FAAH and MAGL inhibition: Evolving approaches to treating substance use disorders

Abstract

Substance use disorder (SUD) remains a critical public health issue characterized by high rates of relapse and limited effective pharmacotherapies, particularly for non-opioid substances. A key challenge in addressing SUD lies in the persistent neuroadaptations within the brain’s reward circuitry. The endocannabinoid (eCB) system plays a crucial role in modulating reward and reinforcement processes and is disrupted by chronic drug exposure. Recent work highlights the therapeutic potential of indirectly modulating cannabinoid 1 (CB1) receptor signaling by targeting eCB-metabolizing enzymes, fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), to restore homeostatic eCB tone. We review and synthesize findings from both genetic and pharmacological studies, highlighting the contributions of FAAH and MAGL across major classes of abused substances and considering their potential as therapeutic targets for SUD treatment.

Introduction

Substance use disorder (SUD) remains a major public health concern in the United States, with far-reaching medical, economic, and societal consequences. One of the greatest challenges in treating SUD is the high rate of relapse. Repeated drug use induces lasting neuroadaptations in the brain’s reward circuitry, which contributes to persistent vulnerability to relapse, even after prolonged periods of abstinence [1,2]. Among the most urgent substance-related crises are opioid use disorder and alcohol dependence, due to their widespread prevalence and the high risk of overdose deaths associated with opioids [3]. Meanwhile, the use of other substances, such as cannabis and cocaine continues to rise [4,5], with no FDA-approved treatments for their dependence. Despite decades of extensive research, few molecular targets have emerged as consistently effective for both preventing SUD and reducing relapse risk.

One promising target is the endocannabinoid (eCB) system, which has been consistently implicated in modulating reward processing and the neurobiology of drug use and dependence [6]. As an example, recent work from our group demonstrated that enhancing levels of the endocannabinoid 2-arachidonylglycerol (2-AG) both systemically and directly within the ventral tegmental area (VTA) reduces opioid reward in a conditioned place preference assay [7]. Systemic enhancement of 2-AG levels also reduced self-administration of opioids and opioid reward-associated increases in activity of the nucleus accumbens (NAc). These effects were dependent on the expression of cannabinoid receptor 1 (CB1), the receptor targeted by endogenous cannabinoids N-arachidonoylethanolamine, also known as anandamide (AEA) and 2-AG. Fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), the primary enzymes responsible for degrading AEA and 2-AG respectively, are essential in regulating CB1 receptor signaling.

Within the mesolimbic dopamine system, CB1 receptors on glutamatergic and GABAergic inputs are well-positioned to modify dopaminergic signaling involved in the processing of both drug, and natural rewards [6]. As will be discussed below, acute and chronic exposure to drugs of abuse disrupt eCB-mediated plasticity of brain regions involved in reward processing [8]. Accordingly, pharmacological therapeutics that restore homeostatic endocannabinoid tone could potentially assist in restoring reward circuitry disrupted in addiction However, one of the main concerns with directly targeting CB1 receptors for therapeutic purposes is the risk of producing cannabimimetic effects and receptor desensitization [9]. As an alternative, indirect modulation of CB1 receptors through inhibition of eCB-degrading enzymes represents a promising therapeutic strategy [10]. This review will primarily focus on the effects of manipulating the eCB-metabolizing enzymes FAAH and MAGL with an emphasis on their main substrates (AEA and 2-AG), on reward and motivated behaviors related to various drugs of abuse. It will then discussed our most recent findings on the effects of MAGL manipulation on opioid reward and analgesia, and conclude with a brief description of eCB role in synaptic plasticity.

Endocannabinoid system components

The eCB system in the brain functions as a neuromodulatory network that helps maintain homeostasis across multiple neural processes, including reward [11], learning and memory [12], appetite [13], sleep [14], pain [15], among others. Back in the 1950s–1960s, researchers began to isolate cannabis compounds which led to the identification of Δ⁹-tetrahydrocannabinol (THC), the primary psychoactive compound [[16], [17], [18]], though its mechanism of action remained unclear for about two decades. During the 1980s–1990s, THC was found to bind a receptor in the brain, ultimately resulting in the discovery of the CB1 [19,20]. Subsequently, THC was also found to bind a second receptor in peripheral tissues, leading to the discovery of CB2 receptors [21]. In 1992, AEA was identified as the first CB1 receptor endogenous ligand [22], and 2-AG was identified in 1995 [23,24].

The eCB system (Fig. 1) is largely composed of the CB1 and CB2 receptors, both inhibitory G protein-coupled receptors (GPCRs), with CB1 receptors being the most abundant receptor in the brain [25]. Although CB2 receptors was initially identified as a peripheral receptor, recent studies have demonstrated its role in modulating neuronal activity (see Grabon et al., 2023, for review) [26]. In the brain, CB1 receptors are abundantly expressed in neurons within regions relevant to SUD and neuropsychiatric disorders [[27], [28], [29], [30]], whereas CB2 receptors are predominantly expressed in glial cells and play a role in immunomodulation (Howlett et al., 2002). The two main endogenous ligands are AEA, a partial agonist of CB receptors [31], and 2-AG, a full agonist of CB receptors [[32], [33], [34]] and the most abundant eCB in the mature brain [25].

Fig. 1.

Endocannabinoid Synthesis, Release, and Degradation. Neuronal depolarization and calcium influx can induce AEA synthesis via N-acyl phosphatidylethanolamine (NAPE) phospholipase D (NAPE-PLD) and 2-AG synthesis by diacylglycerol (DAG) lipase (DAGL). AEA is released in an autocrine manner; 2-AG is released in a retrograde manner, and both act on Gi/o-coupled CB1 receptors to inhibit neurotransmitter release and hyperpolarize the cell. Eventually, AEA is postsynaptically metabolized by FAAH and 2-AG is presynaptically metabolized by MAGL. Figure created using BioRender.com.

