Context: Nutmeg [Myristica fragrans Houtt. (Myristicaceae)] has a long-standing reputation of psychoactivity. Anecdotal reports of nutmeg use as a cheap marijuana substitute, coupled to previous studies reporting a cannabimimetic-like action, suggest that nutmeg may interact with the endocannabinoid system. Objective: The study evaluates nutmeg fractions for binding capacity with various CNS receptors and their potential interaction with the endocannabinoid system. Materials and methods: Dichloromethane (DF) and ethyl acetate (EF) fractions were prepared from the methanol extract of powdered whole nutmeg. The HPLC-profiled fractions were assayed by the NIMH Psychoactive Drug Screening Program (PDSP) in a panel of CNS targets at a 10 lg/mL concentration. The fractions were also screened for fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL) inhibition, initially at a concentration of 500 lg/mL, then by concentration-dependent inhibition studies.Results: None of the tested fractions showed significant binding to CNS receptors included in the PDSP panel. However, both fractions exerted significant inhibition of the FAAH and MAGL enzymes. The DF fraction inhibited FAAH and MAGL enzymes at IC 50 values of 21.06 ± 3.16 and 15.34 ± 1.61 lg/mL, respectively. Similarly, the EF fraction demonstrated FAAH and MAGL inhibition with IC 50 values of 15.42 ± 3.09 and 11.37 ± 6.15 lg/mL, respectively. Discussion and conclusion: The study provides the first piece of evidence that nutmeg interacts with the endocannabinoid system via inhibition of the endocannabinoid catabolizing enzymes. This mechanism provides insight into reported cannabis-like action as well as expands the potential therapeutic utility of nutmeg.ARTICLE HISTORY

The inhibition of endocannabinoid metabolizing enzymes offers a novel therapeutic target for treatment of depression and anxiety. Previous studies in our laboratory have established cannabis‐like effects of nutmeg extracts in animal models. However, these effects were not coupled to binding to cannabinoid receptors. The main purpose of our study was to examine the effect of nutmeg extracts on the activity of fatty acid amide hydrolase (FAAH) and monoacylglyceryl lipase (MAGL). Total nutmeg extract (TE) was prepared and successively extracted with solvents of various polarities. The extracts were fingerprinted by HPLC and tested for FAAH and MAGL inhibition against positive controls. The total extract showed a concentration‐dependent inhibition for both FAAH and MAGL with IC50 values of 17.71 and 5.17 mg/mL, respectively. The dichloromethane and ethylacetate fractions showed the highest enzyme inhibition. The IC50 values of FAAH and MAGL inhibition by the ethylacetate fraction were 15.21and 49.42 mg/mL, respectively. The IC50 values of FAAH and MAGL inhibition by the dichloromethane fraction were 32.00 and 32.86 mg/mL, respectively. Inhibition of endocannabinoid metabolizing enzymes by nutmeg extracts explains the cannabis‐like effect exerted by nutmeg. Such inhibition also offers potential utilization of nutmeg compounds for indirect modulation of the endocannabinoid system.