Potential Utility of Cannabidiol in Stress-Related Disorders

Abstract

Background:

The endocannabinoid (eCB) system plays an important role in homeostatic regulation of anxiety and stress responses; however, the eCB system can be disrupted following traumatic stressors. Additionally, traumatic or chronic stressors that occur during adulthood or early life can cause long-lasting disturbances in the eCB system. These alterations interfere with hypothalamic–pituitary–adrenal axis function and may be involved in lifelong increased fear and anxiety behaviors as well as increased risk for development of post-traumatic stress disorder (PTSD).

Methods:

This review focuses on the implications of trauma and significant stressors on eCB functionality and neural pathways, both in adolescence and into adulthood, as well as the current state of testing for CBD efficacy in treating pediatric and adult patients suffering from stress-induced eCB dysregulation. Articles were searched via Pubmed and included studies examining eCB modulation of stress-related disorders in both clinical settings and preclinical models.

Conclusion:

Given the potential for lifelong alterations in eCB signaling that can mediate stress responsiveness, consideration of pharmaceutical or nutraceutical agents that impact eCB targets may improve clinical outcomes in stress-related disorders. However, caution may be warranted in utilization of medicinal cannabinoid products that contain delta-9-tetrahydrocannabinol due to pronounced euphorigenic effects and potential to exacerbate stress-related behaviors. Other cannabinoid products, such as cannabidiol (CBD), have shown promise in reducing stress-related behaviors in pre-clinical models. Overall, pre-clinical evidence supports CBD as a potential treatment for stress or anxiety disorders resulting from previously stressful events, particularly by reducing fearful behavior and promoting extinction of contextual fear memories, which are hallmarks of PTSD. However, very limited clinical research has been conducted examining the potential effectiveness of CBD in this regard and should be examined further.

Introduction

Post-traumatic stress disorder (PTSD) is psychiatric disorder that can develop after either direct or indirect exposure to a traumatic event such as death, the threat of death, serious physical injury, or sexual violence.¹ A diagnosis of PTSD requires the presence of multiple symptoms lasting at least 1 month following the traumatic event. One of the prominent symptoms is avoidant behavior toward stimuli associated with the trauma, which can include people, locations, situations, and even thoughts and memories.¹

Intrusion symptoms such as involuntary reexperiencing of the traumatic event can include fear memories, recurrent memories, disassociation, and intense physical reactions related to triggering cues, which are other highly prominent PTSD symptoms.^1–4 Numerous studies have further examined PTSD with symptoms of altered arousal and reactivity such as hypervigilance, altered sleep patterns, aggressive and irritable behavior, increased startle responses, and decreased concentration.^1–4 Each symptom can be attributed to altered activity in numerous brain regions and dysfunction in neural circuits that underlie PTSD, and the duration and severity of the disorder are costly to both the individual and the society they live in.^5–8

The prevalence of PTSD ranges from 1.3% to 12.2% depending on the country of residence and social background. Children are especially vulnerable to trauma as childhood abuse of any kind is associated with a 70% greater risk of developing PTSD.⁹ In 2019, an estimated 8.9 per 1000 children in the United States were victims of child abuse and/or neglect.⁹ While the overall rates of victimization have not changed in recent years, child mortality rates have increased by 10.8% in the period from 2015 to 2019, suggesting that victims may be exposed to more traumatic aspects of maltreatment.⁹ The effects of childhood trauma persist into adulthood likely due to trauma occurring during important brain development periods, which results in long-lasting effects.¹⁰

Currently, the only FDA-approved treatment for PTSD in adults is selective serotonin reuptake inhibitors (SSRIs), while the FDA has not approved any medications for PTSD in the pediatric population.^11,12 Even as an approved treatment in adults, the successful response rate of SSRIs for patients rarely exceeds 60% and the full remission rate following treatment is less than 30%.⁴ Importantly, recent studies indicate that patients who experienced childhood trauma between the ages of 4 and 7 years had the lowest response to 8 weeks of SSRI treatment as adults.¹³

SSRIs also present unpleasant side effects, including sleep disturbances, headaches, nausea, appetite changes, and sexual dysfunction. These findings show a need for novel therapeutics that can assist with efficacious therapies, specifically trauma-focused cognitive-behavioral therapy.^4,14,15

The endocannabinoid (eCB) system is an important component of stress response regulation that can be dysregulated in PTSD patients.¹⁶ eCBs such as N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG) play a key role in regulation of the stress response and maintenance of homeostatic states.^17–21