AEA and 2-AG are synthesized by the enzymes NAPE-PLD and DAGL, respectively, in postsynaptic dendrites [[35], [36], [37], [38]]. Specifically, the canonical synthesis pathway of AEA involves the hydrolysis of N-arachidonoyl phosphatidyl ethanolamine (NAPE) by NAPE-PLD [39]. For the synthesis of 2-AG, the canonical pathway involves the cleavage of arachidonoyl-containing phosphatidylinositol bisphosphate (PIP₂) by phospholipase to form diacylglycerol (DAG), which is subsequently hydrolyzed by diacylglycerol lipase (DAGL) [40]. Due to their lipophilic nature, eCB are produced specifically “on-demand.” Although there is still no clear mechanism for how eCBs are transported across membranes, carrier-mediated diffusion has been suggested [41,42], and evidence supports that both eCBs may be transported by the same membrane transporter [43]. Recently, it was shown that 2-AG is “on-demand released” by microvesicles [44] highlighting new avenues for future studies on eCB transport mechanisms. Following synthesis, AEA and 2-AG act on Gi/o coupled cannabinoid receptors on the presynaptic cell to inhibit adenylyl cyclase, voltage-gated calcium channels (VGCCs), and the subsequent intracellular cascade required for vesicle-membrane fusion and neurotransmitter release events. Additionally, CB1 receptor activation can stimulate the MAPK pathway, recruit beta-arrestins, and activate GIRK channels that further suppress presynaptic transmission [35,45]. In this way, eCBs can have net excitatory or inhibitory effects on the postsynaptic cell depending on the neurotransmitter release profile of the presynaptic cell that is modified. The retrograde messenger nature of eCBs allows them to function as a “gain control” mechanism through which cells can regulate their own input [46], relevant for shaping adaptive processes like reward learning and affect regulation. Endocannabinoid release can also have homosynaptic (impacting the original stimulating afferent) or heterosynaptic (impacting nearby afferents) effects, as is noted in the hippocampus and amygdala [47]. This allows local eCB signaling to have a rich variety of effects on larger circuit function.

Once eCBs dissociate from the receptor, they are internalized for subsequent degradation. The mechanism of internalization remains unclear with some studies supporting passive diffusion and others suggesting carrier-mediated transport [[48], [49], [50]]. After internalization, eCBs are primarily degraded through hydrolysis, although they may also undergo oxidation via alternative enzymatic pathways [51,52]. AEA is mostly hydrolyzed by the FAAH enzyme—located in postsynaptic dendrites and somata—into free arachidonic acid and ethanolamine [[53], [54], [55], [56]], while 2-AG is primarily metabolized by MAGL—predominantly found in presynaptic axon terminals [56]—into arachidonic acid and glycerol [57]. The development of genetic mouse lines lacking the FAAH or MAGL gene, as well as pharmacological compounds that act as inhibitors have proven to be effective in inducing higher levels of the AEA and 2-AG, respectively [[58], [59], [60], [61]]. Studies using these knockout mouse lines and/or inhibitors have shed light on how manipulating these enzymes can influence or benefit various neuropsychiatric and neurodegenerative disorders [62,63]. Building on preclinical findings demonstrating their therapeutic potential, significant efforts have been made to develop selective and potent FAAH and MAGL inhibitors as candidate treatments for these conditions. The most commonly used preclinical FAAH inhibitor is URB597, which was introduced over 20 years ago [60], while JZL184 [64] has been extensively used to inhibit MAGL. These inhibitors allow indirect modulation of cannabinoid receptors, particularly CB1 in the brain, by increasing levels of AEA and 2-AG, thereby influencing CB1 receptor-dependent synaptic mechanisms.

Although the main substrates for FAAH and MAGL are AEA and 2-AG, respectively, there are other substrates for these enzymes [54,[65], [66], [67]]. Among these, the fatty acid ethanolamides oleoylethanolamide (OEA) and palmitoylethanolamide (PEA), ligands of Peroxisome Proliferator–Activated Receptor Alpha (PPAR-α), have been shown to modulate the effects of drugs of abuse [68]. In particular, a few studies have demonstrated their effects on nicotine reward [69]. For example, FAAH inhibition or administration of OEA/PEA has been linked to a reduction in nicotine reward and VTA dopamine neuronal activity [70,71]. Therefore, FAAH inhibition can alter nicotine reward through substrates other than AEA. However, this review will focus on findings related to the primary substrates of FAAH and MAGL in the context of drugs of abuse and their therapeutic potential.

FAAH and MAGL in substance use disorder: from genetics to pharmacological modulation

Over the past several decades, both preclinical and clinical research have identified the eCB system as a promising target for modulating the effects of drugs of abuse, given its involvement in neural processes that govern the brain’s reward circuitry. While several reviews have explored in depth the interaction between components of the eCB system—particularly CB1 receptors—and drugs of abuse [72], this review focuses specifically on the metabolic enzymes FAAH and MAGL, and their roles in various SUDs. Targeting eCB-degrading enzymes provides an indirect means of modulating CB1 receptor activity, representing a promising therapeutic strategy [10]. As mentioned above, FAAH and MAGL metabolize the endogenous cannabinoids AEA and 2-AG, respectively, and changes in the activity of these enzymes can greatly influence eCB tone and downstream signaling in the brain. To date, most clinical investigations have focused on FAAH, particularly a well-studied single nucleotide polymorphism (SNP) in the FAAH gene that has been associated with increased vulnerability to drug use [73], while preclinical studies have primarily employed pharmacological inhibitors of FAAH and MAGL to probe their functional roles in drug reward, relapse and withdrawal. Below, we synthesize findings from both genetic and pharmacological studies, highlighting the contributions of FAAH and MAGL across major classes of abused substances and considering their potential as therapeutic targets for SUD treatment. Commonly used preclinical rodent models are summarized in Table 1.

Table 1.

Preclinical models of addiction-related behavior.

Assay	Tests	Simplified Description	Example Measure(s)	Reference
Conditioned place preference (CPP)	Drug preference/reward	Drug administration is repeatedly paired over several days with one of two or three chambers, and resulting chamber preference is tested following conditioning	Percent of time spent in drug-paired chamber versus non drug-paired chamber	Lynch et al. (2010)
Conditioned place aversion (CPA)	Drug aversion	Drug administration is repeatedly paired over several days with one of two or three chambers, and resulting chamber preference is tested following conditioning	Percent of time spent in drug-paired chamber versus non drug-paired chamber	Lynch et al. (2010)
Self-administration (SA)	Drug reinforcement, acquisition, drug-seeking/craving, reinstatement	Animal must press a correct lever or nose poke a certain number of times to obtain an intravenous drug infusion	Number/percent of correct lever presses or nose pokes, number of drug infusions earned	Lynch et al. (2010)
Two-bottle choice	Ethanol preference/reward	Animal is presented with two bottles, preference for ethanol is tested	Volume of ethanol versus water consumed	Sinclair (1976)
Operant behavior	Reward-seeking/craving, reward learning, extinction learning, reinstatement	Animal must press a correct lever or nose poke a certain number of times to obtain a non-drug reinforcer (food, water, intracranial stimulation, etc.)	Number/percent of correct lever presses or nose pokes, number of reinforcers earned	Everitt et al. (2018)
Open-field	Anxious behavior in drug withdrawal	Animal is allowed to explore a large, empty chamber	Total distance traveled, percent of time spent in center versus near walls	Seibenhener and Wooten (2015)
Elevated plus maze		Animal is allowed to explore an elevated, plus-shaped maze. Two opposing arms are enclosed and dark, two opposing arms are open	Percent of time spent in closed versus open arms	Sousa et al. (2006)
Tail suspension test	Anhedonia/depressive behavior in drug Withdrawal	Animal is suspended by the tail	Instances/duration of effort (struggling, rearing) versus despair (immobility)	Powell et al. (2012)
Sucrose preference test		Animal is presented with two bottles, preference for a normally appealing stimulus (sucrose solution) is tested	Volume of sucrose solution versus water consumed	Powell et al. (2012)

