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Cited by 233Cannabis and Cannabinoid ResearchMedicinal Plant Extracts EffectsNeuroscience and Neuropharmacology Research

The endocannabinoid system as a target for novel anxiolytic drugs

Open access
Patel, Sachin, Hill, Mathew N., Cheer, Joseph F., Wotjak, Carsten T., Holmes, Andrew·2017·Neuroscience & Biobehavioral Reviews
DOI 10.1016/j.neubiorev.2016.12.033PMC PMC5407316
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Abstract

The endocannabinoid (eCB) system has attracted attention for its role in various behavioral and brain functions, and as a therapeutic target in neuropsychiatric disease states, including anxiety disorders and other conditions resulting from dysfunctional responses to stress. In this mini-review, we highlight components of the eCB system that offer potential 'druggable' targets for new anxiolytic medications, emphasizing some of the less well-discussed options. We discuss how selectively amplifying eCBs recruitment by interfering with eCB-degradation, via fatty acid amide hydrolase (FAAH) and monoacylglycerol lipase (MAGL), has been linked to reductions in anxiety-like behaviors in rodents and variation in human anxiety symptoms. We also discuss a non-canonical route to regulate eCB degradation that involves interfering with cyclooxygenase-2 (COX-2). Next, we discuss approaches to targeting eCB receptor-signaling in ways that do not involve the cannabinoid receptor subtype 1 (CB1R); by targeting the CB2R subtype and the transient receptor potential vanilloid type 1 (TRPV1). Finally, we review evidence that cannabidiol (CBD), while representing a less specific pharmacological approach, may be another way to modulate eCBs and interacting neurotransmitter systems to alleviate anxiety. Taken together, these various approaches provide a range of plausible paths to developing novel compounds that could prove useful for treating trauma-related and anxiety disorders.

AI snapshot

Written from the paper’s full text.

TL;DR

This mini-review argues that the endocannabinoid system offers multiple druggable targets for novel anxiolytic drugs beyond CB1R, including FAAH, MAGL, COX-2, CB2R, TRPV1, and cannabidiol. It synthesizes rodent and human evidence suggesting that augmenting anandamide or 2-AG signaling, or modulating non-CB1R pathways, may reduce anxiety, especially under stress or high aversiveness.

Key findings

  • FAAH inhibition elevates anandamide and produces anxiolytic-like effects in rodents, particularly under high environmental aversiveness; the human FAAH 385A allele (rs324420) has been associated with reduced trait anxiety and altered corticoamygdala/amygdala threat responses.
  • MAGL inhibition elevates 2-AG and can produce anxiolytic-like effects under high aversiveness, but reports are mixed; chronic high-dose MAGL inhibition can desensitize CB1R and produce a phenotype more like CB1R antagonism.
  • COX-2 inhibition, including with substrate-selective COX-2 inhibitors (e.g., LM-4131) and traditional inhibitors (Lumiracoxib, Celecoxib), reduces anxiety-like behavior in mice; effects were CB1R-dependent under unstressed conditions but not after acute foot-shock stress, where SK potassium channels were implicated.
  • TRPV1 appears to oppose CB1R in fear/anxiety circuits, and CBD shows anxiolytic effects in clinical reports and rodent assays, with efficacy inversely correlated with dose; proposed mechanisms include TRPV1 agonism/desensitization, negative allosteric modulation of CB1R, and 5-HT1A receptor interactions.

Methods

  • Narrative mini-review, not a primary experimental study; it synthesizes previously published preclinical rodent, human genetic, epidemiological, and clinical literature.
  • The review organizes evidence around candidate eCB targets: FAAH, MAGL, COX-2, CB2R, TRPV1, and CBD.
  • No systematic search strategy, inclusion criteria, meta-analysis, or primary sample is stated in the paper.