Other less-studied eCBs may also produce additional effects, such as N-stearoylethanolamine (SEA) and N-palmitoylethanolamine (PEA), which have anti-inflammatory functions; N-oleoylethanolamide (OEA) regulates appetite and 1-arachidonoylglycerol (1-AG) is the biologically inactive form of 2-AG.²² Phytocannabinoids, which are extracted from the Cannabis sativa plant, can also interact with the eCB system and produce a variety of physical and psychological effects.²³

Among the most prevalent and well-researched phytocannabinoids are the psychotropic delta-9-tetrahydrocannabinol (THC) and nonpsychotropic cannabidiol (CBD), the latter of which has been shown to reduce PTSD-related symptoms.²⁴

In this review, we will discuss clinical and pre-clinical data examining the potential role of the eCB system in PTSD and neurotypical brain development, how eCB regulation of brain development may be altered by childhood traumas, and the potential use of CBD-based therapeutics in both adult and pediatric patients who present with PTSD symptoms.

Brief Overview of the eCB System and Its Relationship to Adaptive Stress Responses

The eCB system plays a significant role in modulation of the neuroendocrine stress response and maintains physiologic homeostasis by regulating physical and cognitive processes such as appetite, mood, energy usage, pain response, and cardiovascular and respiratory function.¹⁶ eCBs modulate synaptic function through retrograde signaling to cannabinoid receptor type 1 (CB1R) and cannabinoid receptor type 2 (CB2R) located at presynaptic terminals from numerous cell types, including glutamatergic, GABAergic, and monoaminergic neurons and neuroimmune cells typically inhibiting neurotransmitter release.^25,26

Studies show that AEA, a fatty acid eCB, maintains the tone of neurotransmitter release during nonstress states.^17,18 AEA has high affinity for CB1R and moderate affinity for CB2R; however, the downstream signals generated by AEA are moderate for CB1R and low for CB2R.^27,28 2-AG, the other major fatty acid eCB, mediates the return to baseline after a stressful event takes place and contributes to synaptic plasticity.^19–21 2-AG possesses moderate affinity for both CB1R and CB2R, but is thought to create stronger intracellular signals than AEA, indicating potential for higher efficacy of 2-AG.^27,28

Hydrolysis of eCBs is undertaken by two major degradative enzymes: monoacylglycerol lipase (MAGL), which hydrolyzes 2-AG, and fatty acid amide hydrolase (FAAH), which hydrolyzes AEA and other N-acylethanolamines such as SEA, PEA, and OEA.^29–31

Specifically in terms of the stress response, CB1R is thought to play an inhibitory role in the hypothalamic–pituitary–adrenal (HPA) axis, the function of which is crucial for activation of classic neuroendocrine stress responses (Fig. 1).^32,33 During an acute stress response, the corticotropin-releasing hormone (CRH) is released from neurons in the paraventricular nucleus (PVN) within the hypothalamus, initiating HPA responses.^34,35 PVN CRH neurons respond to and integrate inputs from the amygdaloid complex, prefrontal cortex, hippocampus, and brain stem.^36–38

FIG. 1.

Endocannabinoid interactions with the HPA axis stress response. In response to stress, the PVN CRH is released, which binds to CRHR1 in the amygdala, hippocampus, mPFC, PVN, and other brain regions. CRH increases FAAH levels in most brain areas, which in turn reduce AEA and remove AEA-mediated inhibition of the HPA axis. CRH is also released to the anterior pituitary gland, which stimulates the release of ACTH into the circulation. ACTH at the adrenal glands induces CORT release into the circulation and provides direct negative feedback to the PVN to reduce production of CRH and ultimately ACTH. CORT also stimulates production of 2-AG in the amygdala, hippocampus, and mPFC, where it binds to CB1 and CB2 receptors on glutamatergic and GABAergic neurons. This inhibits amygdala activation and excites the hippocampus and mPFC activation, reducing HPA axis activity through the level of the PVN. Many of these endocannabinoid systems are disrupted in PTSD. Created with BioRender.com. 2-AG, 2-arachidonoyl glycerol; ACTH, adrenocorticotropic hormone; AEA, anandamide; CB1, cannabinoid type 1; CB2, cannabinoid type 2; CORT, cortisol/corticosterone; CRH, corticotropin-releasing hormone; CRHR1, corticotropin-releasing hormone receptor 1; eCB, endocannabinoid; FAAH, fatty acid amide hydrolase; HPA, hypothalamic–pituitary–adrenal; PFC, prefrontal cortex; PVN, paraventricular nucleus of hypothalamus.

