In contrast to the acute anxiolytic effects of CBD, its enhancement of extinction and disruption of fear memory consolidation and reconsolidation involve cannabinoid receptors. CBD-induced disruption of consolidation is blocked by CB1 and CB2 receptor antagonists infused centrally . Disruption of reconsolidation by CBD is also blocked by systemic or central CB1 receptor antagonist treatment [38, 51]. Extinction enhancement by CBD is blocked by central CB1 receptor antagonism [41, 42]. These results indicate that CBD regulation of learned fear processing is mediated at least in part by cannabinoid receptor activation. However, CBD shows little affinity for CB1 or CB2 receptors . This suggests that its cannabinoid receptor-dependent effects on extinction and fear memory consolidation and reconsolidation occur indirectly by modulating endocannabinoid signalling, which we summarize below.
Endocannabinoid signalling has also been implicated in the consolidation and reconsolidation of fear memory. Inhibiting FAAH or MAGL to elevate anandamide or 2-AG levels was shown to enhance fear memory consolidation [92, 93], while FAAH inhibition also modulates the consolidation of stronger memory associated with fear generalization . These effects likely involve both CB1 [86, 94–98] and CB2 [93, 99–101] receptor signalling. Fear memory reconsolidation is also modulated by endocannabinoid signalling as FAAH inhibition enhances the reconsolidation of fear memory . However, the role of cannabinoid receptors in mediating this effect appears to be complex given that both agonists and antagonists have been shown to impair fear memory reconsolidation [85, 97, 102–104]. Post-retrieval fear memory destabilization, which is required to make reconsolidation of the fear memory trace amenable to pharmacological disruption, is enhanced by CB1 receptor activation [105, 106]. However, the involvement of MAGL/2-AG and CB2 receptor signalling in regulating the reconsolidation of fear memory remains to be elucidated.
Cannabinoids have attracted considerable interest as candidate therapeutics for a range of neurological and psychiatric disorders due to the ubiquitous nature of endocannabinoid signalling and CB1 receptor expression throughout the brain [12, 13]. CB1 (and CB2) receptors and the other molecular mediators underlying endocannabinoid signalling are expressed in brain areas important for cognition, emotional regulation, defensive behaviours and their accompanying physiological responses (e.g. prefrontal cortex, hippocampus, amygdala, bed nucleus of stria terminalis, striatum, hypothalamus, periaqueductal grey, midbrain serotonergic and adrenergic nuclei), while both phytocannabinoids and endocannabinoids also act at various non-cannabinoid targets expressed in these areas (see below). Thus, cannabinoids are well placed to modulate the aberrant neural circuit dynamics that have been implicated in anxiety-related disorders [2, 11•, 14].
Cannabinoids: a Brief Overview
Evidence from preclinical studies has shown that the non-psychotropic phytocannabinoid cannabidiol and the endocannabinoid anandamide have acute anxiolytic effects and also regulate learned fear by dampening its expression, enhancing its extinction and disrupting its reconsolidation. The findings from the relevant clinical literature are still very preliminary but are nonetheless encouraging.
The evidence reviewed above demonstrates the potential utility of the phytocannabinoid cannabidiol and pharmacological inhibitors of FAAH, to elevate levels of the endocannabinoid anandamide, for the treatment of anxiety-related disorders in the future. Such cannabinoid-related medicines could be used in various ways to treat these disorders. Given their acute anxiolytic effects, cannabidiol and FAAH inhibitors could be used as adjuncts to first-line SSRI or SNRI treatment, which have a delayed therapeutic response. Such drugs could be an improvement over benzodiazepines, which have abuse liability, a less favourable side effect profile and can interfere with extinction, which forms the theoretical basis for exposure therapy used in the psychological treatment of certain anxiety-related disorders [1, 10]. In this respect, cannabinoids could be combined with existing or novel psychological therapies to facilitate extinction enhancement and/or fear memory reconsolidation disruption, both of which may result in a lasting reduction of fear. Cannabinoid-related medicines could also be given as anxiolytics on their own but further research is needed to determine their effects when given repeatedly as the few studies that have examined this issue have found mixed results [107–110]. The potential for certain adverse effects should also be examined more thoroughly given the reports of cannabinoid use being linked to executive dysfunction [111, 112]. Nevertheless, based on the evidence reviewed here, further research on cannabinoid regulation of fear and anxiety appears to be warranted and below we suggest various lines of enquiry for future work in this area.
Endocannabinoid Signalling: a Target for Regulating Fear and Anxiety
Acute systemic CBD treatment or infusion of CBD into discrete areas of the fear circuit before or after conditioning reduces fear memory encoding [26–29], although the clinical relevance of interfering with the formation of fear memory is somewhat limited. CBD also reduces learned fear expression acutely when given systemically [30–33] or centrally into some [31, 34–36], but not all [31, 37], areas of the fear circuit. Reconsolidation is disrupted by CBD treatment after memory retrieval [38–40], while extinction is potentiated by CBD given systemically or centrally [33, 41–43], although these opposing effects of CBD both lead to reduced learned fear.
