The eCB System in Fear and Stress: Preclinical Evidence
An Introduction to the eCB System
Regulation of Fear and Stress by CB1 Receptor Agonists
Regulation of Fear and Stress by FAAH Inhibitors
Regulation of Fear and Stress by MAGL Inhibitors
- 1.FAAH inhibitors currently have the most consistent rationale as candidate PTSD treatments. Preclinical research consistently indicates that FAAH inhibition can enhance fear extinction and consolidation and suppress multiple aspects of the stress response, particularly, changes in anxiety and neuroendocrine function.
- 2.Exogenous direct CB1 receptor agonists have some promise for the regulation of fear and stress, as they also enhance fear extinction and dampen stress responses. Notably, these effects are highly dependent on dose and may still carry the risk of effects on other CB1-mediated functions, such as appetite, cognition, and motor coordination.
- 3.MAGL inhibitors may have some potential to mitigate stress-induced anxiety, but consistent evidence supporting their utility as PTSD treatments is presently lacking.
The eCB System in Fear and Stress: Evidence From Human Studies
Experimental Evidence: THC
Experimental Evidence: FAAH Inhibition
- Green D.G.J.
- Kim J.
- Kish S.J.
- Tyndale R.F.
- Hill M.N.
- Strafella A.P.
- et al.
- Zabik N.L.
- Iadipaolo A.S.
- Marusak H.A.
- Peters C.
- Burghardt K.
- Rabinak C.A.
|Study Registration||Study Population||Dosing Information||Outcome Measures||Effects of Treatment (vs. Placebo)|
|FAAH Inhibition: PF-04457845|
| EudraCT 2016-005013-47 [Mayo et al. (|
|Healthy adults, N = 45||4 mg/day for 10 days||Fear-potentiated startle|
|Conditioned fear extinction||No effect|
|Recall of extinction (24 hours later)||Greater|
|Skin conductance response||Reduced|
|NCT01665573 (results not reported)||Healthy adults, N = 150||Unknown dose, unknown duration||Psychophysiology|
|Conditioned fear extinction||NA|
|NCT02216097 (premature termination)||PTSD, N = 14||4 mg/day for 7 days||Neuroimaging|
|Fear extinction retention||NA|
|EudraCT 2014-002456-90 (premature termination)||Comorbid PTSD and AUD, N = 150, women only||4 mg/day for 4 weeks + exposure therapy||Clinical questionnaires|
|Clinician-administered PTSD Scale||NA|
|Alcohol consumption (TLFB)||NA|
|FAAH Inhibition: JNJ-42165279|
| NCT01826786 [Paulus et al. (|
|Healthy adults, N = 45, men only||100 mg/day for 4 days||Neuroimaging|
|Emotional face processing||Reduced (amygdala, ACC, insula)|
|Breathing restriction||Increased (ACC, anterior insula)|
|Fear conditioning and extinction||No effect|
| NCT02432703 [Schmidt et al. (|
The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: A double-blind, randomized, placebo-controlled proof-of-concept study.
Neuropsychopharmacology. 2021; 46: 1004-1010
|Social anxiety disorder, N = 149||25 mg/day for 12 weeks||Clinical questionnaires|
|Liebowitz Social Anxiety Scale||No effect|
|Hamilton Anxiety Ratings Scale||Significant decrease|
|Hamilton Depression Rating Scale||No change (low to start with)|
|Clinical Global Impression Scale||Greater improvement|
|Drug levels, anandamide||Higher dose may be needed|
|NCT02498392 (results not yet reported)||MDD + anxious distress, N = 161||25 mg/day for 6 weeks + SSRI||Clinical questionnaires|
|Hamilton Depression Rating Scale||TBD|
|Hamilton Anxiety Rating Scale||TBD|
|Plasma drug concentrations||TBD|
|EudraCT 2020-001965-36 (ongoing)||PTSD (N = 90), placebo-controlled, blinded||25 mg × 2/day, 12 weeks + exposure therapy||Clinical questionnaires|
|Clinician-administered PTSD Scale||TBD|
|Pittsburgh Sleep Quality Index||TBD|
|Conditioned fear extinction||TBD|
|Skin conductance response||TBD|
|Subjective stress ratings||TBD|
|MAGL Inhibition: Lu AG06446|
|NCT04597450 (ongoing)||PTSD (N = 30), placebo-controlled, blinded||Not reported||Neuroimaging|
|Facial affect recognition||TBD|
|Card guessing task||TBD|
Experimental Evidence: MAGL Inhibition
Clinical Trials: THC
Clinical Trials: FAAH Inhibition
- Huggins J.P.