Limitations

  • The paper states that many approaches remain early-stage; clinical investigation of COX-2 inhibition for anxiety is “essentially untouched,” and MAGL inhibition parameters/kinetics need resolution before clinical movement.
  • The paper states that CBD’s anxiolytic mechanisms remain undetermined and that data on CBD–THC/phytocannabinoid interactions are lacking.
  • Evident from the text: as a narrative mini-review, it does not systematically assess study quality or quantify effects, and it repeatedly notes mixed or preliminary findings across cited studies.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.neubiorev.2016.12.033

Cites

172 of 172 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 136 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Gene deletion or selective pharmacological inhibition of FAAH produces anxiolytic-like effects more reliably under conditions of high environmental aversiveness.

    “gene deletion or selective pharmacological inhibition of FAAH, produced anxiolytic-like effects more reliably under conditions of high environmental aversiveness (Bluett et al., 2014; Carnevali et al., 2015; Gray et al., 2015; Haller et al., 2014; Haller et al., 2009; Hill et al., 2013b; Lomazzo et al., 2015; Naidu et al., 2007; Patel and Hillard, 2006; Rossi et al., 2010).”
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    • cites Bluett et al., 2014 source

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    • cites Carnevali et al., 2015 source

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    • cites Gray et al., 2015 source

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  • Premisecitation

    Inhibition of FAAH and elevation of AEA signaling attenuates behavioral indices of fear and anxiety-related behavior in rodents.

    “It has been well established that inhibition of FAAH, and elevation of AEA signaling, can significantly attenuate behavioral indices of fear and anxiety-related behavior in rodents.”
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    • cites Kathuria et al., 2003 source

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  • Premisereasoning

    FAAH is the primary metabolic enzyme of AEA.

    “As genetic or pharmacological inactivation of FAAH results in a dramatic elevation in tissue levels of AEA, but not 2-AG, FAAH is considered as the primary metabolic enzyme of AEA.”
    Quote in the paperSubstantial claim
  • Interpretationreasoning

    Increasing AEA via FAAH inhibition could provide a therapeutic approach that selectively targets pathological forms of anxiety without side-effects that characterize many conventional anxiolytics.

    “the potential for increasing AEA, via FAAH inhibition, to preferentially modulate states of high anxiety could provide a therapeutic approach that selectively targets pathological forms of anxiety, without attendant side-effects (e.g., cognitive impairment, abuse-liability) that characterize many conventional anxiolytics.”
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  • Premisecitation

    Chronic unpredictable stressors impair 2-AG signaling.

    “chronic unpredictable stressors have been shown to impair 2-AG signaling (Hill et al., 2005; Zhang et al., 2015)”
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    Interpretationreasoning

    Reduction in AEA signaling in response to aversive environmental conditions promotes an anxiety-like state, whereas FAAH inhibition normalizes AEA signaling and produces a reduction in anxiety-like behavior.

    “it appears that the reduction in AEA signaling in response to aversive environmental conditions acts to promote the development of an anxiety-like state, whereas inhibition of FAAH, and resultant potentiation of AEA signaling, acts to normalize AEA signaling and produce an associated reduction in anxiety-like behavior”
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    • cites Gunduz-Cinar et al., 2013a

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    • cites Morena et al., 2016b

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    Premisecitation

    Under conditions of stress, FAAH activity is rapidly increased in anxiety-regulating brain regions such as the amygdala, with a concomitant reduction in the signaling pool of AEA.

    “under conditions of stress, FAAH activity has been found to be rapidly increased in brain regions regulating anxiety, such as the amygdala, with a concomitant reduction in the signaling pool of AEA (Bluett et al., 2014; Gray et al., 2015; Hill et al., 2013b; Patel et al., 2005; Rademacher et al., 2008).”
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    • cites Hill et al., 2013b

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    Premisecitation

    AEA levels are reduced in patients with major depression and PTSD.

    “a number of studies have detected reduced levels of AEA in patients suffering from stress-related psychiatric illnesses, including major depression (Hill et al., 2009) and PTSD (Neumeister et al., 2013).”
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    • cites Hill et al., 2009 source

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    Premisecitation

    A genetic variant in the human FAAH gene destabilizes FAAH protein, reduces FAAH-mediated AEA hydrolysis, and enhances AEA signaling.

