rs324420 — FAAH Pro129Thr

The "Bliss Gene" — FAAH and Your Endocannabinoid System

The FAAH gene encodes fatty acid amide hydrolase¹¹ fatty acid amide hydrolase
an enzyme that breaks down anandamide, your brain's natural "bliss molecule", which binds to the same receptors as THC from cannabis. The rs324420 variant changes a single amino acid at position 129 from proline to threonine, making the enzyme more vulnerable to breakdown. Carriers of the A allele produce less stable FAAH enzyme, resulting in elevated anandamide levels throughout the brain and body²² elevated anandamide levels throughout the brain and body.

This common variant occurs in approximately 38% of Europeans (33% heterozygous AC, 5% homozygous AA), with markedly higher frequencies in African populations (~45%) and lower in East Asians (~10%)³³ markedly higher frequencies in African populations (~45%) and lower in East Asians (~10%). The geographic distribution has led researchers to investigate whether this variant influences not just individual psychology but national happiness levels across cultures⁴⁴ national happiness levels across cultures.

The Mechanism

The Pro129Thr substitution doesn't change FAAH's catalytic activity — the enzyme still breaks down anandamide at normal rates when it's present. The critical difference is protein stability⁵⁵ protein stability. The threonine variant (A allele) is more sensitive to proteolytic degradation, meaning cells produce approximately 50% less FAAH enzyme in AA homozygotes compared to CC individuals. This leads to chronically elevated anandamide signaling through CB1 cannabinoid receptors, primarily in the amygdala, prefrontal cortex, and hippocampus — brain regions central to fear processing, stress response, and emotional regulation⁶⁶ fear processing, stress response, and emotional regulation.

Elevated anandamide acts like a natural anxiolytic, dampening the amygdala's threat response and enhancing fronto-amygdala connectivity. In neuroimaging studies, A-allele carriers show reduced amygdala activation when viewing threatening faces⁷⁷ A-allele carriers show reduced amygdala activation when viewing threatening faces and faster fear extinction learning — the ability to unlearn fear associations after a threat is no longer present.

The Evidence

Fear extinction and trauma response: Multiple fMRI studies demonstrate that A-allele carriers show enhanced fear extinction recall⁸⁸ Multiple fMRI studies demonstrate that A-allele carriers show enhanced fear extinction recall, the neurobiological foundation of exposure therapy for PTSD and anxiety disorders. In a study of 55 healthy adults, AC heterozygotes showed significantly greater extinction recall compared to CC individuals, with distinct neural activation patterns in the ventromedial prefrontal cortex. This suggests the A allele may confer resilience to trauma-related symptoms, though one large veteran study (N=949) found no protective effect against PTSD development after military deployment⁹⁹ one large veteran study (N=949) found no protective effect against PTSD development after military deployment.

Pain sensitivity: Women with the AA genotype undergoing breast cancer surgery reported significantly less sensitivity to cold pain¹⁰¹⁰ Women with the AA genotype undergoing breast cancer surgery reported significantly less sensitivity to cold pain (β = −1.48, 95% CI −2.14 to −0.8) and required less postoperative analgesia. A rare case report documented a Scottish woman with complete pain insensitivity, anxiety immunity, and accelerated wound healing¹¹¹¹ a Scottish woman with complete pain insensitivity, anxiety immunity, and accelerated wound healing, who carried both the AA genotype and a rare deletion in FAAH-OUT, a regulatory pseudogene.

Mood and well-being: The relationship with happiness is complex. A longitudinal study of 2,822 individuals found that each A-allele was associated with lower subjective well-being scores¹²¹² A longitudinal study of 2,822 individuals found that each A-allele was associated with lower subjective well-being scores at both timepoints (B: −0.52, p = 0.007). However, cross-national studies show countries with higher A-allele frequencies report greater national happiness¹³¹³ countries with higher A-allele frequencies report greater national happiness, with Ghana, Nigeria, and Mexico ranking highest. The paradox may reflect that chronically elevated anandamide leads to CB1 receptor downregulation over time, potentially disrupting normal reward processing.

Substance use: The A allele shows divergent effects across substances¹⁴¹⁴ divergent effects across substances. For cannabis, AA individuals have roughly half the dependence rate of CC carriers (11% vs 26%) and report less subjective pleasure from marijuana — likely because they already have elevated endogenous cannabinoid tone. However, for alcohol, A-allele carriers with European ancestry show more severe alcohol dependence¹⁵¹⁵ A-allele carriers with European ancestry show more severe alcohol dependence when they do develop problems (13 more binge drinking days per month), potentially via an indirect pathway through lower subjective well-being. The A allele has also been associated with increased risk of methamphetamine dependence in Malaysian populations¹⁶¹⁶ increased risk of methamphetamine dependence in Malaysian populations (OR 2.0-3.7 depending on ethnicity).

Athletic performance: Elite volleyball and rink-hockey players with the A allele were 2-3 times more likely to achieve "super athlete" status¹⁷¹⁷ Elite volleyball and rink-hockey players with the A allele were 2-3 times more likely to achieve "super athlete" status, possibly due to enhanced stress coping and pain tolerance during training and competition. However, contradictory evidence exists, with some studies showing the AA genotype more common in sedentary individuals than elite athletes.

Practical Implications

If you carry the A allele, your endocannabinoid system is running at a higher baseline, with downstream effects on how you process fear, pain, stress, and reward. This may make you more resilient to acute stressors and physical pain, but potentially more vulnerable to mood disturbances if you experienced childhood trauma, which can interact with the A allele to increase anxiety and depression risk¹⁸¹⁸ interact with the A allele to increase anxiety and depression risk.

For mental health treatment, A-allele carriers may respond particularly well to exposure-based therapies for anxiety and PTSD, given the enhanced fear extinction consolidation. FAAH inhibitors — drugs designed to mimic the A-allele effect — are in clinical trials for anxiety disorders and showed promise in a 12-week trial for social anxiety¹⁹¹⁹ promise in a 12-week trial for social anxiety, though results have been mixed.

For pain management, AA individuals may require less analgesia for acute pain but should still discuss post-operative pain plans with providers, as individual variation is substantial. The reduced pain sensitivity doesn't eliminate pain entirely.

For substance use, recognize that if you have the A allele, cannabis will likely be less appealing and addictive, but alcohol may pose greater risk if you develop problematic use patterns, particularly if you also struggle with low mood.

Interactions

The FAAH rs324420 variant interacts with other endocannabinoid and stress-response genes. CNR1 rs2180619 (cannabinoid receptor 1) and CRHR1 rs110402 (corticotropin-releasing hormone receptor 1) have been studied for interactions with FAAH in stress response, though a large veteran study found no significant gene-gene interaction effects²⁰²⁰ a large veteran study found no significant gene-gene interaction effects. The COMT rs4680 variant (which affects dopamine metabolism) has been shown to interact with FAAH rs324420 in modulating placebo analgesia response²¹²¹ interact with FAAH rs324420 in modulating placebo analgesia response.

Early life stress represents a critical environmental interaction. Individuals with the A allele who experienced repetitive childhood trauma show significantly higher anxiety and depression scores²²²² Individuals with the A allele who experienced repetitive childhood trauma show significantly higher anxiety and depression scores compared to CC carriers with similar trauma exposure, suggesting chronically elevated anandamide during neurodevelopment may disrupt normal CB1 receptor function and long-term stress response systems.