- Smart T.S.
- Langman S.
- Taylor L.
- Young T.
- Schmidt M.E.
- Liebowitz M.R.
- Stein M.B.
- Grunfeld J.
- Van Hove I.
- Simmons W.K.
- et al.
- D’Souza D.C.
- Cortes-Briones J.
- Creatura G.
- Bluez G.
- Thurnauer H.
- Deaso E.
- et al.
Clinical Trials: MAGL Inhibition
Acknowledgments and Disclosures
- Diagnostic and Statistical Manual of Mental Disorders: DSM-5.5th ed. American Psychiatric Publishing, Inc, Arlington2013
- Trauma and PTSD in the WHO World Mental Health Surveys.Eur J Psychotraumatol. 2017; 8: 1353383
- Remission from post-traumatic stress disorder in the general population.Psychol Med. 2012; 42: 1695-1703
- Functional neuroanatomy of emotion and its regulation in PTSD.Harv Rev Psychiatry. 2018; 26: 116-128
- Impaired fear inhibition is a biomarker of PTSD but not depression.Depress Anxiety. 2010; 27: 244-251
- Neural changes in extinction recall following prolonged exposure treatment for PTSD: A longitudinal fMRI study.Neuroimage Clin. 2016; 12: 715-723
- Psychological treatments for adults with posttraumatic stress disorder: A systematic review and meta-analysis.Clin Psychol Rev. 2016; 43: 128-141
- Psychological therapies for chronic post-traumatic stress disorder (PTSD) in adults.Cochrane Database Syst Rev. 2013; 12: CD003388
- Guidelines for treatment of PTSD.J Trauma Stress. 2000; 13: 539-588
- Beyond the manual: The insider’s guide to Prolonged Exposure therapy for PTSD.Cogn Behav Pract. 2003; 10: 22-30
- Efficacy of prolonged exposure therapy, sertraline hydrochloride, and their combination among combat veterans with posttraumatic stress disorder: A randomized clinical trial.JAMA Psychiatry. 2019; 76: 117-126
- Cognitive behavioral therapy for posttraumatic stress disorder in women: A randomized controlled trial.JAMA. 2007; 297: 820-830
- The nature and course of subthreshold PTSD.J Anxiety Disord. 2010; 24: 918-923
- Pretreatment biomarkers predicting PTSD psychotherapy outcomes: A systematic review.Neurosci Biobehav Rev. 2017; 75: 140-156
- Effectiveness of internet-delivered cognitive behavioral therapy for posttraumatic stress disorder: A systematic review and meta-analysis.Depress Anxiety. 2016; 33: 783-791
- Treatment of Posttraumatic Stress Disorder: An Assessment of the Evidence.National Academies Press, Washington, DC2008
- Integrating endocannabinoid signaling and cannabinoids into the biology and treatment of posttraumatic stress disorder.Neuropsychopharmacology. 2018; 43: 80-102
- Molecular characterization of a peripheral receptor for cannabinoids.Nature. 1993; 365: 61-65
- Structure of a cannabinoid receptor and functional expression of the cloned cDNA.Nature. 1990; 346: 561-564
- Isolation and structure of a brain constituent that binds to the cannabinoid receptor.Science. 1992; 258: 1946-1949
- 2-Arachidonoylglycerol: A possible endogenous cannabinoid receptor ligand in brain.Biochem Biophys Res Commun. 1995; 215: 89-97
- Chemical probes of endocannabinoid metabolism.Pharmacol Rev. 2013; 65: 849-871
- Enzymatic synthesis and degradation of anandamide, a cannabinoid receptor agonist.Biochem Pharmacol. 1993; 46: 791-796
- A comprehensive profile of brain enzymes that hydrolyze the endocannabinoid 2-arachidonoylglycerol.Chem Biol. 2007; 14: 1347-1356
- The endocannabinoid system: An emotional buffer in the modulation of memory function.Neurobiol Learn Mem. 2014; 112: 30-43
- Effects of intra-amygdala infusion of CB1 receptor agonists on the reconsolidation of fear-potentiated startle.Learn Mem. 2006; 13: 316-321
