ARMODAFINIL
DEXTROAMPHETAMINE
METHYLPHENIDATE
MODAFINIL
- Cytochrome P450 enzyme substrate: CYP3A4, CYP1A2
- Action to be taken: Caution with close monitoring
- Rationale: The existence of multiple pathways for armodafinil metabolism, as well as the fact that a non-CYP-related pathway is the most rapid in metabolizing armodafinil, suggest that there is a low probability of substantive effects on the overall pharmacokinetic profile of NUVIGIL due to CYP inhibition by concomitant medications. In vitro data demonstrated that armodafinil shows a weak inductive response for CYP1A2 and possibly CYP3A activities in a concentration-related manner and that CYP2C19 activity is reversibly inhibited by armodafinil. Other CYP activities did not appear to be affected by armodafinil. An in vitro study demonstrated that armodafinil is a substrate of P-glycoprotein. Due to the partial involvement of CYP3A enzymes in the metabolic elimination of armodafinil, coadministration of potent inducers of CYP3A4/5 or inhibitors of CYP3A4/5 could alter the plasma levels of armodafinil. In vitro studies show that cannabis is a substrate of CYP3A4 and CYP2C9. In addition in vitro studies have shown that cannabis may have weak inhibition of CYP3A4 and CYP2D6. Furthermore synthetic cannabis has shown to be a weak CYP1A2 inhibitor. Therefore based on available data, interaction between armodafinil and cannabis may be observed. Concomitant adminstration should be used with caution due to potential increased serum concentrations of armodafinil.
DEXTROAMPHETAMINE
- Action to be taken: Caution with close monitoring
- Rationale: Studies indicate that the combination of marijuana and amphetamine had an additive effect on heart rate, blood pressure. Available data suggests that higher doses of marijuana - amphetamine combination may produce harmful psychological and cardiovascular effects but not above that of simple addition.
METHYLPHENIDATE
- Action to be taken: Caution with close monitoring
- Rationale: Methylphenidate is not metabolized by cytochrome P450 to a clinically relevant extent. Inducers or inhibitors of cytochrome P450 are not expected to have any relevant impact on methylphenidate pharmacokinetics. Conversely, the d- and l-enantiomers of methylphenidate did not relevantly inhibit cytochrome P450 1A2, 2C8, 2C9, 2C19, 2D6, 2E1 or 3A. Methylphenidate coadministration did not increase plasma concentrations of the CYP2D6 substrate desipramine. Study by Kollins et al. found that co-administration of Methylphenidate and THC results in additive effects on heart rate and rate-pressure product. These increases in cardiovascular stress occur in combination with a slight, though statistically non-significant attenuation of THC-induced changes in inhibitory control (CPT commission errors). In addition, 10 mg THC produced robust subjective effects associated with drug liking. These data raise the possibility that the combination of prescription stimulants, such as MPH, and THC, especially in smoked form, may be a desirable “cocktail” for young adults seeking euphorogenic effects of marijuana without adversely impacting cognitive performance.
MODAFINIL
- Cytochrome P450 enzyme substrate: CYP3A4
- Action to be taken: Caution with close monitoring
- Rationale: Induction of metabolizing enzymes, most importantly cytochrome P-450 (CYP) 3A4, has also been observed in vitro. Based on in vitro data, modafinil is metabolized partially by the 3A isoform subfamily of hepatic cytochrome P450 (CYP3A4). In addition, modafinil has the potential to inhibit CYP2C19, suppress CYP2C9, and induce CYP3A4, CYP2B6, and CYP1A2. Because modafinil and modafinil sulfone are reversible inhibitors of the drug-metabolizing enzyme CYP2C19, co-administration of modafinil with drugs which are largely eliminated via that pathway, may increase the circulating levels of those compounds. Due to the partial involvement of CYP3A4 in the metabolic elimination of modafinil, co-administration of potent inducers of CYP3A4 or inhibitors of CYP3A4 could alter the plasma levels of modafinil. In vitro studies show that cannabis is a substrate of CYP3A4 and CYP2C9. In addition in vitro studies have shown that cannabis may have weak inhibition of CYP3A4 and CYP2D6. Furthermore synthetic cannabis has shown to be a weak CYP1A2 inhibitor. Therefore based on available data concomitant administation of cannabis and modafinil may result in the increased concentrations of modafinil and cannabis. This interaction warrants close monitoring of potential adverse effects.
References
- Nuvigil (armodafinil) package insert. Cephalon, Inc. Frazer, PA 2007
- Ashino, T. Hakukawa K, et al. Inhibitory effect of synthetic cannabinoids on CYP1A activity in mouse liver microsomes. The journal of toxicological sciences. Volume 39, Issue 6, Pages 815 -820, 2014
- Watanabe K, Yamaori S, Funahashi T, et al. Cytochrome P450 enzymes involved in the metabolism of tetrahydrocannabinols and cannabinol by human hepatic microsomes. Life Sci. 2007;80:1415-1419.
- Stout SM, Cimino NM. Exogenous cannabinoids as substrates, inhibitors, and inducers of human drug metabolizing enzymes: a systematic review. Drug Metab Rev. 2014;46:86-95.
- EVANS, M. A. (1974). Clinical Studies With Marijuana And Dextroamphetamine Combination (Order No. 7501694). Available from ProQuest Dissertations & Theses Global. (302709551). Retrieved from https://search-proquest-com.gate.lib.buffalo.edu/docview/302709551?accountid=14169
- Kollins SH, Schoenfelder EN, English JS, et al. An exploratory study of the combined effects of orally administered methylphenidate and delta-9-tetrahydrocannabinol (THC) on cardiovascular function, subjective effects, and performance in healthy adults. Journal of substance abuse treatment. 2015;48(1):96-103. doi:10.1016/j.jsat.2014.07.014.
- Ritalin (methylphenidate) package insert. Novartis Pharmaceuticals Corp. East Hanover, NJ 2017
- Provigil (modafinil) package insert. Cephalon, Inc. Frazer, PA 2007