Dual FAAH and MAGL inhibition in preclinical models of substance use disorders

There are relatively few studies using dual FAAH and MAGL inhibitors to test their effects in relation to drugs of abuse. Preclinical results of dual inhibition have been mixed, depending on the context in which they were used, with some studies showing beneficial effects while others suggest it may not be the best approach. For example, although the dual inhibitor JZL195 produces additive effects in pain models its cataleptic effects are also additive, and it elicits THC-like effects that are not observed when only one of the enzymes is inhibited [74], suggesting it may produce subjective effects similar to those of THC. Supporting this, another study showed that the dual FAAH-MAGL inhibitor SA-57 produced a magnitude of ICSS depression comparable to that induced by THC, indicating that SA-57 may also have THC-like effects on reward-related behavior [75]. In relation to opioid effects, dual inhibition has shown beneficial results in heroin-seeking behavior in a mouse self-administration model [76], and in separate studies, it has been beneficial in reducing most of the somatic opioids withdrawal effects [77,78]. While preclinical studies of dual FAAH-MAGL inhibition provide useful insights, most published research on the effects of these enzymes in the context of drugs of abuse has focused on their independent inhibition, while in clinical studies, the main findings have centered on SNPs in the gene encoding FAAH. The following sections summarize these studies.

Clinical findings: FAAH and human substance use

Genetic studies

The most prevalent human polymorphism in the FAAH gene is C385A (rs324420), which leads to a missense mutation (Pro129Thr), which increases enzyme degradation without affecting catalytic activity, in turn increasing AEA levels [79]. This variant has been associated with a variety of drug use and dependence [73,80], suggesting that this naturally occurring variant may serve as a risk factor for SUD. An fMRI study found that carriers of the FAAH 385A allele exhibit lower threat-related amygdala activity and higher ventral striatal activity [81]. These findings suggest that reduced amygdala activity may contribute to addiction pathology by diminishing the perception of harm or threat, while increased ventral striatal activity may enhance reward sensitivity, mechanisms that could help explain the higher prevalence of drug use observed in individuals carrying the A allele of the FAAH 385 SNP [81]. Building on these findings, the following sections summarize how the FAAH C385A polymorphism and enzymatic manipulation of FAAH influence responses to various drugs of abuse, and how these substances, in turn, alter key components of the eCB system.

Cannabis

Early genetic studies revealed that Caucasian male and female carriers of the FAAH A allele were more likely to use cannabis but showed lower rates of dependence [82]. During abstinence, men and women homozygous for the C allele reported more severe withdrawal symptoms [83,84], supporting the hypothesis that reduced FAAH activity may buffer against cannabis withdrawal. A subsequent clinical trial using the FAAH inhibitor PF-04457845 provided further support, demonstrating reduced withdrawal symptoms and decreased cannabis use in cannabis-dependent adult males [85]. However, these findings have yet to be validated in females and younger populations, highlighting the need for broader investigation. Collectively, these findings suggest that lower FAAH activity may alleviate withdrawal symptoms, offering potential therapeutic benefits during periods of cannabis abstinence. Despite these promising results, no additional clinical studies involving FAAH inhibitors for substance use disorders have been conducted.

Molecular studies in cannabis users reveal consistent alterations in AEA levels and FAAH expression. Elevated AEA levels have been reported in the cerebrospinal fluid (CSF) of frequent cannabis users [86], and similarly, individuals with cannabis use disorder show increased plasma AEA levels, particularly during early abstinence [87]. In parallel, FAAH activity is downregulated in the brains of cannabis users when compared to healthy controls [88,89]. Together, these findings suggest that chronic cannabis use disrupts the eCB system, particularly through reduced FAAH, which may contribute to emergence of abstinence-related symptoms. Of note, all the studies in this section included both male and female individuals.

Psychostimulants

The FAAH C385A SNP has been associated with methamphetamine use in male [90,91] and females [91] and heightened subjective responses to cocaine in males [92] and amphetamine in male and females [92,93]. These findings add to a growing body of evidence suggesting that this FAAH gene variant may be overrepresented among individuals with SUDs. In the case of psychostimulants, this association may contribute to an enhanced subjective response to the drug’s effects [92,93].

Alcohol

The relationship between FAAH and alcohol use has been thoroughly reviewed by Niemelä and Terry [94]. Several studies have linked the FAAH A allele to increased severity of alcohol dependence in certain ethnic populations [95,96] and a higher risk of developing alcohol use disorder (AUD) [97]. This allele has also been linked to a stronger urge to drink and reduced sensitivity to alcohol’s aversive effects [98], which may help explain the higher levels of alcohol consumption observed in male and female carriers of the A allele. One study report reduced FAAH brain levels in individuals (mainly females) with AUD [99], while postmortem studies reveal brain region-specific variability in FAAH levels that may be influenced by comorbid factors such as suicide risk [100,101]. Together these findings support a role for FAAH in modulating alcohol-related behaviors and vulnerability to AUD.

Nicotine

To date, only one study has reported that male and females carrying the FAAH A allele are more likely to initiate smoking compared to C allele carriers, though no differences were observed in the progression of early smoking behaviors [102]. This finding aligns with other studies that have not found a relationship between the FAAH C385A SNP and nicotine use disorder [73,82], suggesting a limited role for FAAH genetic variation in nicotine dependence.

Opioids

Despite substantial preclinical evidence demonstrating interactions between the eCB and opioid systems, human data remains limited. One study found that non-medical prescription opioid users (male and female) had elevated plasma AEA levels, though FAAH activity remained unchanged [103]. This suggests potential dysregulation of eCB signaling in opioid users without direct FAAH involvement.