- The role of prefrontal cortex CB1 receptors in the modulation of fear memory.Cereb Cortex. 2009; 19: 165-175
- The cannabinoid receptor agonist WIN 55,212-2 facilitates the extinction of contextual fear memory and spatial memory in rats.Psychopharmacology (Berl). 2006; 188: 641-649
- Cannabinoids modulate hippocampal memory and plasticity.Hippocampus. 2010; 20: 1126-1138
- Differential effects of CB1 receptor agonism in behavioural tests of unconditioned and conditioned fear in adult male rats.Behav Brain Res. 2015; 279: 9-16
- The cannabinoid system in the retrosplenial cortex modulates fear memory consolidation, reconsolidation, and extinction.Learn Mem. 2015; 22: 584-588
- The involvement of cannabinoids and mTOR in the reconsolidation of an emotional memory in the hippocampal-amygdala-insular circuit.Eur Neuropsychopharmacol. 2017; 27: 336-349
- Involvement of the infralimbic cortex and CA1 hippocampal area in reconsolidation of a contextual fear memory through CB1 receptors: Effects of CP55,940.Neurobiol Learn Mem. 2016; 127: 42-47
- Endocannabinoid signaling negatively modulates stress-induced activation of the hypothalamic-pituitary-adrenal axis.Endocrinology. 2004; 145: 5431-5438
- Inhibition of restraint stress-induced neural and behavioural activation by endogenous cannabinoid signalling.Eur J Neurosci. 2005; 21: 1057-1069
- Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis.Neuropsychopharmacology. 2009; 34: 2733-2745
- Cannabinoid receptor activation in the basolateral amygdala blocks the effects of stress on the conditioning and extinction of inhibitory avoidance.J Neurosci. 2009; 29: 11078-11088
- Cannabinoid receptors activation and glucocorticoid receptors deactivation in the amygdala prevent the stress-induced enhancement of a negative learning experience.Neurobiol Learn Mem. 2012; 97: 393-401
- Synergistic interactions between cannabinoids and environmental stress in the activation of the central amygdala.Neuropsychopharmacology. 2005; 30: 497-507
- Neurobiological interactions between stress and the endocannabinoid system.Neuropsychopharmacology. 2016; 41: 80-102
- Endocannabinoid signaling and the hypothalamic-pituitary-adrenal axis.Compr Physiol. 2016; 7: 1-15
- Endogenous cannabinoid release within prefrontal-limbic pathways affects memory consolidation of emotional training.Proc Natl Acad Sci U S A. 2014; 111: 18333-18338
- Differential role of the hippocampal endocannabinoid system in the memory consolidation and retrieval mechanisms.Neurobiol Learn Mem. 2008; 90: 1-9
- Endocannabinoid interactions in the regulation of acquisition of contextual conditioned fear.Prog Neuropsychopharmacol Biol Psychiatry. 2019; 90: 84-91
- Enhancing endocannabinoid neurotransmission augments the efficacy of extinction training and ameliorates traumatic stress-induced behavioral alterations in rats.Neuropsychopharmacology. 2018; 43: 1284-1296
- 2-AG promotes the expression of conditioned fear via cannabinoid receptor type 1 on GABAergic neurons.Psychopharmacology (Berl). 2015; 232: 2811-2825
- Enhanced anandamide signaling reduces flight behavior elicited by an approaching robo-beetle.Neuropharmacology. 2017; 126: 233-241
- FAAH genetic variation enhances fronto-amygdala function in mouse and human.Nat Commun. 2015; 6: 6395
- Facilitation of contextual fear memory extinction and anti-anxiogenic effects of AM404 and cannabidiol in conditioned rats.Eur Neuropsychopharmacol. 2008; 18: 849-859
- Fluoxetine facilitates fear extinction through amygdala endocannabinoids.Neuropsychopharmacology. 2016; 41: 1598-1609
