GLP-1R agonist medications for addiction treatment

Abstract

The emergence of medications that emulate the glucagon-like peptide 1 (GLP-1), including GLP1-receptor agonists (GLP-1RA) has dramatically improved outcomes in the treatment of type 2 diabetes (T2D) and obesity, significantly reducing complications from their metabolic consequences including cardiovascular and chronic kidney disease. GLP-1 is an incretin hormone synthetized peripherally in the intestine and centrally in the nucleus tractus solitarius and olfactory bulb. GLP-1 signals via GLP-1 receptors, which are widely expressed in peripheral organs and in the brain. The regulation of food intake by GLP-1RA medications appears to involve both peripheral and central mechanisms, although the central mechanisms by which they reduce food consumption are still not fully understood.

The use of GLP-1RA medications has also been associated with reports of reduced craving for addictive substances, and preliminary evidence from clinical trials has shown reduced alcohol and tobacco consumption in patients with obesity or diabetes who were being treated with these medications [1]. Specifically, in the case of alcohol use disorders (AUD), a case report of six patients treated with Semaglutide for obesity who suffered from AUD, showed reduction in AUD symptoms (assessed with the Alcohol Use Disorder Identification Test [AUDIT]) [2]. A clinical remote study that relied on social media platform to recruit AUD participants reported reductions in alcohol consumed per day in patients with AUD treated with Semaglutide or with Tirzepatide [3]. However, as of today, the only RCT that has evaluated the effects of GLP-1R agonist medications in AUD failed to show reductions in heavy alcohol drinking days after 26 weeks of treatment with exenatide, a first generation GLP-1RA, except in AUD patients who also suffered from obesity [4]. Interestingly, this trial showed that exenatide significantly attenuated the activation of the ventral striatum (location of the nucleus accumbens [NAc]) and of the septal region, which are regions that mediate drug reward and conditioning [5]. Currently, a follow up RCT study is evaluating the effects of once-a-week Semaglutide in patients who are obese and suffer from AUD. Clinical trials to evaluate the effects of GLP-1RA medications for tobacco cessation have produced mixed results. One study reported benefit after 6 weeks of treatment with exenatide when added to nicotine replacement therapy (NRT) [6], whereas two studies showed no differences in abstinence rates after 12 weeks of treatment with dulaglutide compared to placebo, in patients who were also receiving varenicline and behavioural counselling [7, 8]. Meanwhile, reports based on retrospective cohort analyses from electronic health record (EHR) comparing GLP-1R agonist medications with other anti-obesity or antidiabetic medications seem to indicate better outcomes for cannabis use disorders in patients suffering from obesity or T2D [9].

Importantly, these preliminary emerging clinical findings are consistent with preclinical studies that for the past decade have documented that various GLP-1RA drugs reduced the rewarding effects of alcohol, nicotine, cocaine and opioids and reduced cue and drug-induced relapse in rodent models of addiction [4]. Several plausible neurobiological mechanisms underlying GLP-1 emulating medications on addiction can be invoked. GLP-1 receptors are expressed in the brain dopamine (DA) reward pathway, where they modulate DA release in the NAc [10], which is crucial for food and drug reward, driving conditioning and the motivation to consume them [10]. Indeed, preclinical studies have shown that GLP-1RAs decrease drug (cocaine)-induced DA increases in NAc (reviewed in previous works) [4], and that optogenetic stimulation of GLP1-R reduced drug-taking, whereas GLP-1R knockout mice consumed larger doses of various drugs than their wild-type littermates [11, 12]. Another proposed mechanism, shown in a rodent model of nicotine self-administration, invokes a role for the habenula, which through the pedunculopontine nucleus inhibits DA neurons mediating negative reinforcement. The habenula projects to and receives afferents from limbic regions involved with emotions and motivation and presumably balances the positive and negative experiences from the receipt or the omission of an expected reward, respectively. In the case of nicotine, GLP-1R activates the medial habenular pathway making the effects of nicotine aversive and reducing drug-taking, whereas the inhibition of GLP-1R in the habenula leads to escalation of nicotine intake [11]. Additionally, because negative reinforcement drives drug-taking in addiction, as a means to escape the negative emotional state associated with drug withdrawal [13], GLP-1RA could protect against stress-induced drug-taking in addictions as it does with stress-induced food consumption. Finally, the anti-inflammatory effects of GLP-1RA medications could also be beneficial, because there is growing recognition of neuroinflammatory processes contributing to substance use disorder (SUD) [14]. Intriguingly, GLP-1RA medications appear to reduce inflammation through their central effects—in part via Δ and κ opioid receptors—an effect that is lost after pharmacological blockade or genetic removal of GLP-1R in the brain [15].

The overlap in molecular and neuronal circuits that drive excessive food intake and addiction has been noted by multiple investigators [16]. Notably, for both obesity and addiction, there is evidence of reduced sensitivity of the DA brain reward circuit [17] and of impaired function of the habenular circuit [18, 19]. This overlap is also relevant to the potential benefit that GLP-1 emulating medications may offer for addressing multiple SUD as opposed to specific ones, as is the case for current United States Food and Drug Administration (FDA) approved medications. Given the high prevalence of individuals using multiple substances, clinical proof of therapeutic efficacy for GLP-1 emulating medications could provide the first treatment for polysubstance use. If effective, they could provide a treatment for stimulant and cannabis use disorders, for which there are currently no FDA-approved medications. Further, because weight gain, particularly among women undergoing treatment for SUD or for smoking cessation, contributes to relapse into drug-taking, the anti-obesity effects of GLP-1RA medications could provide and added benefit.

Although it is likely that some of these medications are already being used off-label for the treatment of SUD, their approval by the FDA for a SUD indication will provide a mechanism for their reimbursement. If reimbursed this would make these medications accessible to patients who otherwise are not able to afford them. To get FDA approval, trials will need to show that these medications are not only effective, but also safe and well tolerated by individual with SUD. This requires a sequential set of clinical trials to first determine safety (phase I trials), then efficacy (phase II trials) and then comparability with standard treatments (phase III). In safety trials for SUD the FDA additionally requires that trials evaluate the medication tested in combination with the drug misused to assure of its safety. Longer follow-up trials (6–12 months) that evaluate their benefits by themselves or in combination with other SUD medications will help evaluate their long-term benefits, compliance and risk of relapse with medication discontinuation. Although in general GLP-1 emulating medications are safe, further weight loss in very low body mass index patients might not be desirable and their gastrointestinal side effects might interfere with compliance particularly in patients suffering from opioid use disorder who are at higher risk of constipation.

The excitement that the new GLP-1RA medications bring to the addiction field exemplifies the translational opportunities that emerge from integrating knowledge across transdiagnostic clinical domains. The promising results emerging with the novel GLP-1 emulating medications highlight the pressing need to conduct rigorous clinical trials to determine their efficacy, safety and acceptability for treating SUD.

Nora D. Volkow: Project administration (lead); resources (equal); supervision (equal); writing—original draft (equal); writing—review and editing (equal). Rong Xu: Data curation (supporting); validation (supporting); writing—review and editing (supporting).

None.

None.