Cannabis, including medical cannabis, is increasingly promoted to treat diverse clinical symptoms due to ECS’s involvement in numerous physiological processes. However, this approach continues to face regulatory hurdles and demands for robust efficacy and safety, particularly concerning psychotropic effects. An alternative strategy is the development of pharmacological agents that selectively target the mechanisms of cannabis-derived compounds, offering broad therapeutic potential with higher regulatory compliance. Accordingly, the ECS has emerged as a key regulator of neurophysiological dysfunction in psychiatric disorders, with particular interest towards AEA, which modulates synaptic signalling. The development of selective, potent, efficacious and safe FAAH inhibitors represents a major pharmacological avenue to increase endogenous AEA concentrations, aimed at improving clinical symptoms and improving social and occupational functioning.

This review summarises recent developments in FAAH-selective compounds. Of the ten identified FAAH inhibitor RCTs, eight were completed, one was terminated early, and one was withdrawn due to a change in business objectives and insufficient funding. Although these inhibitors are intended for neuropsychiatric conditions such as pain, depression, anxiety and schizophrenia, most RCTs remain at Phase I, focusing on safety, tolerability, pharmacokinetics and pharmacodynamics. Only two compounds, PF-04457845 (now JZP150) and JNJ-42165279, have progressed to Phase II with mixed outcomes (Table 1). Both demonstrated pharmacodynamic target engagement, evidenced by elevated plasma and CSF AEA, yet clinical efficacy was limited. While modest efficacy was observed in cannabis dependence, neither compound showed clinical benefit for osteoarthritis pain or PTSD.

The limited clinical success of FAAH inhibitors despite promising preclinical profiles highlights the broader challenges in neuropsychiatric drug development. It raises questions about the predictive validity of preclinical behavioural models for complex, heterogeneous syndromes such as PTSD or depression. However, the lack of efficacy in PTSD may reflect its etiological heterogeneity, which arises from diverse trauma types, with resilience influenced by complex genetic and environmental factors. It is plausible that only specific subsets of individuals with PTSD may benefit from FAAH inhibitor intervention, highlighting the need for improved patient stratification. However, Mayo et al. has frequently proposed that disrupted CB₁R signalling might underlie PTSD pathophysiology, limiting the therapeutic effects of increased central AEA concentrations [80, 95, 101].

These variable outcomes suggest that while increasing AEA holds therapeutic promise, it is unlikely to offer a universal solution for psychiatric disorders. Several trials remain ongoing or recently concluded, and their outcomes may refine our current supposition. Future RCTs should aim to improve participant characterisation for inclusion, consider variables such as type, severity and frequency/duration of trauma exposure, age, duration of illness, and cannabis consumption. Additionally, identifying predictive biomarkers, whether biomolecular or related to clinical onset, could help preselect individuals more likely to benefit from future FAAH-targeted interventions. For instance, variation at the FAAH C385A polymorphism (rs324420) may support genotype-based stratification, as C/C carriers exhibit higher FAAH activity and lower baseline AEA concentrations [38, 122], potentially conferring greater benefit from FAAH inhibition compared with C/A or A/A carriers. Complementary baseline screening of peripheral AEA and other major FAAH substrates in blood or CSF (i.e., OEA and PEA) could further identify individuals predisposed to deficient NAE tone prior to symptom onset. Neuroimaging markers may also be leveraged to screen for amygdala hyperreactivity or disrupted prefrontal limbic connectivity, common features in PTSD, depression and anxiety disorders [123–126]. Finally, clinical phenotyping could refine patient selection, noting that individuals displaying predominantly hyperarousal symptoms might yield greater benefit from AEA enhancement given its anxiolytic properties [71, 127].

A primary consideration with future FAAH-selective RCTs is balancing efficacy with safety. The fatal outcome of the BIA 10-2474 serves as a cautionary reminder of the inherent risks associated with Phase I RCTs and the absolute necessity for adhering to rigorous safety protocols and ethical standards. Furthermore, new compounds must undergo independent validation by the broader scientific community. CNS effects, though not life-threatening, were already observed in animal toxicology studies of BIA 10-2474 [108], related severe adverse events were not observed during the single ascending dose study preceding the fatal outcome. Importantly, other FAAH inhibitors assessed in RCTs to date, including PF-04457845 (now JZP150) and JNJ-42165279, have demonstrated good overall tolerability, with no reports of brain microhaemorrhages or comparable severe adverse events [82]. Adverse events in these RCTs have been typically mild to moderate. While it remains unconfirmed whether inhibition of other lipid lipases was responsible for the toxicity observed with BIA 10-2474 [107], these findings reinforce the importance of evaluating off-target effects. Non-selective FAAH inhibitors could inadvertently disrupt broader lipid networks of which the ECS is a part [13], impacting other signalling and membrane-support lipids, further emphasising the need for comprehensive safety profiles in therapeutic development. In this context, it is important to also recognise that AEA engages targets beyond CB₁R that may contribute to its therapeutic efficacy and broader pharmacological footprint. As a CB₂R ligand, albeit expressed at comparatively lower levels in the CNS compared to CB₁R, AEA-CB₂R activation may also be relevant to psychiatric disorders [128, 129]. CB₂R signalling has been implicated in neuroimmune and neuroinflammatory processes that are increasingly recognised in psychiatric conditions [130–132]. However, the translation of CB₂R-mediated AEA mechanisms to clinical psychiatric outcomes remains in its infancy, requiring more direct evidence. AEA also acts as an agonist at the transient receptor potential vanilloid 1 (TRPV1) ion channel [133, 134], which has been proposed as a potential therapeutic target in anxiety, depression, and psychosis [135]. As aforementioned, FAAH is also the principal enzyme responsible for OEA and PEA hydrolysis, with its inhibition linked to elevation of these NAEs. This potentially expands the lipid mediator network of targets, including PPAR-α, PPAR-γ, GPR55, and GPR119, through which OEA and PEA act as ligands [134, 136–138].