Preclinical findings: FAAH and rodent models of substance use disorders

Cannabis

A knock-in mouse model expressing the human FAAH C385A SNP revealed increased cannabis vulnerability in adolescent female mice, a pattern not observed in their male littermates [104]. Results from FAAH inhibitors have been mixed. For example, URB597 shows no abuse liability, as measured using conditioned place preference, a measure of reward, in male rats [105,106] and self-administration in male non-human primates [107] whereas FAAH inhibitor, AM3506, produces reinforcing effects [108]. With regards to the effects of FAAH inhibition in preclinical reinstatement models, URB597 did not promote drug-seeking behavior for THC or AEA [107].

Psychostimulants

Currently, no FDA-approved medications exist for treatment of psychostimulant dependence, such as cocaine use disorder. Preclinical studies in male mice have shown that repeated cocaine exposure alters the expression of various genes [109,110], and proteins [111] involved in the eCB system, including the FAAH enzyme [[109], [110], [111]]. Therefore, FAAH may serve as a potential target for the development of pharmacological treatments. FAAH inhibitors have thus been examined in preclinical models across various stages of cocaine self-administration.

Although cocaine has been studied more extensively, far fewer investigations have explored FAAH regulation and manipulation in the context of other psychostimulants, such as amphetamine and methamphetamine. Nonetheless, these drugs similarly upregulate FAAH expression [[109], [110], [111]]. Both amphetamine [112] and methamphetamine [113] have been reported to increase FAAH protein and mRNA levels in male rats, respectively. While these studies differ in experimental regimen and brain regions examined, the consistent increase in FAAH expression suggests a common effect of psychostimulant exposure.

Interestingly, in behavioral models, FAAH inhibitors do not affect the acquisition or the maintenance phase of cocaine self-administration across male species [107,114,115], possibly due to their lack of effect on cocaine-induced dopaminergic neuron activity [70]. On the other hand, FAAH inhibitors have been shown to reduce both cue- [[114], [115], [116]], and stress-induced reinstatement in male rodents [115,116]. Notably, the FAAH inhibitor, URB597 appears to be more effective than PMSF, as it reduced reinstatement without affecting food self-administration [115]. The FAAH inhibitor, URB597 also reverses gene expression changes and reduces neuronal activity in key brain regions involved in SUD [114] and have been shown to protect against cocaine neurotoxicity in male mice [117]. Despite these promising findings, some studies report that FAAH inhibition may enhance certain addiction-related behaviors. For example, the inhibitor URB597 has been found to enhance cocaine CPP [118] and cocaine behavioral sensitization [119] in male mice. These divergent effects highlight the complexity of targeting FAAH in psychostimulant addiction.

Alcohol

Behavioral studies indicate that reduced FAAH activity is associated with increased alcohol intake and decreased sensitivity to alcohol’s effects. FAAH-deficient male [120] and female mice [121] and those treated with FAAH inhibitors show increased alcohol intake and preference [122]. Similarly, FAAH C385A knock-in male mice, which model the human FAAH SNP, also display increased alcohol drinking [123]. Conversely, in Marchigian Sardinian alcohol-preferring rats, excessive drinking is linked to FAAH hyperactivity in the amygdala, and this behavior is attenuated by local FAAH inhibition. Notably, this pattern is absent in male Wistar rats [124], which has been interpretated as in some genetic backgrounds, increased FAAH activity may drive excessive drinking as a form of self-medication. These findings underscore the complexity of developing FAAH-targeted therapies, particularly in the context of genetic variability across populations. In addition to its effects on drinking behavior, FAAH inhibition has been shown to alleviate some behaviors related to alcohol withdrawal, as it reduces alcohol intake and preference after acute withdrawal [125], and counteracts alcohol withdrawal-associated anxiety [126].

Nicotine

Nicotine addiction-related behaviors have been studied extensively in the context of FAAH manipulation. FAAH knockout male and female mice exhibit enhanced nicotine CPP [127] and elevated DA release in the nucleus accumbens [128]. Similarly, FAAH inhibition with URB597 enables a subthreshold dose of nicotine to induce CPP [127]. In addition to increasing nicotine preference, FAAH inhibition also intensifies the somatic signs of nicotine withdrawal [127], and its inhibition during abstinence periods results in anhedonia-like and depressive-like behaviors in male rats [129]. However, other studies report opposing effects. URB597 prevents nicotine CPP [130] and the acquisition of nicotine self-administration in male rats [130] and non-human primates [95]. As well, cue- [130,132] and nicotine-induced reinstatement of nicotine-seeking behavior [[130], [131], [132]] was reduced with FAAH inhibition. These effects may relate to the reduced firing of VTA-DA neurons [71] and decreased DA levels in the NAc [130] of male rats. Additionally, FAAH inhibition reduces anxiety-like symptoms during nicotine withdrawal in male rats [133]. Taken together, these findings highlight the complex and context-dependent effects of FAAH inhibition on nicotine-related behaviors. Divergent outcomes across studies may reflect species-specific differences, dosing regiments, or methodological variability.

Opioids

Decades of preclinical research have highlighted the synergistic interaction between the CB1 and opioid systems in the context of drug reward, dependence and withdrawal (for reviews, see Refs. [[134], [135], [136]]. However, FAAH has been relatively understudied in preclinical models of opioid dependence. Opioid exposure alters endogenous cannabinoid levels across different brain regions of male rats [[137], [138], [139], [140], [141]], and it also alters FAAH expression in male mice [142] and enzymatic activity [137]. However, the patterns of AEA dysregulation vary depending on the brain region, the regimen of opioid exposure, and the specific stage of opioid use.

Behavioral pharmacology studies further highlight the nuanced role of FAAH. In one study, FAAH inhibition with URB597 did not enhance the reinforcing effects of heroin at any dose tested in male rats [143]. This finding is notable because the same study showed that direct activation of the CB1 receptor with exogenous ligands (THC and WIN55,212–2) potentiated heroin’s reinforcing properties, suggesting that indirectly targeting the eCB system, such as FAAH inhibition, may be a safer approach to avoid potential unwanted synergistic effects with opioids. Supporting this, FAAH inhibition had no effect on the acquisition of morphine CPP in male and female mice [7] or on morphine-induced reinstatement of CPP in male rats [144], but it was effective in reducing certain somatic withdrawal symptoms in male mice and rats [78,145,146]. Similar reduction in withdrawal symptoms has been observed in FAAH knockout mice [145].

Together, both clinical and preclinical evidence underscores FAAH’s role in modulating substance use behaviors. The FAAH C385A polymorphism consistently associates with altered responses to various drugs, and FAAH inhibition shows therapeutic potential for reducing withdrawal symptoms, reducing relapse vulnerability, and mitigating neurotoxic effects. However, findings remain mixed depending on the substance and behavioral paradigm, and concerns about long-term safety and potential abuse liability require further investigation. FAAH continues to remain a promising—though complex—therapeutic target. Realizing its clinical potential will require careful evaluation of safety profiles, as well as personalized approaches that consider individual genetic variation and sex differences.