    “a genetic variant in the human FAAH gene has been identified that destabilizes FAAH protein, reduces FAAH-mediated AEA hydrolysis and enhances AEA signaling (Boileau et al., 2015; Chiang et al., 2004; Cravatt et al., 2001; Dincheva et al., 2015; Sipe et al., 2002; Sipe et al., 2010).”
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    • cites Boileau et al., 2015

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    • cites Chiang et al., 2004

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    • cites Cravatt et al., 2001

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    Premisenone given

    DAGL is the primary enzyme involved in 2-AG synthesis, and MAGL is the primary enzyme involved in 2-AG hydrolysis.

    “with diacylglycerol lipase (DAGL) being the primary enzyme involved in synthesis, and MAGL being the primary enzyme involved in hydrolysis of 2-AG.”
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    Premisecitation

    Relatively low circulating AEA correlates with higher anxiety scores in major depression and with the degree of intrusive symptoms in PTSD.

    “relatively low circulating levels of AEA correlate with higher scores on measures of anxiety in major depression (Hill et al., 2008) and the degree of intrusive symptoms in PTSD (Hill et al., 2013a).”
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    • cites Hill et al., 2008

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    • cites Hill et al., 2013a

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    Interpretationreasoning

    Genetically-driven augmentation of AEA signaling confers a phenotype of reduced anxiety and proposes a plausible neural basis for this influence.

    “These epidemiological and genetic data indicate that genetically-driven augmentation of AEA signaling confers a phenotype of reduced anxiety and propose a plausible neural basis for this influence.”
    Quote in the paperSubstantial claim

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    Premisecitation

    The 385A allele (rs324420) is associated with reduced indices of trait anxiety, enhanced corticoamygdala connectivity, and reduced activation and accelerated habituation of amygdala BOLD responses to threat cues.

    “This polymorphism (385A allele; rs324420) has been repeatedly associated with reduced indices of trait anxiety, as well as enhanced corticoamygdala connectivity and reduced activation and accelerated habituation of amygdala blood-oxygen-level dependent (BOLD) responses to threat cues (Demers et al., 2016; Dincheva et al., 2015; Gee et al., 2016; Gunduz-Cinar et al., 2013b; Hariri et al., 2009).”
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    • cites Gee et al., 2016

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    Premisecitation

    Some reports indicate that MAGL inhibitors fail to affect anxiety-like behavior, and heightened emotional arousal can impair anxiolytic-like effects of MAGL inhibitors administered directly into the basolateral amygdala.

    “there are some reports that MAGL inhibitors fail to affect anxiety-like behavior (Lomazzo et al., 2015) and that heightened emotional arousal can impair anxiolytic-like effects of MAGL inhibitors administered directly into the basolateral amygdala (Morena et al., 2016a).”
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    Interpretationcitation

    2-AG signaling is a regulator of emotional behavior, and amplification of 2-AG signaling can attenuate anxiety-related readouts, particularly after exposure to stressful stimuli.

    “Collectively, this indicates that 2-AG signaling is also a regulator of emotional behavior, whereby amplification of 2-AG signaling can attenuate anxiety-related readouts, particularly after exposure to stressful stimuli.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    There is emerging support for a relationship between 2-AG and stress-related indices in humans and rodents, suggesting MAGL inhibition may be another therapeutic avenue for anxiety disorders and other conditions associated with adverse responses to stressors.

    “Thus, there is emerging support for a relationship between 2-AG and stress-related indices in humans, as well as rodents, suggesting MAGL inhibition may be another therapeutic avenue for the treatment of anxiety disorders and other conditions associated with adverse responses to stressors.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: Rodent models of anxiety-like behavior are valid predictors of human anxiety and of anxiolytic drug efficacy.

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    Premisecitation

    MAGL inhibition disrupts initial fear extinction acquisition and augments fear expression via 2-AG-mediated agonism of CB1R on GABAergic neurons.

