Resumen

OSTOS VALVERDE, Aline et al. Endocannabinoids and Orexins in the Modulation of the Sleep-Wake Cycle and Substance Abuse (second of two parts). Rev. Fac. Med. (Méx.) [online]. 2025, vol.68, n.6, pp.8-24.  Epub 27-Feb-2026. ISSN 2448-4865.  https://doi.org/10.22201/fm.24484865e.2025.68.6.02.

Sleep disorders are highly prevalent among individuals with substance use disorders (SUD). It has been reported that approximately seven out of ten patients entering detoxification treatment experience difficulties falling or staying asleep, and that a similar proportion of drug users consume substances as a form of self-medication to regulate the sleep-wake cycle. Beyond affecting quality of life, sleep disturbances increase vulnerability to relapse and the severity of SUD. In Mexico, alcohol is the most commonly used substance (over 70 ٪ of the population), whereas globally, cannabis remains the most widely used illicit drug, with 219 million users reported in 2021. Therefore, both in the Mexican and global contexts, it is of great relevance to identify the intersections between sleep disturbances and SUD, including the underlying neurobiological mechanisms, such as those mediated by the orexinergic and endocannabinoid systems.

This work constitutes the second part of a comprehensive analysis of the neurobiological systems linking sleep regulation with vulnerability to drug use. The first part addressed the relevance of the sleep-wake cycle, mediated by homeostatic (Process S) and circadian (Process C) factors, as well as the participation of various neurotransmitters. In this second part, the focus is on the role of the endocannabinoid and hypocretin/orexin systems in the regulation of sleep and their relationship with reinforcement and addiction mechanisms.

Both orexins and endocannabinoids modulate motivation and reward circuits involved in the consumption of alcohol, opioids, and psychostimulants. Moreover, both systems actively participate in the regulation of the sleep-wake cycle. Activation of the orexinergic system promotes wakefulness, whereas its dysfunction has been associated with narcolepsy. Conversely, disruption of the endocannabinoid system has been shown to produce sleep disturbances, even during abstinence. Experimental evidence from murine models demonstrates that antagonizing OX1R/OX2R receptors or blocking CB1R receptors reduces drug-seeking behavior and relapse. Therefore, the pharmacological modulation of these systems is proposed as a promising strategy to treat sleep disorders and improve rehabilitation outcomes in patients with SUD.

Palabras llave : Endocannabinoids; orexins; sleep-wake cycle; substance addiction; neurobiology.

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