Clinical findings: MAGL and human substance use

Genetics

Unlike the FAAH gene, SNPs in the MAGL gene have not been directly associated with SUDs. However, emerging evidence suggests possible associations. For example, the MAGL SNP rs604300 may influence the relationship between childhood sexual abuse and risk for cannabis dependence [147], while rs549662 has been associated with smoking withdrawal symptoms in humans [148]. Nonetheless, much of our current understanding of MAGL’s role in SUD is based on findings from preclinical studies.

Clinical studies

Clinical investigations targeting MAGL in the context of SUD are relatively limited compared to those involving FAAH. However, due to promising preclinical findings, MAGL inhibitors have been evaluated in clinical trials for other conditions including pain, Tourette syndrome, obesity, and cancer (reviewed in Ref. [66]. While these studies are ongoing and published reports are not yet available, early data suggest that MAGL inhibitors are generally well-tolerated, with no major safety concerns identified to date [10,149,150].

Preclinical findings: MAGL and rodent models of substance use disorders

Cannabis

Despite limited studies examining the relationship between MAGL and cannabis dependence, two studies suggest that MAGL inhibition may help alleviate cannabis withdrawal symptoms. One study demonstrated that JZL184 attenuated CB1 antagonist, rimonabant-precipitated withdrawal symptoms in THC-dependent male mice [151], suggesting that elevated 2-AG levels can buffer against withdrawal symptoms. Supporting this finding, another study showed that JZL184 effectively reduced spontaneous withdrawal symptoms, such as paw tremors and head twitches, but did not affect other behavioral phenotypes, including marble burying and struggling in the tail suspension test, during either spontaneous or precipitated withdrawal in male mice [152]. Together, these findings suggest that MAGL inhibition may mitigate select aspects of THC withdrawal, particularly those associated with abstinence, although its efficacy may vary depending on the specific withdrawal context and behavioral measures assessed.

Alcohol

Alcohol use disorder (AUD) is a complex condition often linked to early-life adversity including exposure to stressful events [153]. Multiple studies have identified early-life stress, such as childhood trauma, as a significant risk factor for developing neuropsychiatric disorders, including AUD [153,154]. Preclinical evidence demonstrates that both early-life stress and adolescent alcohol exposure lead to long-lasting changes in emotional processing, including increased anxiety-like behaviors and elevated expression of MAGL and CB1 receptors in the amygdala of male rats [155], suggesting dysregulation of emotion and stress-related neural circuits.

MAGL inhibition by JZL184 has shown to be effective in alleviating alcohol abstinence-related anxiety-like behavior in male mice [156,157], female mice [157] and male rats [156], supporting its potential to mitigate emotional withdrawal symptoms. Additionally, during alcohol abstinence, alcohol-dependent rats showed increased alcohol intake, which were reduced by MAGL inhibition [156]. This is particularly relevant as both clinical and preclinical evidence supports a strong, and bidirectional relationship between anxiety and alcohol use, where anxiety can drive alcohol consumption, and alcohol use can, in turn, exacerbate anxiety with sex differences observed in mice [158].

Pain is another key contributor to alcohol misuse, with both acute and chronic pain frequently co-occurring with alcohol use disorder [159,160]. Alcohol is often used for its analgesic properties, but this can lead to alcohol dependence, especially as abstinence may be accompanied by pain hypersensitivity [160]. Notably, MAGL inhibition with JZL184 reverses ethanol withdrawal-induced pain hypersensitivity in male and female mice [161], and similar effects have been observed in male rats, where JZL184 reduced hypersensitivity and implied the lateral habenula as a key neural substrate for this response [161,162].

At a molecular level, alcohol exposure alters eCB signaling pathways. Specifically, chronic ethanol reduces 2-AG levels within the CeA [156], and DAGL and MAGL mRNA expression in the NAc of male rats compared to controls, however no difference in these enzymes were observed between control and chronically alcohol-exposed female rats [158]. Furthermore, in a polysubstance use model, male mice with prior methamphetamine exposure exhibited higher ethanol consumption and reduced MAGL levels and activity in the forebrain [163]. Postmortem studies provide additional support, revealing reduced MAGL enzymatic activity in the prefrontal cortex of individuals with alcohol dependence [100]. Together, these findings underscore the involvement of MAGL in regulating alcohol-related behaviors, affective states, and withdrawal responses, and support its potential as a therapeutic target for AUD.

Psychostimulants

Cocaine exposure has been shown to differentially alter MAGL protein expression depending on the regimen of exposure and brain region studied. While acute systemic cocaine administration does not alter MAGL levels in male mice, repeated exposure leads to increased MAGL protein expression in the prefrontal cortex [111]. During abstinence from cocaine self-administration, MAGL expression is reduced in the NAc of male rats, and pharmacological inhibition of this enzyme enhances cue-induced cocaine-seeking behavior [164], suggesting a maladaptive shift in 2-AG signaling that may promote relapse vulnerability. In contrast, protein expression of DAGL, responsible for 2-AG synthesis, is upregulated during abstinence, and its inhibition attenuates cue-induced reinstatement [164], pointing to a complex, region-specific role for eCB tone in cocaine-related behaviors. Furthermore, alterations in the ratio of one of the DAGL isoforms to MAGL have been reported in the cerebellum following cocaine exposure [110], indicating broader disruptions in eCB homeostasis. In terms of behavioral studies, stress has been shown to potentiate cocaine-induced reinstatement in a CB1-dependent manner [165]. A follow-up study showed that corticosterone, or MAGL inhibition in the prelimbic cortex prior to cocaine-induced reinstatement, potentiated the response, suggesting that MAGL inhibition may engage stress-related mechanisms and might not be beneficial in the context of cocaine reinstatement [166]. Consistent with the interaction between stress, eCB signaling, and cocaine, a study reported that in male pre-adolescent mice with a genetic variation in the monoamine oxidase A gene and a history of early-life stress, repeated cocaine exposure enhanced 2-AG–dependent plasticity in dopaminergic neurons of the ventral tegmental area (VTA). This enhancement led to greater suppression of inhibitory input onto these neurons and increased cocaine-induced hyperlocomotion [167] highlighting how stress and 2-AG can modulate cocaine-related behavioral and neuronal adaptations. However, in those genetically modified animals, pretreatment with a MAGL inhibitor prevents the development of cocaine-induced hyperlocomotion [167] but not necessarily will be of benefit to wild type mice, suggesting that the effects of MAGL inhibition on cocaine reinstatement might depend on genetic vulnerabilities.