    “MAGL inhibition has been found to disrupt, rather than promote, initial fear extinction acquisition (Hartley et al., 2016) and augment fear expression via 2-AG-mediated agonism of CB1R on GABAergic neurons (Llorente-Berzal et al., 2015).”
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    Premisecitation

    Healthy volunteers exposed to chronic stressors exhibit progressively diminished circulating 2-AG levels, which correlate with the onset of reductions in measures of positive emotion.

    “a recent study found that healthy volunteers exposed to chronic stressors exhibited progressively diminished circulating 2-AG levels, which correlated with the onset of reductions in measures of positive emotion (Yi et al., 2016).”
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    Premisecitation

    COX-2 is the immediate-early gene product of PTGS2 and is expressed in an activity-dependent manner in many tissues, including neurons.

    “COX-2 is the immediate-early gene product of prostaglandin synthase-2 (PTGS2) expressed in an activity-dependent manner in many tissues, including neurons (Kaufmann et al., 1996).”
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    Premisecitation

    COX-2 regulates eCB signaling at the synaptic, neurochemical and behavioral level in a manner that only partially overlaps with FAAH and MAGL inhibition, and may have a role in anxiety-like behavior and stress-responsivity.

    “emerging data that one of these pathways, COX-2, regulates eCB signaling at the synaptic, neurochemical and behavioral level in a manner that only partially overlaps with FAAH and MAGL inhibition (Hermanson et al., 2014; Hermanson et al., 2013), but nonetheless may have a role in the mediation of anxiety-like behavior and stress-responsivity (Gamble-George et al., 2016; Hermanson et al., 2013).”
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    Premisecitation

    Traditional COX-2 inhibitors inhibit the ability of COX-2 to oxidize arachidonic acid as well as eCBs, elevating levels of both substrates, whereas substrate-selective COX-2 inhibitors block eCB oxidation without attendant actions on arachidonic acid.

    “traditional COX-2 inhibitors which, although selective for COX-2 over COX-1, inhibit the ability of COX-2 to oxidize AA, as well as eCBs, and thereby elevate levels of both substrates. This pharmacological property can be avoided by substrate-selective COX-2 inhibitors (SSCIs), which block eCB oxidation without attendant actions on AA (Duggan et al., 2011; Hermanson et al., 2014; Windsor et al., 2”
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    • cites Windsor et al., 2012

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    Premisecitation

    Acute exogenous administration of prostaglandin E2 and D2 has anxiolytic-like actions, and prostaglandin E2 receptor null mutant mice exhibit reduced anxiety-like behavior.

    “acute exogenous administration of prostaglandin E2 and D2 have been shown to have anxiolytic-like actions (Suzuki et al., 2011; Zhao et al., 2009), and prostaglandin E2 receptor null mutant mice exhibit reduced anxiety-like behavior (Savonenko et al., 2009).”
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    • cites Suzuki et al., 2011

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    • cites Savonenko et al., 2009

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    Premisecitation

    Inhibition of COX-2 causes accumulation of eCBs, increases the tissue content of AEA and to a lesser degree 2-AG, and enhances eCB-mediated retrograde synaptic suppression.

    “inhibition of COX-2 causes accumulation of eCBs as revealed, firstly, by increases in the tissue content of AEA and, to a lesser degree, 2-AG and, secondly, by enhanced eCB-mediated retrograde synaptic suppression - in the form of depolarization-induced suppression of inhibition (DSI) and tonic eCB-suppression of glutamate release (Hermanson et al., 2013; Kim and Alger, 2004; Slanina and Schwe”
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    • cites Hermanson et al., 2013 source

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    • cites Kim and Alger, 2004

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    • cites Slanina and Schweitzer, 2005

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    Premisecitation

    Recent evidence implicates glial and mitochondrial CB1R in eCB-mediated mnemonic processes, together with a known role for astrocytes and mitochondria in stress- and anxiety-related processes.

    “recent evidence for glial (Han et al., 2012) and mitochondrial CB1R (Hebert-Chatelain et al., 2016) in eCB-mediated mnemonic processes, together with a known role for astrocytes (Oliveira et al., 2015) and mitochondria (Manji et al., 2012) in stress- and anxiety-related processes.”
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    Premisecitation

    CB1R is prominently expressed in various neuronal subpopulations, but also in astroglia and intracellular organelles such as mitochondria.