In terms of the cannabinoid receptor-dependent effects of CBD on learned fear regulation described above, CBD increases anandamide levels by inhibiting its transporter-mediated reuptake and degradation by FAAH . CBD also binds to the fatty acid binding proteins that transport anandamide intracellularly to FAAH for its degradation, which may play a role in the inhibition of anandamide metabolism by CBD. There is also evidence that CBD reduces MAGL-mediated degradation of 2-AG [67, 68]. However, whether these putative mechanisms are involved in CBD regulation of learned fear processing remains to be confirmed.
Cannabidiol is a non-psychotropic component of marijuana that binds to CB1 receptors with only comparably very low affinity 17, 18 and is devoid of overt cannabimimetic or pro-psychotic properties. 17 Biochemical studies indicate that cannabidiol may enhance endogenous anandamide signaling indirectly, by inhibiting the intracellular degradation of anandamide catalyzed by the enzyme fatty acid amide hydrolase (FAAH). 19 Furthermore, preliminary clinical case reports suggest that cannabidiol might exert antipsychotic effects in schizophrenic patients. 20, 21, 22 In addition, experimental studies show that cannabidiol reduces psychosis-like effects of Δ 9 -tetrahydrocannabinol and synthetic analogs. 22, 23
The search for safe and effective drugs to treat schizophrenia is hindered by the complex nature of this disorder, which is known to involve multiple brain neurotransmitters. 1 Among them are the endogenous cannabinoids, a family of lipid messengers that target the same cell surface receptors engaged by Δ 9 -tetrahydrocannabinol in marijuana. 2 Because Δ 9 -tetrahydrocannabinol and other direct-acting cannabinoid agonists can induce psychotic symptoms both in healthy volunteers 3, 4, 5 and schizophrenic patients, 6, 7 it has been suggested that hyperactivity of the endocannabinoid system might contribute to psychotic states. 8, 9 This idea has fueled two large-scale clinical trials with CB1-type cannabinoid receptor antagonists in schizophrenia, which yielded, however, negative results. 10, 11 A diametrically opposite view — namely that certain components of the endocannabinoid system might have a protective role in schizophrenia — was suggested by studies with antipsychotic-naïve schizophrenic patients, in which it was found that the symptom intensity experienced by these subjects was negatively correlated with cerebrospinal levels of anandamide, 12, 13 an endocannabinoid transmitter known to be involved in the regulation of pain, mood and cognition. 14 Consistent with these clinical observations, animal experiments have shown that pharmacological blockade of anandamide degradation attenuates, rather than enhances, psychotic-like behaviors induced in rodents by amphetamine and phencyclidine. 15, 16
Men and women age 18–50 years who had a diagnosis of schizophrenia or schizophreniform psychosis according to the DSM-IV criteria were eligible for the study. All patients were hospitalized at baseline and through day 28 after random assignment to treatment. A total number of 42 inpatients of the Department of Psychiatry and Psychotherapy of the University of Cologne participated in the study. In all, 37 patients were suffering from acute paranoid schizophrenia (DSM-IV 295.30). Another 5 patients were initially diagnosed as suffering from schizophreniform psychosis (DSM-IV 295.40) based on the duration of illness, but were followed-up and diagnosed with paranoid schizophrenia after completing the study. Only acutely psychotic patients with a total Brief Psychiatric Rating Scale (BPRS) score ⩾36 and a BPRS THOT factor (thought disorders) score ⩾12 were eligible to participate. Patients with a positive urine drug screening for illicit drugs in general and cannabinoids in particular were not allowed to participate to avoid an interaction of currently bioactive cannabinoids (including cannabidiol) with treatment. Further exclusion criteria were relevant psychiatric disorders including substance use disorders, previous treatment with a depot antipsychotic within 3 months before the participation in the study, a history of treatment resistance, defined by the persistence of severe symptoms despite adequate treatment with at least two antipsychotics or prior treatment with clozapine, a relevant and/or unstable medical condition and an insufficient contraception, pregnancy or breast-feeding in female patients.
Serum levels of anandamide, palmityolethanolamide and oleoylethanolamide were determined at baseline, day 14 and day 28 by liquid chromatography/mass spectrometry as described previously. 24, 25
FAAH activity was measured at 37 °C for 30 min in 0.5 ml of Tris buffer (50 m, pH 7.5) containing fatty acid-free bovine serum albumin (0.05%, w/v), protein from tissue homogenates of the rat brain membranes (50 μg), cannabidiol (0.3 μ, 1 μ, 3 μ, 10 μ, 30 μ, 0.3 m, 0.1 m, and 1 m) and ( 3 H-ethanolamine) anandamide (10 000 d.p.m., specific activity 20 Ci mmol −1 ). For concentration response the drug CBD was dissolved in dimethyl sulfoxide and added to the samples at a final concentration of 1% dimethyl sulfoxide. The reactions were stopped with chloroform/methanol (1:1, 1 ml), and radioactivity was measured in the aqueous layers by liquid scintillation counting.