Despite these findings, other psychostimulants such as methamphetamine have not been studied in this context. Thus, the role of MAGL and broader eCB signaling in methamphetamine use and withdrawal remains an important area for future investigation.

Nicotine

MAGL appears to play a nuanced role in nicotine-related behaviors, affecting both reward and withdrawal processes in a context-dependent manner. Mice lacking MAGL or treated with JZL184 fail to acquire nicotine-conditioned place preference, suggesting enhanced 2-AG reduces nicotine’s sensitivity to nicotine’s rewarding effects in male and female mice [148]. Notably, JZL184 does not alter food preference or LiCl-induced aversion, indicating that the effects are selective and not attributable to generalized disruption of reward or aversion processing. In contrast, to JZL184’s effects in CPP, it does not alter nicotine self-administration but enhances cue-induced nicotine-seeking behavior in male mice [168], suggesting that the effects of MAGL inhibition vary across different phases of addiction, such as reward acquisition versus relapse. Regarding withdrawal, MAGL mRNA expression in male mice positively correlates with the severity of nicotine withdrawal. Both genetic deletion of MAGL and pharmacological inhibition with JZL184 significantly reduce somatic withdrawal symptoms without producing JZL184 tolerance upon repeated administration [148]. Together, these findings suggest that MAGL plays a complex and context-dependent role in nicotine-related behaviors, influencing both reward and withdrawal processes, and that MAGL inhibition may hold therapeutic potential for alleviating nicotine withdrawal symptoms.

Opioids

Increasing evidence implicates the eCB system as a key modulator of opioid-related behaviors [72]. However, studies specifically examining MAGL within this context remain limited. Repeated morphine exposure has been shown to increase MAGL expression in the dorsal hippocampus during morphine CPP in male rats [142]. Notably, these changes are specific to animals that acquire morphine CPP and are reversed following extinction. Additionally, pharmacological inhibition of MAGL in male rats using MJN110 attenuates the acquisition of morphine CPP [138], suggesting that 2-AG degradation contributes to the rewarding effects of opioids and blocking this process reduces opioid reward. Consistent with this, we have obtained similar results using JZL184 that reduces morphine and oxycodone CPP, as well as oxycodone self-administration in male and female mice [7], findings discussed in more detail in the next section of this review. These behavioral studies support a role of MAGL in opioid reward.

In the context of opioid withdrawal, both genetic and pharmacological MAGL inhibition, using either JZL184 or MJN110, effectively reduces somatic signs of naloxone-precipitated morphine withdrawal, including jumping and tremors in male mice and rats [77,138,145,169]. Although systemic MJN110 can block conditioned place aversion (CPA) to opioid withdrawal, these effects appear to be brain region specific. For example, MAGL inhibition reduces withdrawal-induced CPA when targeted to the basolateral amygdala and insular cortex but not when administered in the bed nucleus of the stria terminalis (BNST) or central amygdala of male rats [169]. These findings highlight a multifaceted role for MAGL in opioid use, influencing both the neuroadaptations associated with opioid reward and the somatic and affective components of opioid withdrawal. This supports its potential utility as a therapeutic target in opioid use disorder.

Taken together, findings from studies across multiple substance use disorder models indicate that MAGL plays a key role in modulating reward, emotional regulation, and withdrawal symptoms. While MAGL inhibition shows the most consistent benefit in alleviating withdrawal symptoms, particularly for cannabis, nicotine, alcohol, and opioids, its effects on drug reward and seeking behaviors appear more variable and context dependent. In some cases, such as nicotine and cocaine, MAGL inhibition may enhance cue-induced relapse behavior. Nonetheless, the ability of MAGL inhibitors to reduce negative affective states and somatic withdrawal symptoms—key drivers of relapse—positions MAGL as a promising pharmacological target in the treatment of substance use disorders, especially in managing withdrawal and potentially reducing relapse risk.

Therapeutic implications of MAGL

The persistent rewarding nature of opioid drugs continues to drive one of the most devastating public health crises in US history [3], with opioids accounting for approximately 76 ​% of drug overdose deaths in 2022 [170]. Additionally, despite the lethality associated with opioid misuse, they remain unrivaled standards for treating acute, extreme pain in clinical settings, stressing the need to dissect analgesia from reward for effective pain management that does not risk the development of opioid dependence. Chronic opioid exposure leads to long-lasting dysregulation of the brain’s reward circuitry that contributes to the negative physiological and psychological symptoms of withdrawal, which negatively reinforces continued use in individuals with opioid use disorder [171]. Although several opioid replacement therapies are available to reduce relapse risk, they carry significant limitations, including their own misuse potential and limited impact on the overall crisis. Pharmacotherapies that reduce opioid-induced activation of reward pathways without impairing analgesia could help address both pain and misuse risk, functioning as a valuable complement to opioid analgesics for pain management and medications for opioid use disorder.

Recent findings from our group demonstrate that pretreatment with JZL184 during morphine and oxycodone CPP conditioning or during acquisition of oxycodone self-administration prevents the development of CPP and reduces oxycodone self-administration in both male and female mice [1], indicating that MAGL inhibition attenuates opioid reward. These effects were dependent on CB1 in the VTA, as conditional CB1 deletion in this region abolished JZL184’s ability to attenuate morphine CPP. Additionally, fiber photometry in vivo imaging revealed that JZL184 dampens opioid-induced neuronal and dopamine activity in the NAc, a key region involved in reward processing. Importantly, JZL184 did not impair opioid-mediated analgesia, suggesting that MAGL inhibition selectively attenuates opioid reward while preserving analgesic efficacy. This supports its potential as an adjuvant strategy to reduce misuse liability. In fact, preclinical studies have demonstrated the therapeutic potential of MAGL inhibitors across multiple pain models, including inflammatory, neuropathic, and cancer-related pain (for review, see Refs. [[172], [173], [174]]). Other MAGL inhibitors such as MJN110 and the dual MAGL/FAAH inhibitor SA-57 have also reduced opioid reward behaviors [76,138]; MJN110 tested in morphine CPP [138] and SA-57 in heroin self-administration [76] in male mice, supporting the therapeutic promise of this pharmacological approach. These findings support the use of MAGL inhibitors as adjuvants in opioid-based pain management, helping to counteract the rewarding effects of opioids to prevent dependence while maintaining pain relief.