    “The receptor is prominently expressed in various neuronal subpopulations, but also in astroglia and intracellular organelles, such as mitochondria (Busquets-Garcia et al., 2015).”
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    Premisecitation

    The anxiolytic-like effects of LM-4131 in the light-dark exploration test are fully prevented by co-administration of a CB1R antagonist, consistent with eCB-dependency of the COX-2 inhibitor's effects.

    “the anxiolytic-like effects of LM-4131 were fully prevented (in the light-dark exploration test) by co-administration of a CB1R antagonist - consistent with eCB-dependency of the COX-2 inhibitor’s effects (Hermanson et al., 2013).”
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    • cites Hermanson et al., 2013 source

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    Premisecitation

    Drug effects generalized across assays, sexes, and ages, and were maintained under conditions of repeated stress or drug treatment, consistent with a robust anxiolytic-like action resistant to tolerance.

    “Drug effects generalized across assays (elevated plus-maze, conditioned fear), sexes and ages, and were maintained under conditions of repeated stress or drug treatment - consistent with a robust anxiolytic-like action that was resistant to tolerance.”
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    • cites Gamble-George et al., 2016 source

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    Premisecitation

    CB2R was thought to be confined to immune cells and absent from the central nervous system, but this was later found to be questionable given the lack of specificity of the antibodies used.

    “For some time, the CB2R was thought to be confined to immune cells and absent from the central nervous system (CNS) (Atwood et al., 2012; Fernandez-Ruiz et al., 2007; Parolaro, 1999), but this was later found to be questionable given the lack of specificity of the antibodies used (Ashton, 2012; Baek et al., 2013).”
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    • cites Parolaro, 1999

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    Premisecitation

    The effects of LM-4131 are prevented by the SK potassium channel blocker Apamin and mimicked by the SK channel activator 1-EBIO.

    “the effects of LM-4131 could be prevented by administration of the small-conductance calcium activated (SK) potassium channel blocker, Apamin, and were mimicked by administration of the SK channel activator 1-EBIO (Gamble-George et al., 2016).”
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    Interpretationreasoning

    Under unstressed conditions, COX-2 inhibitors exert anxiolytic-like effects via CB1R-mediated eCB signaling, but following exposure to stress these effects become uncoupled from this canonical mechanism of action.

    “Taken together, these preliminary findings suggest that under unstressed conditions, COX-2 inhibitors exert anxiolytic-like effects via CB1R-mediated eCB signaling but, following exposure to stress, these effects become uncoupled from this canonical mechanism of action.”
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    Premisecitation

    A potential link between variants in the human CNR2 and major depression has been proposed.

    “A potential link between variants in the human CNR2 and major depression (Onaivi et al., 2008) has also been proposed.”
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    Interpretationcitation

    Anxiety-related behaviors result from a balance between eCB-mediated inhibition via CB1R and excitation via TRPV1 of anxiety-mediating circuits.

    “One scenario is that anxiety-related behaviors result from a balance between eCB-mediated inhibition (via CB1R) and excitation (via TRPV1) of anxiety-mediating circuits that, when operating correctly, serves as a system for switching between passive (e.g., freezing) and active (e.g., escape) behavioral responses based on the proximity of threat”
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    • cites Almeida-Santos et al., 2013

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    Premisenone given

    CNS expression of TRPV1 had been disputed for some time.

    “As was the case for CB2R, CNS expression of the non-selective cation channel TRPV1 had been disputed for some time.”
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    Premisecitation

    Genetic and pharmacological manipulations of CB2R function in rodents alter social interaction and aggression, inhibitory avoidance learning, and prepulse inhibition of the startle response.

