Methamphetamine addiction: do biological rhythms matter, and could they play a role in treatment?

Problems arising from methamphetamine (MA) use continue to increase globally, with key challenges including its high addiction propensity, and a lack of effective treatments that can be delivered to scale. Chronobiology may play a critical role in MA use and dependence; with Vrajová et al. [1] recently highlighting the key role that sleep disturbances play in relapse to MA addiction and reviewing key underlying molecular mechanisms. MA is a potent CNS stimulant that triggers a cascading release of monoamines, mainly dopamine, producing multiple rewarding effects including euphoria and alertness [2]. Repeated use of MA can rapidly lead to dependence, with consequential dopaminergic dysfunction including reduced dopamine release, and depleted dopamine transporter and receptor availability [3]. The etiology of MA addiction is complex and involves the reviewed biological pathways [1] in addition to psychological and sociocultural factors [3]. A bidirectional relationship between MA addiction and the circadian system is also apparent, and we argue that dopaminergic effects in these relationships are important to consider. While MA use causes circadian disruption, evidence also shows that circadian system abnormalities play an important role in the development and progression of MA use disorder [4].

MA and Circadian Rhythms

Amphetamine-type stimulants, including MA, impact numerous functions regulated by the circadian system, including body temperature, appetite, mood, and alertness. Studies have investigated the effect of these drugs on direct outputs of the circadian clock and on mechanisms that underlie its function [4]. Additionally, 3,4-methylenedioxymethamphetamine, another amphetamine-type stimulant, is able to directly affect the circadian clock through dysregulation of core clock genes which generate and maintain circadian rhythmicity [5]. Despite this, there has been limited evaluation of the impact of chronic MA use on biological rhythms.

Conversely, there is evidence that circadian system disruption increases vulnerability to addiction [3]. Mutations in key genes involved in the generation and maintenance of circadian rhythms have been linked to drug-seeking behaviors [6], and environmentally derived circadian disruptions including shift work increase risk for substance use disorders. However, circadian factors have largely been ignored by the addiction field or viewed from a limited lens. For example, sleep-timing disturbances and poor quality sleep have often been viewed as consequences of the lifestyle associated with drug use (e.g. engagement in all-night binges, and erratic lifestyles that favor “owl” rather than “lark” patterns of behavior) [6]. The bidirectional link between addiction and the circadian system constitutes a basis for examining circadian inputs to MA addiction, not just outputs, as potential therapeutic targets.

MA and the Synchrony of Circadian and Ultradian Oscillations

Rhythms are pervasive, playing a fundamental role at multiple levels of biological organization. Numerous physiological and behavioral functions are regulated to periods of approximately 24 h by the circadian clock located in the suprachiasmatic nuclei (SCN) [7]. Other physiological and behavioral functions have substantially shorter or longer periods. Ultradian rhythms, for example, recur within a 24-h period (e.g. cycles of rapid eye movement [REM] and non-REM sleep, feeding, drug-taking behavior). Ultradian oscillations are usually well-integrated with the circadian system, as they lack the period stability and expression robustness of circadian outputs due to their non-reliance on the SCN [8]. As such, ultradian rhythms are usually masked by circadian rhythms. However, what happens when the relationship between these rhythms is disrupted with MA use?

It is plausible that MA-induced disruption to ultradian oscillations puts these shorter oscillations out of phase with the SCN-master clock, causing perpetual internal confusion which may be one important mechanism of the longer-term adverse health and psychological consequences of MA use disorder.

The Curious Case of MA and Biological Rhythms

Preclinical models have demonstrated that: (1) MA administration delays behavioral activity rhythms, (2) MA behavioral rhythms persist in the absence of intervention or resetting by another stimulus, and (3) SCN-lesioned animals display a robust ultradian activity rhythm. Together these lines of evidence demonstrate that MA-induced rhythms run independently of the circadian pacemaker [7, 8].

While MA-induced rhythms have historically been attributed to an MA-sensitive circadian oscillator, they are better understood as the output of a dopaminergic ultradian oscillator (DUO) [6]. Dopamine plays a central role in setting the frequency of ultradian rhythms, with dopaminergic dysfunction amplifying and lengthening ultradian rhythms [8]. While the DUO is normally synchronous with the circadian clock, disrupted dopamine levels can uncouple its alignment with the SCN pacemaker [7, 8]. Hence, the study of MA-induced rhythmic changes is likely to aid our understanding of some of the core physiological and psychological disturbances, including to sleep, mood, and reward system-related neurophysiology and behavior associated with chronic MA use and withdrawal.

Phase Resetting as a Treatment Goal?

Chronic MA use leads to marked dopaminergic dysregulation [1, 2] and may lead to altered ultradian rhythms coordinated by the DUO, leading to instability in their relationship with the circadian system. Efforts to reinforce the integrity of rhythmicity, as well as stabilize the dopamine system, may be a valid goal for the treatment of MA use disorder.

Phase resetting can be accomplished using chronotherapeutic interventions including light or melatonin administration. Melatonin has the added benefit of providing a protective effect on the dopamine system and may attenuate cellular apoptosis and dysfunction, and dopaminergic degeneration induced by MA [9]. There is preclinical research to suggest the role of melatonin supplementation in the control of drug-seeking behavior, withdrawal, and relapse [3]. Melatonin is well-tolerated, with no addiction liability, and has demonstrated high efficacy for circadian disorders, including those with a psychopathological component (e.g. seasonal affective disorder) [10]. The benefits of melatonin and related agonists (e.g. agomelatine) for the management of substance use disorders warrant continued evaluation [9, 10].

Conclusions

The contribution of Vrajová et al. [1] is important in highlighting an issue of significant concern in both the sleep medicine and addiction fields. We further propose that MA-induced disruption to rhythmic outputs may occur through a dopamine-dependent oscillator. Stabilizing the timing of the circadian system, therefore, may assist in the clinical management of MA use disorder. Melatonin may provide a useful clinical adjunct through two disparate mechanisms: protection of DA systems affected by MA and the ability to normalize rhythmicity.

Disclosure Statement

Financial disclosure: None.

Nonfinancial disclosures: None.

Conflict of interest statement. None declared.