Beyond their preventive potential in preclinical models of SUDs, MAGL inhibitors have also been shown to alleviate multiple symptoms of opioid withdrawal as reported in published studies [77,138,145,169]. While the precise mechanisms by which MAGL inhibition dissociates the effects on opioid reward, withdrawal, and analgesia remain unclear, one possibility is the differential co-expression of CB1 and MOR across distinct brain regions that independently regulate these distinct behavioral outcomes. Altogether, these results position MAGL inhibition as a compelling multifaceted therapeutic strategy, capable of reducing opioid reward, mitigating withdrawal symptoms, and preserving analgesia, underscoring its promise not only as an adjunctive treatment with opioids in pain management but also as a preventive intervention for opioid use disorder and relapse.

While MAGL inhibitors show promise as a treatment for OUD, several potential limitations need to be considered. For example, preclinical studies have shown that MAGL inhibition can attenuate intracranial self-stimulation (ICSS) [75] and reduce food consumption in mice [75], suggesting possible effects on natural reward-related processes. Consistent with this, experiments reported that MAGL inhibition enhances DA signaling [175], and another study demonstrated that 2-AG can be self-administered and increase NAc shell DA levels [176], indicating the complexity of the actions of 2-AG. However, none of these studies examined MAGL inhibitors in combination with an opioid or after opioid exposure, which may yield different outcomes. Other studies, including our own, show that MAGL inhibitors do not produce an effect on their own [7], as they fail to induce place preference or aversion [7]. Cannabimimetic effects are another consideration of MAGL inhibitors; although findings are mixed [[177], [178], [179], [180], [181], [182]], they may represent a limitation for clinical safety. MAGL inhibitors have already been tested in clinical trials, unrelated to drugs of abuse [150,183], and reports indicate that they are safe, well tolerated and show no evidence of psychoactive properties [150,183] based on available data. Ultimately, clinical decisions depend on risk-to-benefit ratio, how severe the disease is, and can the treatment provide enough benefit that its risks are outweighed by the harm caused by the disease itself? In the case of OUD, the risk of overdose death and the detrimental impact on quality of life, among other factors, is likely far greater than the potential risk associated with MAGL inhibition. While there may be some off-target effects, the potential benefits to patients and society will likely outweigh those risks.

Endocannabinoids as regulators of synaptic plasticity relevant to reward

Enhancing levels of AEA and 2-AG through FAAH and MAGL inhibition, respectively, clearly influences the behavioral effects of addictive drugs, however the mechanisms behind these effects remain unclear. These eCBs have emerged as critical modulators of synaptic plasticity within brain circuits that govern motivation, reward, and reinforcement. Notably, their role in shaping dopaminergic signaling in the mesolimbic pathway has positioned them as central players in the neurobiology of SUDs [184,185]. Understanding how eCB signaling modulates synaptic inputs and plasticity in these circuits can elucidate the mechanisms by which FAAH and MAGL inhibitors exert therapeutic effects, and, more broadly, enhance our understanding of the neurobiology of SUDs.

Insights into endogenous cannabinoid action have been gained from studies on exogenous cannabinoids such as Δ9-tetrahydrocannabinol (Δ9-THC) and synthetic CB1 receptor agonists, finding that they modulate reward-related behavior by acting on GABAergic inputs to dopaminergic neurons in the VTA. By inhibiting GABA_A-mediated inhibitory postsynaptic currents, exogenous cannabinoids disinhibit VTA dopamine neuron activity, enhancing dopamine release in the nucleus accumbens (NAc) [186,187], a core component of the brain’s reward circuitry. These compounds can be dose-dependently reinforcing, as evidenced by conditioned place preference and self-administration paradigms when administered both systemically and directly into the NAc shell and posterior VTA [6]. Similarly, the endogenous cannabinoids 2-AG and AEA can also enhance dopamine release in the NAc, support self-administration under specific conditions, and promote reward-seeking behavior [175,176,188]. 2-AG has been identified as particularly necessary for cue-driven reward seeking and the attribution of incentive salience to predictive cues, an important feature of both addictive behavior and reinforcement learning [189]. However, as discussed above, FAAH and MAGL inhibition have been shown to be effective in reducing drug reinforcement and associated NAc neural activity, suggesting that eCB activity may have a more nuanced influence on motivated behavior than previously assumed, especially in the context of drug reward. In parsing these conflicting results, it might be considered that ‘optimal’ levels of eCB mobilization and degradation maintain physiological reward responses, with drug-induced deviations from this balance contributing to aggravation of reward appraisal systems in addiction [8,190]. To this end, future studies of eCB contributions to dysregulation of drug-oriented behavior and its neural substrates could be enhanced by assessment of how eCB system alterations impact natural reward processing in drug dependent states, across different phases of addiction and to a variety of substances to better elucidate context-specific eCB influence on reward.

Known mechanisms of endocannabinoid-mediated synaptic plasticity

While additional studies are needed to clarify how elevating AEA and 2-AG through FAAH and MAGL inhibition impacts SUD-related behaviors, numerous electrophysiological studies have examined how eCBs influence synaptic strength and circuit-level plasticity. eCBs are synthesized postsynaptically in a demand-dependent manner (Fig. 1), typically in response to specific patterns of presynaptic stimulation that trigger calcium influx via voltage-gated calcium channels, as in the case of depolarization-induced suppression of excitation (DSE) or inhibition (DSI) [191,192]. Another mechanism involves postsynaptic activation of G_q-coupled receptors such as metabotropic glutamate (mGluR), muscarinic acetylcholine (M1/M3), or dopamine (D2) receptors, independent of calcium influx [191,[193], [194], [195]]. Once produced, eCBs act in an autocrine or retrograde paracrine manner on presynaptic CB1 receptors to suppress neurotransmitter release, thereby modulating excitatory or inhibitory input strength [196]. These transient changes can lead to longer-lasting forms of synaptic plasticity—such as endocannabinoid-mediated long-term potentiation (eCB-LTP) or depression (eCB-LTD)—which bias synaptic connectivity and influence behavioral outputs. This plasticity has been documented in nearly all major nodes of addiction-related circuitry, including the NAc, VTA, dorsolateral striatum, prefrontal cortex, hippocampus, basolateral amygdala, and bed nucleus of the stria terminalis [195,[197], [198], [199], [200], [201]].

Addictive drugs can disrupt normal eCB-mediated plasticity, likely contributing to pathological learning processes such as cue-reward associations and behavioral sensitization. For instance, chronic exposure to CB1 receptor agonists impairs eCB-LTD at excitatory inputs in the NAc [202], while repeated cocaine use enhances eCB-LTD at inhibitory synapses in the VTA through brain-derived neurotrophic factor (BDNF)-dependent mechanisms [203,204]. Even a single dose of cocaine can abolish eCB-LTD in the NAc [205], and exposure to stress, morphine, and nicotine disrupts long-term potentiation (LTP) of GABAergic input to the VTA [206]. Collectively, these findings suggest a loss of eCB-mediated regulatory control, resulting in a hyperexcitable reward system that subserves compulsive drug seeking. Elevating 2-AG and AEA levels might then, in this context, restore this regulatory control and buffer against drug-induced behavioral changes, as illustrated by the restoration of cocaine-disrupted eCB-LTD in the NAc and associated social behavior by FAAH inhibition [114].