- Discovery of a NAPE-PLD inhibitor that modulates emotional behavior in mice.Nat Chem Biol. 2020; 16: 667-675
- Impaired anandamide/palmitoylethanolamide signaling in hippocampal glutamatergic neurons alters synaptic plasticity, learning, and emotional responses.Neuropsychopharmacology. 2019; 44: 1377-1388
- Stress-induced modulation of endocannabinoid signaling leads to delayed strengthening of synaptic connectivity in the amygdala.Proc Natl Acad Sci U S A. 2020; 117: 650-655
- Corticotropin-releasing hormone drives anandamide hydrolysis in the amygdala to promote anxiety.J Neurosci. 2015; 35: 3879-3892
- Emotional arousal state influences the ability of amygdalar endocannabinoid signaling to modulate anxiety.Neuropharmacology. 2016; 111: 59-69
- Modulation of anxiety through blockade of anandamide hydrolysis.Nat Med. 2003; 9: 76-81
- 2-arachidonoylglycerol modulation of anxiety and stress adaptation: From grass roots to novel therapeutics.Biol Psychiatry. 2020; 88: 520-530
- Pharmacological inhibition of 2-arachidonoilglycerol hydrolysis enhances memory consolidation in rats through CB2 receptor activation and mTOR signaling modulation.Neuropharmacology. 2018; 138: 210-218
- 2-arachidonoylglycerol signaling impairs short-term fear extinction.Transl Psychiatry. 2016; 6: e749
- Anxiety, stress, and fear response in mice with reduced endocannabinoid levels.Biol Psychiatry. 2016; 79: 858-868
- Inhibition of diacylglycerol lipase impairs fear extinction in mice.Front Neurosci. 2018; 12: 479
- Biphasic effects of cannabinoids in anxiety responses: CB1 and GABA(B) receptors in the balance of GABAergic and glutamatergic neurotransmission.Neuropsychopharmacology. 2012; 37: 2624-2634
- Fast feedback inhibition of the HPA axis by glucocorticoids is mediated by endocannabinoid signaling.Endocrinology. 2010; 151: 4811-4819
- Endogenous cannabinoid signaling is essential for stress adaptation.Proc Natl Acad Sci U S A. 2010; 107: 9406-9411
- Rapid elevations in limbic endocannabinoid content by glucocorticoid hormones in vivo.Psychoneuroendocrinology. 2010; 35: 1333-1338
- Recruitment of prefrontal cortical endocannabinoid signaling by glucocorticoids contributes to termination of the stress response.J Neurosci. 2011; 31: 10506-10515
- Swim stress differentially affects limbic contents of 2-arachidonoylglycerol and 2-oleoylglycerol.Neuroscience. 2012; 204: 74-82
- Acute stress suppresses synaptic inhibition and increases anxiety via endocannabinoid release in the basolateral amygdala.J Neurosci. 2016; 36: 8461-8470
- Stress promotes drug seeking through glucocorticoid-dependent endocannabinoid mobilization in the prelimbic cortex.Biol Psychiatry. 2018; 84: 85-94
- Monoacylglycerol lipase inhibition-induced changes in plasma corticosterone levels, anxiety and locomotor activity in male CD1 mice.Horm Behav. 2013; 63: 752-758
- Involvement of 2-arachidonoylglycerol signaling in social challenge responding of male CD1 mice.Psychopharmacology (Berl). 2015; 232: 2157-2167
- Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats.Neuroscience. 2010; 168: 371-386
- Functional redundancy between canonical endocannabinoid signaling systems in the modulation of anxiety.Biol Psychiatry. 2017; 82: 488-499
- Therapeutic endocannabinoid augmentation for mood and anxiety disorders: Comparative profiling of FAAH, MAGL and dual inhibitors.Transl Psychiatry. 2018; 8: 92
- Endocannabinoid modulation of predator stress-induced long-term anxiety in rats.Neuropsychopharmacology. 2016; 41: 1329-1339
