The human body makes its own cannabis-like chemicals. Known as endocannabinoids, these natural molecules act as messengers in the brain and body, helping to fine-tune mood, stress, sleep, appetite and pain. One of the most important is anandamide.
A recent systematic review published in Translational Psychiatry aimed to understand whether enhancing the expression of the endocannabinoid anandamide may offer an alternative pharmacological approach to the treatment of psychiatric conditions, including depression, anxiety, and cannabis use disorder (CUD).
Key Takeaways:
- The endocannabinoid system helps regulate mood, stress and emotion, and is altered in conditions such as depression, anxiety and post-traumatic stress disorder (PTSD).
- A class of experimental drugs called FAAH inhibitors works by blocking the enzyme that breaks down anandamide, so levels of this natural molecule rise.
- In laboratory and early human studies, FAAH inhibitors reliably increased anandamide and were generally well tolerated.
- So far only two compounds have reached mid-stage (Phase II) trials, and the clinical benefits have been modest at best.
- Important: FAAH inhibitors are experimental research compounds. None is an approved or available treatment for any psychiatric condition.
What is the endocannabinoid system?
The endocannabinoid system (ECS) is a signalling network found throughout the brain, nervous system, immune system and many organs. It helps the body maintain balance, and it plays a part in a wide range of everyday processes, including how we handle stress or experience pain.
The ECS has two main receptors, called cannabinoid type 1 (CB1) and type 2 (CB2). These are switched on by the body’s own endocannabinoids, which are made “on demand” when cells need them. The two best-studied endocannabinoids are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Because the ECS is so widespread, researchers have long been interested in whether it could be a target for new mental health treatments.
Anandamide, the Endocannabinoid System, and Psychiatry
Anandamide binds strongly to the CB1 receptor, which is closely linked to mood, anxiety and emotion. Researchers have noticed that anandamide levels are often different in people with certain psychiatric conditions. Although importantly, the findings are not always consistent.
For example, anandamide can be raised in people with schizophrenia, where it may have an early protective effect; frequent cannabis use appears to blunt this rise. In major depressive disorder, some studies have found reduced anandamide that loosely tracks with symptom severity, though results vary. Higher anandamide has also been associated with lower anxiety, better emotional regulation, and an improved ability to “switch off” fear responses. This is why it has drawn interest in post-traumatic stress disorder (PTSD).
Taken together, anandamide appears to act as a natural buffer against stress, fear and anxiety. That has prompted scientists to ask whether altering levels of anandamide could help some people. One way to do that is to slow down the enzyme that destroys it.
The enzyme fatty acid amide hydrolase (FAAH) is the main enzyme that breaks anandamide down. If you block FAAH, anandamide naturally accumulates. In theory, this offers a targeted way to raise endocannabinoid activity. Drugs designed to do this are called FAAH inhibitors.
What did the review study?
The authors carried out a targeted review of published studies and clinical-trial registries (searching PubMed and Scopus for human studies from January 2022 to August 2025). They focused on FAAH-selective inhibitors, examining their effects on anandamide, their safety, and whether they eased symptoms across depression, anxiety, PTSD and cannabis use disorder (CUD). Here is an overview of the main compounds discussed in the review.
URB597
One of the most extensively studied FAAH inhibitors. In animal studies, it quickly and durably raised anandamide, with a reassuring safety profile and no signs of abuse potential. However, its clinical development has largely stalled, so its effects in humans remain unknown. The only registered human trial was withdrawn due to a lack of funding.
PF-04457845 (now called JZP150)
A highly selective FAAH inhibitor that raises anandamide and shows safety in early trials. In men with cannabis dependence, an earlier study reported reduced cannabis use and withdrawal symptoms, and in healthy volunteers, it improved fear-extinction memory and dampened stress responses. Despite this promise, a Phase II PTSD trial in 282 adults did not show a difference to placebo and was discontinued. A Phase II trial in cannabis use disorder found that cannabis use failed to a similar degree in both the drug and placebo groups.
JNJ-42165279
This compound produced large increases in anandamide and was well tolerated. In a trial for social anxiety disorder, it showed a moderate signal of benefit, but did not clearly outperform placebo on its main measures. Trials in depression, general anxiety, PTSD and autism spectrum disorder largely also have not met their primary goals, although a few secondary measures improved.
BIA 10-2474
BIA 10-2474 is a less selective FAAH inhibitor and caused toxicity in animal studies. In a Phase I human trial, higher repeated doses led to severe neurological harm. One participant died, and four others were hospitalised. The compound was subsequently abandoned. Notably, the better-targeted FAAH inhibitors above have not shown these severe effects.
Others in early development
CC-97489 (also known as BMS-986368) is a dual FAAH/monoacylglycerol lipase (MAGL) inhibitor being explored for epilepsy. It has completed early Phase I trials whose results are not yet published. URB937 is a “peripherally restricted” inhibitor that raises anandamide mostly outside the brain and has shown promise in animal pain models, but has no human data yet.
What does this mean for the future?
The appeal of FAAH inhibitors is simple. Through raising anandamide, a key regulator of mood, stress and pain, they might help conditions where the endocannabinoid system is out of balance. The review found strong biological effects in the laboratory and in early human studies that these drugs do raise anandamide, yet this has not reliably translated into meaningful symptom improvement in patients.
The authors suggest the path forward lies in precision psychiatry by carefully selecting who takes part in trials, accounting for factors such as trauma type and genetics (for instance, a common variation in the FAAH gene), and using biomarkers to identify the people most likely to benefit. Above all, they stress that balancing effectiveness with safety must remain the priority. For now, raising anandamide appears to be a promising idea but will more rigorous trials before any firm conclusions can be drawn.