Despite extensive preclinical characterisation, clinical investigations into URB597 remain limited. This may partly reflect delays due to licensing issues following multiple corporate acquisitions [139] and safety concerns after the BIA 10-2474 incident, which may have intermittently detracted pharmaceutical interest towards FAAH irreversible inhibitors. Irreversible inhibition can extend enzyme inhibition beyond the elimination half-life, increasing the risk of idiosyncratic drug-related toxicity [140]. In the BIA 10-2474 incident, FAAH inhibition was maintained for over 72 h at doses above 2.5 mg, although drug exposure was designed to last between 4–6 h [141]. In contrast, URB597 has a relatively short half-life (~2 h) [70], and its ability to avoid competition for FAAH activity with endogenous ligands (i.e., AEA, OEA, PEA) may enhance potency, favouring lower doses and reducing the risk of ceiling concentration effects [142].

Future investigations into the second FAAH isoform (FAAH-2) may offer additional therapeutic avenues. Although in vitro assays demonstrated FAAH-2 accounts for less than 10% of the relative rate of AEA hydrolysis, compared to FAAH [62], intact cell studies with [¹⁴C]-AEA indicated that FAAH-2 can achieve hydrolysis rates up to 40% of FAAH’s efficiency [67]. Moreover, FAAH-2’s distinct membrane topology, oriented toward the luminal compartment of the endoplasmic reticulum and localising to lipid droplets, raises the possibility of isoform-specific inhibitors targeting distinct AEA pools [62, 67, 143, 144]. However, its limited expression in the brain and predominance in peripheral tissues [62, 143, 145, 146] may restrict its relevance for neurobiological applications. Additionally, the absence of FAAH-2 in lower order mammals complicates preclinical research using conventional animal models [147].

Although beyond the scope of this review, the therapeutic potential of monoacylglycerol lipase (MAGL) inhibitors, responsible for the hydrolysis of 2-AG (Fig. 1), warrants mention. Preclinical studies using JZL-184 [82] have shown that elevated cerebral concentrations of 2-AG are associated with anxiolytic, antinociceptive, anti-inflammatory properties, and anti-depressive-like effects [148–150]. However, a Phase II RCT for the MAGL inhibitor Lu-Ag06466 (formerly ABX-1431) in Tourette Syndrome and Chronic Motor Tic Disorder (NCT03625453) failed to meet its primary endpoint, though benefits were noted in participants with comorbid attention deficit hyperactivity disorder (ADHD) [151]. Additionally, CNS-related, treatment-emergent side effects have been reported in both preclinical and clinical settings [151, 152]. Dual FAAH/MAGL inhibitors are also under investigation. Preclinical studies into inhibitor JZL-195 [153] have demonstrated efficacy in models of traumatic brain injury, migraine-like pain and sporadic Alzheimer’s disease [154–156]. However, such dual inhibition represents a potent ECS intervention that may limit therapeutic applicability. Currently, no clinical outcomes are available for CC-97489, the only dual FAAH/MAGL undergoing RCTs.

AEA’s agonist activity toward TRPV1 (“endovanilloid” signalling) has also been considered, based on the premise that combining FAAH inhibition with TRPV1 blockade might shift elevated AEA activity away from TRPV1-mediated effects toward CB₁R-directed signalling [157]. Observed in animal models, the dual approach has been associated with antidepressant-like effects (forced swim test) [158–160], reduced anxiety-like behaviour (elevated plus maze) [161], and inhibition of contextual fear memory [162]. However, to our knowledge, no RCTs have been conducted, to date, that employ dual FAAH/TRPV1 inhibitors.

In summary, FAAH inhibitors have not yet fulfilled their clinical promise that arose from preclinical data. Ongoing and future clinical trials are critical in overcoming the current challenges and clarifying their role in psychiatric treatment. Careful patient stratification, precision psychiatry approaches, rigorous safety and selectivity evaluation will be essential to unlock the full therapeutic potential of FAAH-targeted interventions in mood, anxiety, and trauma-related disorders.