- Cannabinoid CB 2 receptors mediate the anxiolytic-like effects of monoacylglycerol lipase inhibition in a rat model of predator-induced fear.Neuropsychopharmacology. 2020; 45: 1330-1338
- Endocannabinoid signalling modulates susceptibility to traumatic stress exposure.Nat Commun. 2017; 8: 14782
- Endocannabinoid concentrations in hair are associated with PTSD symptom severity.Psychoneuroendocrinology. 2016; 67: 198-206
- Reductions in circulating endocannabinoid levels in individuals with post-traumatic stress disorder following exposure to the World Trade Center attacks.Psychoneuroendocrinology. 2013; 38: 2952-2961
- Cannabinoid facilitation of fear extinction memory recall in humans.Neuropharmacology. 2013; 64: 396-402
- Testing the effects of Δ9-THC and D-cycloserine on extinction of conditioned fear in humans.J Psychopharmacol. 2012; 26: 471-478
- Cannabinoid modulation of prefrontal-limbic activation during fear extinction learning and recall in humans.Neurobiol Learn Mem. 2014; 113: 125-134
- Influence of Δ9-tetrahydrocannabinol on long-term neural correlates of threat extinction memory retention in humans.Neuropsychopharmacology. 2019; 44: 1769-1777
- Effects of acute Δ9-tetrahydrocannabinol on next-day extinction recall is mediated by post-extinction resting-state brain dynamics.Neuropharmacology. 2018; 143: 289-298
- Stress-related factors in cannabis use and misuse: Implications for prevention and treatment.J Subst Abuse Treat. 2009; 36: 400-413
- Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress.Drug Alcohol Depend. 2017; 177: 136-144
- Protective effects of elevated anandamide on stress and fear-related behaviors: Translational evidence from humans and mice.Mol Psychiatry. 2020; 25: 993-1005
- A missense mutation in human fatty acid amide hydrolase associated with problem drug use.Proc Natl Acad Sci U S A. 2002; 99: 8394-8399
- FAAH gene variation moderates stress response and symptom severity in patients with posttraumatic stress disorder and comorbid alcohol dependence.Alcohol Clin Exp Res. 2016; 40: 2426-2434
- The fatty acid amide hydrolase C385A variant affects brain binding of the positron emission tomography tracer [11C]CURB.J Cereb Blood Flow Metab. 2015; 35: 1237-1240
- Fatty acid amide hydrolase binding is inversely correlated with amygdalar functional connectivity: A combined positron emission tomography and magnetic resonance imaging study in healthy individuals.J Psychiatry Neurosci. 2021; 46: E238-E246
- A common genetic variant in fatty acid amide hydrolase is linked to alterations in fear extinction neural circuitry in a racially diverse, nonclinical sample of adults [published online ahead of print May 29].J Neurosci Res. 2021;
- Fear extinction learning and anandamide: An fMRI study in healthy humans.Transl Psychiatry. 2021; 11: 161
- Cannabinoid polymorphisms interact with plasma endocannabinoid levels to predict fear extinction learning.Depress Anxiety. 2021; 38: 1087-1099
- Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity.Mol Psychiatry. 2013; 18: 813-823
- Individual differences in frontolimbic circuitry and anxiety emerge with adolescent changes in endocannabinoid signaling across species.Proc Natl Acad Sci U S A. 2016; 113: 4500-4505
- Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase: A randomized, controlled experimental medicine trial.Biol Psychiatry. 2020; 87: 538-547
- The effects of FAAH inhibition on the neural basis of anxiety-related processing in healthy male subjects: A randomized clinical trial.Neuropsychopharmacology. 2021; 46: 1011-1019
