC and CBD Some studies, although reduce its activity to less from CO2 -extracted cannabis oil. fewer, show the opposite.2,37 than half of normal, which O ne C B1 a nt agon i st , may contr ibute to the Rimonabant, was brief ly approved in which raises the possibility of interactions difficulty of dosing warfarin; over a third Europe for treating obesity, but severe with statins by non-metabolic means.39-40 of all patients who take warfarin end up psychiatric complications (depression and CB1 activation may even inhibit HMG-CoA in the emergency room before an optimal suicidal behavior) forced its removal from reductase, although this was only shown dose is found, according to a 2008 report.47 41 the market. in cancer cells. THC and CBD can both inhibit CYP2C9, Epidemiological data, however, compliThe major interactions between statins and hence amplify warfarin’s effects. This cates the picture. Cannabis use is associand phytocannabinoids will likely be on has been demonstrated in a case study as ated with an overall decrease of metabolic cannabinoid function. Cholesterol levels well as preclinical work.48 Doctors should 1 syndromes. Moreover, while there is an are intimately involved in CB1 receptor be cautious about mixing cannabinoids increased prevalence of prediabetes among function. CB1 has multiple binding sites for with warfarin, although reducing the dose cannabis users, there is no change or a cholesterol, which influences many aspects of warfarin should be enough to prevent lower incidence of diabetes compared to of its signaling.42-43 The cholesterol precuradverse effects. the general population. It is not clear if this sor pregnenalone decreases CB1 activity.44 is due to uncontrolled confounding factors Cholesterol similarly inhibits CB1, but it Cannabinoid-Cannabinoid or if the effect of CB1 activation changes also directs CB1 to its proper location Interactions between healthy and insulin insensitive in neurons.42-43,45-46 If the latter effect is It would be inappropriate to address individuals. It is possible that the endocanmore dominant, cannabinoids—especially cannabinoid-drug interactions without nabinoid system buffers insulin sensitivity psychoactive cannabinoids—could become mentioning the influence of many cannarather than strictly inhibiting it.38 less effective in patients taking statins. binoid and terpenoid compounds on Statins: Statins reduce the synthesis This would be relevant for the treatment each other, sometimes called the “entouof cholesterol by blocking HMG-CoA of multiple sclerosis, pain, cachexia and rage” effect.49-50 Cannabis is a plant, not a reductase, an important early step in the epilepsy, among others (i.e., conditions for drug. Different varietals (i.e., strains) and SONOMA MEDICINE
production of cholesterol by the liver. This effect is not necessarily specific to low-density lipoprotiens. The metabolism of statins is less general than for other drugs mentioned here. Statins are metabolized by CYPs 3A4/5, 2C8/9/19 and 2D6, indicating that phytocannabinoids could change statin metabolism. Prodrugs like simvastatin and lovastatin require metabolism to become active. The more hydrophilic statins (e.g., pravastatin) are excreted by the kidneys with minimal metabolism by CYPs, so these statins are unlikely to be affected by cannabinoids. Cannabinoids are known to be involved in cholesterol metabolism, heart disease and mitochondrial function,
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