    “genetic and pharmacological manipulations of CB2R function in rodents alters social interaction and aggression (Rodriguez-Arias et al., 2015), inhibitory avoidance learning (Garcia-Gutierrez et al., 2013; Ortega-Alvaro et al., 2011) and prepulse inhibition of the startle response (Ishiguro et al., 2010; Ortega-Alvaro et al., 2011).”
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    • cites Rodriguez-Arias et al., 2015

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    Interpretationreasoning

    Postsynaptically-released AEA binds presynaptically- and postsynaptically-located TRPV1 in a retrograde and anterograde manner, respectively.

    “Postsynaptically-released AEA would bind presynaptically- and postsynaptically-located TRPV1 in a retrograde and anterograde manner, respectively.”
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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    AEA can be synthesized presynaptically, given the presynaptic presence of the rate-limiting AEA-synthesizing enzyme NAPE-PLD.

    “in view of the potential for AEA to be synthesized presynaptically (given the presynaptic presence of the rate-limiting AEA-synthesizing enzyme, NAPE-PLD) (Nyilas et al., 2008)”
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    Premisenone given

    There is a relative dearth of data examining the anxiety-related actions of CBD and a lack of knowledge about how CBD's effects are modulated by THC and other phytocannabinoids, the entourage effect.

    “There remains a relative dearth of data examining the anxiety-related actions of CBD and a lack of knowledge about how CBD’s effects are modulated by THC and the other phytocannabinoids found in cannabis – a pharmacological phenomenon referred to as the entourage effect.”
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    Premisecitation

    AEA serves as a full agonist at both CB1R and TRPV1, albeit with different affinity.

    “AEA, which serves as full agonist at both CB1R and TRPV1 albeit with different affinity (Zygmunt et al., 1999).”
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    • cites Zygmunt et al., 1999

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    Premisecitation

    Cannabis does not reliably reduce anxiety and can induce anxiety in normals and increase symptom severity in PTSD patients.

    “cannabis does not reliably reduce anxiety and can even induce anxiety in normals and increase symptom severity in PTSD patients (Cougle et al., 2011).”
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    • cites Cougle et al., 2011

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    Premisecitation

    CBD is a TRPV1 agonist with affinity similar to capsaicin, lacks capsaicin's pain-inducing properties, and can potently desensitize TRPV1 even at low concentrations.

    “CBD is a TRPV1 agonist with an affinity for the receptor similar to the irritant substance found in chili peppers, capsaicin (Bisogno et al., 2001), but lacks the pain-inducing properties of capsaicin and can potently desensitize TRPV1 even at low concentrations (Bisogno et al., 2001).”
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    Premisecitation

    CBD amplifies 5-HT1A-R-mediated inhibition of GABAergic interneurons to disinhibit glutamatergic output in downstream structures.

    “amplifies 5-HT1A-R-mediated inhibition of GABAergic interneurons (Santana et al., 2004) to disinhibit glutamatergic output in downstream structures (Llado-Pelfort et al., 2012).”
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    Premisecitation

    CBD exhibits little to no orthosteric binding potential at CB1R or CB2R and can, under certain conditions, effectively antagonize the receptors even at low nM concentrations.

    “CBD exhibits little to no orthosteric binding potential at CB1R or CB2R and can, under certain conditions, effectively antagonize the receptors even at low nM concentrations (Russo, 2011).”
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    • cites Russo, 2011

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    Premisecitation

    The anti-anxiety properties of CBD are dose-dependent, with efficacy inversely correlated with dose.

    “The anti-anxiety properties of CBD do, however, appear to be dose-dependent, with efficacy inversely correlated with dose (Guimaraes et al., 1990).”
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    • cites Guimaraes et al., 1990

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    Interpretationnone given

    Utilizing CBD to treat anxiety and stress-related disorders is a possibility, albeit via neural mechanisms that might be independent of eCB signaling.

    “Lastly, there is the possibility of utilizing the constituent of cannabis, CBD, to treat anxiety and stress-related disorders, albeit via neural mechanisms that might be independent of eCB signaling.”
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    Interpretationreasoning

    CBD could work as a positive allosteric enhancer of 5-HT1A-R.