- Discovery of PF-04457845: A highly potent, orally bioavailable, and selective urea FAAH inhibitor.ACS Med Chem Lett. 2011; 2: 91-96
- Mechanistic and pharmacological characterization of PF-04457845: A highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.J Pharmacol Exp Ther. 2011; 338: 114-124
- Preclinical characterization of the FAAH inhibitor JNJ-42165279.ACS Med Chem Lett. 2015; 6: 1204-1208
- Prefrontal inputs to the amygdala instruct fear extinction memory formation.Sci Adv. 2015; 1e1500251
- Modulation of the endocannabinoid system by sex hormones: Implications for posttraumatic stress disorder.Neurosci Biobehav Rev. 2018; 94: 302-320
- Nervous and endocrine system dysfunction in posttraumatic stress disorder: An overview and consideration of sex as a biological variable.Biol Psychiatry Cogn Neurosci Neuroimaging. 2020; 5: 381-391
- Acute stress increases circulating anandamide and other N-acylethanolamines in healthy humans.Neuropsychopharmacology. 2012; 37: 2416-2427
- Loss of exercise- and stress-induced increases in circulating 2-arachidonoylglycerol concentrations in adults with chronic PTSD.Biol Psychol. 2019; 145: 1-7
- Endocannabinoid reactivity to acute stress: Investigation of the relationship between salivary and plasma levels.Biol Psychol. 2021; 159: 108022
- An endocannabinoid signal associated with desire for alcohol is suppressed in recently abstinent alcoholics.Psychopharmacology (Berl). 2009; 205: 63-72
- Genetically reduced FAAH activity may be a risk for the development of anxiety and depression in persons with repetitive childhood trauma.Eur Neuropsychopharmacol. 2016; 26: 1020-1028
- Interactions between anandamide and corticotropin-releasing factor signaling modulate human amygdala function and risk for anxiety disorders: An imaging genetics strategy for modeling molecular interactions.Biol Psychiatry. 2016; 80: 356-362
- The short-term impact of 3 smoked cannabis preparations versus placebo on PTSD symptoms: A randomized cross-over clinical trial.PLoS One. 2021; 16e0246990
- Cannabinoid modulation of corticolimbic activation to threat in trauma-exposed adults: A preliminary study.Psychopharmacology (Berl). 2020; 237: 1813-1826
- An efficient randomised, placebo-controlled clinical trial with the irreversible fatty acid amide hydrolase-1 inhibitor PF-04457845, which modulates endocannabinoids but fails to induce effective analgesia in patients with pain due to osteoarthritis of the knee.Pain. 2012; 153: 1837-1846
- Lessons from the fatal French study BIA-10-2474.BMJ. 2016; 353i2727
- Activity-based protein profiling reveals off-target proteins of the FAAH inhibitor BIA 10-2474.Science. 2017; 356: 1084-1087
- The effects of inhibition of fatty acid amide hydrolase (FAAH) by JNJ-42165279 in social anxiety disorder: A double-blind, randomized, placebo-controlled proof-of-concept study.Neuropsychopharmacology. 2021; 46: 1004-1010
- Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: A double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial.Lancet Psychiatry. 2019; 6: 35-45
- Impairments in endocannabinoid signaling and depressive illness.JAMA. 2009; 301: 1165-1166
- Reconsolidation/destabilization, extinction and forgetting of fear memory as therapeutic targets for PTSD.Psychopharmacology (Berl). 2019; 236: 49-57
- The role of endocannabinoids in consolidation, retrieval, reconsolidation, and extinction of fear memory.Pharmacol Rep. 2021; 73: 984-1003
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