Cannabinoid Regulation of Fear and Anxiety : an Update, Eleni P. Papagianni & Carl W. Stevenson, 2019

Cannabinoid Regulation of Fear and Anxiety : an Update

Eleni P. Papagianni & Carl W. Stevenson

Current Psychiatry Reports, 2019, 21, 38

doi : 10.1007/s11920-019-1026-z



Purpose of Review : Anxiety- and trauma-related disorders are prevalent and debilitating mental illnesses associated with a significant socioeconomic burden. Current treatment approaches often have inadequate therapeutic responses, leading to symptom relapse. Here we review recent preclinical and clinical findings on the potential of cannabinoids as novel therapeutics for regulating fear and anxiety.

Recent Findings : Evidence from preclinical studies has shown that the non-psychotropic phyto-cannabinoid 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.

Summary : Based on this preclinical evidence, larger-scale placebo-controlled clinical studies are warranted to investigate the effects of cannabidiol in particular as an adjunct to psychological therapy or medication to determine its potential utility for treating anxiety-related disorders in the future.

Keywords : Cannabidiol . Consolidation . Endocannabinoid . Extinction . Fear conditioning . Reconsolidation


Anxiety- and trauma-related disorders are the most common psychiatric diseases and are associated with inadequate treatment options and thus high social and economic costs. Psychological treatments are often limited or temporary in their effectiveness, while medications can lack efficacy or have unwanted side effects in a considerable number of patients. Psychological therapies can also be combined with medications to enhance treatment synergistically, but some medications can interfere with these therapies. Better options are therefore urgently needed for treating these disorders [1].

With the decriminalization of cannabis, availability of cannabis-derived chemicals (i.e. cannabinoids), and anecdotal evidence for the anxiolytic potential of cannabinoids all becoming ever more widespread, it is important to take stock of the empirical evidence to determine if cannabinoids can live up to their hype as an option for treating anxiety-related disorders in the future. In this narrative review, we begin by describing these disorders and the current therapeutic approaches used in their treatment. We then review the preclinical and clinical studies that have investigated cannabinoid regulation of fear and anxiety. We conclude by outlining future directions for driving forward this promising avenue of research.

Anxiety- and Trauma-Related Disorders and Their Treatment : Current Therapeutic Approaches

Anxiety and fear are emotional responses that occur in anticipation of potential threat or when facing imminent danger, respectively. These responses are adaptive when they occur appropriately in response to relevant aversive stimuli, but they become maladaptive when expressed inappropriately under benign conditions and can lead to the development of anxiety- and trauma-related disorders [2]. The anxiety disorders include generalized anxiety, panic, social anxiety, phobias and separation anxiety, with post traumatic stress-disorder (PTSD) and obsessive-compulsive disorder being related to but now classed separately from anxiety disorders.

Collectively, these anxiety-related disorders are the most prevalent psychiatric diseases and are therefore a significant socioeconomic burden, given their high costs to the health care system and their association with long-term disability, lost work productivity and disrupted social relationships [3]. These disorders are associated with perturbed cognition and emotional regulation. For example, they share common psychological (e.g. excessive fear, apprehension, disturbed concentration and sleep) and somatic (e.g. tachycardia, heart palpitations, sweating) symptoms, with arousal and avoidance behaviour thought to predict long-term disability [4•, 5]. Symptom overlap among the different anxiety-related disorders and with other psychiatric diseases is a diagnostic challenge, while self-medication with alcohol and/or other drugs can progress to substance abuse and lead to significant comorbidity between these diseases [4•, 6].

Anxiety-related disorders are treated using psychological therapies or/and medications. The various psychological approaches include cognitive behavioural therapy, exposure therapy, cognitive processing therapy and eye desensitization reprocessing, with the aim of reducing avoidance behaviour and distress [4•, 7]. Selective serotonin reuptake inhibitors (SSRIs) are typically the first choice of medication, but other types of anti-depressants can be used if the response to SSRI treatment is inadequate; selective noradrenaline reuptake inhibitors (SNRIs) are favoured over tricyclics and monoamine oxidase inhibitors due to their more favourable safety and tolerability profile. Other drug therapies include anti-seizure medications, serotonin1A (5-HT1A) receptor agonists (e.g. buspirone), short-term benzodiazepine treatment for acute anxiety and beta-blockers for reducing somatic symptoms [8, 9].

While psychological and pharmacological therapies are effective [7, 8], both treatment approaches have their drawbacks. The effects of certain psychological treatments (e.g. exposure therapy) can be short-lived, limited outside of the therapeutic context and hindered by drugs of abuse and even certain anxiolytics, all of which can result in symptom relapse after treatment [1]. Medications can lack or have incomplete therapeutic effects, which often take weeks to commence in the case of first-line SSRI or SNRI treatment. Moreover, these treatments can also cause adverse effects (e.g. anxiogenesis, insomnia, agitation, headache, appetite and gastrointestinal disturbances, sexual dysfunction) prior to the onset of or along with their therapeutic effects. Benzodiazepines can cause unwanted central nervous system depressant effects, tolerance and withdrawal with abrupt discontinuation and have abuse liability. This has limited their recent use to managing acute anxiety in the short-term until the onset of therapeutic effects with first-line SSRI/SNRI treatment [9]. Benzodiazepines may also enhance the risk of developing PTSD and comorbid substance abuse disorders, worsen PTSD symptoms and reduce the efficacy of psychological therapies for PTSD treatment [10]. Taken together, these issues highlight the limitations of psychological therapies and medications currently used for treating anxiety-related disorders.

Cannabinoids : a Brief Overview

Cannabis sativa is one of the oldest plants known for its recreational and purported medicinal properties. It consists of more than 400 chemicals known collectively as phytocannabinoids, over 100 of which are pharmacologically active. The psychoactive delta-9-tetrahydrocannabinol (THC) and the non-psychoactive cannabidiol (CBD) are the most abundant phytocannabinoids and are present in different ratios depending on the plant strain. Other phytocannabinoids that have been less well studied to date include tetrahydrocannabivarin, cannabigerol, cannabichromene and cannabicyclol.

The isolation of phytocannabinoids led to the identification of the biological targets by which they exert their effects, including the cannabinoid type 1 (CB1) and type 2 (CB2) receptors. The discovery of endogenous ligands for these receptors, lipid messengers known as endocannabinoids, followed, and the best studied of these to date have been anandamide and 2- arachidonoylglycerol (2-AG) [11•]. 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].