Endocannabinoids in reward sensitization

A hallmark of addiction is the transition from drug “liking” to “wanting,” characterized by heightened mesolimbic dopamine signaling in response to drug-associated cues [207]. Long-term potentiation (LTP) of glutamatergic input to VTA dopamine neurons is one mechanism thought to underlie this sensitization [208]. Interestingly, eCB signaling can serve as an adaptive brake on this process; activation of CB1 receptors by 2-AG suppresses excitatory input to VTA dopamine neurons, limiting their hyperactivity in the face of repeated stimulation [195,209,210]. This intrinsic regulatory role suggests that the eCB system is not simply permissive of reward-seeking, but rather integral to maintaining balance within the reward circuitry. Disruption of this protective mechanism through addictive drug-induced dysregulation or receptor blockade may then tip the scales toward pathological motivation.

However, this buffering effect of eCB signaling does not appear to universally protect against sensitization to all drugs of abuse. For instance, eCBs can facilitate early behavioral and neurochemical sensitization to cocaine [119,167], with FAAH inhibition shown to enhance this effect [119]. This, in conjunction with the findings on psychostimulants discussed above, suggests that eCB enhancement in early sensitization to cocaine may be detrimental. Additionally, enhanced DSI in the VTA, reflecting suppression of RMTg GABA input, was observed in rats with an innate alcohol preference [211], highlighting that individual differences in eCB system tone could subserve differential vulnerability to substance use disorder development. Interestingly, FAAH inhibition in this same rat model had no effect on voluntary drinking or operant alcohol self-administration and instead reduced withdrawal-associated anxiety [126]. Collectively, these findings indicate that eCBs play a role in facilitating early sensitization to drugs of abuse but also exert context-dependent effects. Disentangling the relative contributions of eCB-mediated protective depression of excitatory input versus maladaptive depression of inhibitory input to the VTA will be essential for understanding how this system shapes vulnerability and resilience to addiction.

It is also important to consider that the benefits of eCB modulation might be affected by factors such as genetic vulnerabilities or comorbidities associated with neuropsychiatric disorders. Disorders such as schizophrenia have been associated with dysregulation of the dopaminergic system [212] and alterations in the eCB system, including elevated 2-AG levels [213]. Specifically, the positive symptoms of schizophrenia (psychotic symptoms such as hallucinations and delusions) have been linked to a hyperdopaminergic state [214] and in mouse models with elevated dopamine signaling, MAGL inhibition can exacerbate psychotic-like behaviors [[215], [216], [217]], likely through further increasing dopamine levels [216], which may be detrimental. Individuals with schizophrenia show high rates of comorbid substance use [218,219], potentially reflecting self-medication to alleviate negative or other aversive symptoms [220], possibly via drug-induced modulation of dopamine signaling [221]. In this context, MAGL inhibition might benefit schizophrenia-related negative symptoms, such as anhedonia and social withdrawal, which remain largely resistant to current antipsychotic treatments [222,223]. Therefore, the behavioral and therapeutic effects of MAGL inhibition are likely to be dependent on individual differences, with potential benefits or risks according to the specific balance between dopaminergic activity and eCB system function.

Given the role of eCB signaling in promoting reward-seeking and mesolimbic dopamine release, CB1 receptor antagonists were initially explored as potential treatments for addiction [224]. Indeed, CB1 receptor blockade reduces self-administration of various drugs, cue-evoked dopamine release, and even intake of ethanol or natural rewards like sucrose [175,225,226]. However, clinical translation was hampered by the psychiatric side effects of rimonabant, a CB1 receptor inverse agonist, which led to its market withdrawal [227]. CB1 receptor antagonism also produced aversive effects in animal models, including opioid-like withdrawal symptoms [226]. These findings underscore a critical point: simply blocking a dysregulated eCB system is not equivalent to restoring its function. A more promising strategy may lie in rebalancing eCB tone in select substance use disorder contexts through FAAH and MAGL enhancement or inhibition, allowing for more physiologically relevant, context-dependent modulation of CB1 receptors without the broad suppression and associated side effects of receptor antagonists.

Conclusions

In summary, the enzymes FAAH and MAGL play key roles in regulating the effects of various drugs of abuse, as demonstrated in both clinical and preclinical models. Although clinical studies with pharmacological inhibitors of these enzymes remain limited, preclinical evidence suggests that targeting FAAH and MAGL may offer therapeutic benefits for substance use disorders by reducing drug reinstatement and withdrawal symptoms of some drugs of abuse. Notably, MAGL inhibition has shown promising preclinical effects as a potential treatment for OUD, a persistent public health crisis. Additionally of relevance, FAAH inhibitors have demonstrated efficacy in reducing psychostimulant reinstatement in preclinical studies, a finding of particular relevance given the recent rise in cocaine use and the lack of approved pharmacological treatments for cocaine use disorder. Considering the role of CB1 receptor signaling in synaptic plasticity within reward-related regions and the limited success of exogenous CB1 ligands such as rimonabant, indirect manipulation of CB1 receptors through targeting FAAH and MAGL to alter eCB levels may present a more effective therapeutic strategy. Of note, it should still be considered that the ratio of benefits to risks could be influenced by factors such as genetic vulnerabilities or comorbidities associated with neuropsychiatric disorders. While further studies are needed to advance these approaches clinically, targeting FAAH and MAGL remains a highly promising and attractive avenue for the treatment of SUD.

Author contributions

Charlie Maddox: Conceptualization, Writing (original draft), Visualization, Review and Editing.

Francis S Lee: Conceptualization, Review and Editing.

Anjali M Rajadhyaksha: Conceptualization, Writing (original draft), Visualization, Review and Editing.

Arlene Martínez-Rivera: Conceptualization, Writing (original draft), Visualization, Review and Editing.

Funding statement

Charlie Maddox reports financial support from the Neurobiology of Addiction Training Program (T32DA007237-36). Arlene Martínez-Rivera and Anjali M. Rajadhyaksha report financial support from NIH grants R01DA054368 (NIH-NIDA) and R01DA053261 (NIH-NIDA). Francis S. Lee reports financial support from NIH grants R01DA054368 (NIH-NIDA) and R01NS126590 (NIH-NINDS).

Declaration of competing interest

None declared.