Table 1.

Converging Evidence: The Example of Fatty Acid Amie Hydrolase (FAAH) rs324420 genotype (C/A; C385A)

Source of Evidence	Findings	Benefits	Limitations
In Vitro Function	A allele homozygosity is associated with less FAAH cellular expression in T- lymphocytes and transfected cells due to post-translation mechanism preceding folding (149).	Controlled functional characterization and isolation of step at which allelic variation impacts function	Unclear if similar function is observed in vivo amongst an interactive system
In Vivo Function	A allele carriers had lower [(11)C]CURB PET binding (FAAH binding) (150).	In vivo functional characterization	Often small samples, unclear links to behavior and other relevant phenotypes (e.g., brain function, structure)
Non-human Animal Manipulation	Knock-in mouse model: A allele associated with forebrain FAAH protein expression, hydrolytic activity, and elevated anandamide. A allele associated with increased projections from infralimbic to basolateral amygdala and enhanced fear extinction, and reduced anxiety (13).	Controlled manipulation of system using a variety of means (e.g., pharmacologic, genetic)	Unclear whether translates to humans and related conditions. Questionable phenotypic convergence across species for some phenotypes.
Human Manipulation (Pharmacologic Challenge)	Human: THC administration associated with reduced anxiety and threat-related amygdala reactivity (151).	Manipulation of a specific system allowing causal inferences to be drawn. For some substances, limitations on who can be exposed for human studies.	Temporary and chronic manipulation unclear translation to genetic risk. Uncertain whether artificial manipulations create other systematic changes.
Imaging Genetics and Genomics	A allele associated with decreased threat-related amygdala reactivity and increased amygdala habituation (152).	Provides a tractable and clinically-relevant phenotype. Offers system- level insight.	Molecular mechanisms of association unclear
Psychiatric/Behavioral Association (Candidate or GWAS)	A allele associated with enhancd fear extinction, reduced anxiety and stress sensitivity (10).	Provides clinical relevance	Unclear biological mechanisms
Treatment	Some evidence that FAAH inhibition improves anxiety in rodent models (153). Most common self- reported reason for using cannabis is anxiety reductions. THC administration reduces anxiety in clinical populations (154).	Evaluation of applicable therapeutic potential	Dependent upon other evidence, ability and safety to manipulate target. Lack of regional specificity in humans

The endocannabinoid system has been linked to stress recovery, anxiety, and substance use, across a host of models. Fatty Acid Amide Hydrolase (FAAH) in an enzymatic regulator of endocannabinoid signaling. Within the endocannabinoid system, it primarily degrades the endocannabinoid ligand anandamide.