    “One potential explanation for this interaction is that CBD could work as a positive allosteric enhancer of 5-HT1A–R.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    5-HT1A-R agonists such as Buspirone are clinically prescribed for various Anxiety Disorders, with reasonable response rates.

    “and are clinically prescribed for various Anxiety Disorders, with reasonable response rates (Blessing et al., 2015; Chessick et al., 2006).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Blessing et al., 2015

      Not checked in the free run.

    • cites Chessick et al., 2006

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    CBD's amplification of 5-HT1A-R-mediated inhibition is likely to augment activity at 5-HT neurons in the dorsal raphe nucleus, enhancing 5-HT in corticolimbic projection fields.

    “This in turn is likely to augment activity at 5-HT neurons in the dorsal raphe nucleus (DRN) (Llado-Pelfort et al., 2012), enhancing 5-HT in corticolimbic projection fields to complete a system-level functional loop.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Llado-Pelfort et al., 2012 source

      Not checked in the free run.

42 of 42

  • The paper relies on this without support.

    Rodent models of anxiety-like behavior are valid predictors of human anxiety and of anxiolytic drug efficacy.

    “Taken together, these convergent lines of human and rodent data evidence strengthen the case for examining FAAH inhibition as a tractable approach to alleviating anxiety”
    “suggesting MAGL inhibition may be another therapeutic avenue for the treatment of anxiety disorders and other conditions associated with adverse responses to stressors.”
1 of 1

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • DSM-5 is labeled "Fourth" in its reference

    Minor

    The text cites DSM-5, but its reference entry describes the manual as "Fourth." The edition labels conflict.

  • COX-2 metabolites are assigned to opposite endocannabinoids

    Minor

    The first passage says COX-2 converts 2-AG to prostaglandin-glycerols and AEA to prostaglandin ethanolamides. The later passage reverses those assignments.

  • PAK is described as both enhancing and restricting tonic signaling

    Minor

    The text says P21-associated kinase enhances tonic AEA signaling at hippocampal synapses, while the cited reference's title says p21-activated kinase 1 restricts tonic endocannabinoid signaling in the hippocampus.

3 of 3

Cites

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Cited by

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Related

Authors
Patel, S., Hill, M. N., Cheer, J. F., Wotjak, C. T., & Holmes, A.
Affiliations
  • Vanderbilt University (US)
  • University of Calgary (CA)
  • University of Maryland, Baltimore (US)
  • Max Planck Institute of Psychiatry (DE)
  • National Institutes of Health (US)
Corresponding author
Holmes, Andrew
ORCID
Venue
Neuroscience & Biobehavioral Reviews
Publisher
Elsevier BV
Published
2017-05
Volume
76
Issue
Pt A
Pages
56-66
ISSN
0149-7634 (ISSN-L)
DOI
10.1016/j.neubiorev.2016.12.033
PMC
PMC5407316
OpenAlex
W2606423744
Semantic Scholar
28019c5f700723eb0b44d6d891f5569a76b9a9e7
Cited by
233
References
172
Citations by year
2026: 1 · 2025: 17 · 2024: 20 · 2023: 20 · 2022: 28 · 2021: 26 · 2020: 37 · 2019: 38 · 2018: 37 · 2017: 8
FWCI
4.17
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • Neuroscience & Biobehavioral Reviews (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • Max Planck Digital Library (submittedVersion)
  • MPG.PuRe (Max Planck Society) (submittedVersion)
Funders
  • NIH (DA022340)
  • Brain and Behavior Foundation
  • CIHR and the Natural Sciences and Engineering Research Council of Canada
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Complementary and alternative medicine › Medicinal Plant Extracts Effects
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Keywords
endocannabinoid system, anxiolytics, anxiety disorders, fatty acid amide hydrolase, monoacylglycerol lipase, cyclooxygenase-2, CB2 receptor, TRPV1, cannabidiol, cannabinoid receptor signaling, stress response, trauma-related disorders
MeSH terms
Anxiety, Anxiety Disorders, Humans, Anti-Anxiety Agents, Signal Transduction, Endocannabinoids

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-09.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-09.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

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