CRH then stimulates pituitary adrenocorticotropic hormone (ACTH) release into the circulatory system,³⁹ triggering synthesis of glucocorticoids from the adrenals and releasing them into circulation.⁴⁰ Glucocorticoid signaling through glucocorticoid receptors in brain regions such as the hypothalamus, hippocampus, amygdala, and prefrontal cortex^41,42 mediates physiological and psychological responses following stress, including suppression of the immune system, changes in memory, and mood regulation.^43,44 Glucocorticoid receptors within the hypothalamus also initiate negative feedback regulation of CRH release and return HPA axis function to homeostatic levels^34–35 (Fig. 1).

Importantly, stress-induced CRH also increases the activity of FAAH, reducing AEA levels and ultimately decreasing the inhibitory tone on CB1R signaling on the HPA axis. Similar effects may occur in the amygdala and hippocampus as well.^45,46 AEA levels will remain low as long as the stressor persists, leading to an inability to maintain the homeostatic neurotransmitter tone and increasing the activity of the HPA axis to further extend the body's stress response.^47,48

Counteracting AEA function, CRH-triggered release of ACTH and resulting glucocorticoid release stimulate the release of 2-AG within the hypothalamus and other areas of the brain.^20,48,49 2-AG release increases CB1 signaling, which supports negative feedback regulation of stress responses in the hypothalamus, hippocampus, and prefrontal cortex.^49–51

Given the critical role that the eCB system plays in regulation of synaptic function in the HPA axis and other brain regions regulating prototypical stress responses, harmful disruptions of this system resulting from trauma can reduce the negative feedback to the HPA axis and severely prolong a typically short stress response.¹⁶

Evidence of eCB-Mediated Changes in Brain Function Following Traumatic Stress Across the Life Span

Interest in the study of eCB signaling following traumatic stressors has increased in the last decade, both clinically and pre-clinically. In a clinical study investigating trauma-exposed individuals 4 to 6 years following the attack on the World Trade Center, subjects with PTSD had significantly lower circulating 2-AG levels than those who did not develop PTSD after controlling for factors such as stress from exposure to the attack, sex, alcohol abuse, and depression.

This same study showed that AEA levels had a negative correlation with intrusive PTSD symptoms.⁵² Additional studies have found that individuals with PTSD and a history of trauma have increased expression of CB1R across the brain as well as reduced AEA levels, compared with non-PTSD individuals who have experienced trauma or not.⁵³

Each PTSD subject in these studies had experienced trauma tied to a single specific event, suggesting that an individual traumatic event is enough to cause pervasive and persistent changes to the eCB system years after the event has occurred.^52,53 However, it is possible that lower endogenous levels of eCB signaling may be a risk factor for PTSD development, a question that should be examined further.

Other studies into the long-term effects of trauma on the eCB system show somewhat inconsistent results. One study found that the observed levels of PEA, OEA, and SEA in hair samples were negatively correlated with severity of PTSD symptoms, although AEA and 2-AG concentrations could not be reliably determined in this study.³¹ However, a study by Hauer et al⁵⁴ examining trauma-exposed refugees found increased plasma levels of AEA, 2-AG, OEA, PEA, and SEA in PTSD individuals.

It should be noted that the number of subjects in the Hauer study⁵⁴ (10 PTSD patients, 29 total subjects) and the Wilker study³¹ (38 PTSD patients, 76 total subjects) was low, and studies with larger populations and increased statistical power are needed. Another study found that 2-AG signaling, not AEA, in six healthy male astronauts was significantly reduced after 360 days of mission training under social isolation, suggesting that 2-AG may have a specific role in responding to chronic stressors.⁵⁵

Additional studies show systemic and long-term changes on the eCB system following early life stressors. For instance, one study found higher levels of AEA and 2-AG in subjects with a history of childhood sexual abuse who later developed bipolar disorder as adults, while individuals who developed PTSD had increased levels of OEA.⁵⁶ Another clinical study in pregnant mothers who had experienced childhood trauma found significantly higher levels of 1-AG and lower levels of SEA.²²

Together, these studies suggest that the type and duration of stress and trauma may distinctly impact the eCB system, highlighting potentially complex effects on the eCB system from stress and trauma over varying time periods, which require further study.

In mouse and rat models, exposure to acute and chronic stress produces brain region-specific changes in eCB signaling in the medial prefrontal cortex, hippocampus, and amygdala. Both acute and chronic stressors, such as restraint or pain, typically reduce AEA levels in these three brain regions, while the effects on 2-AG vary.^{20,45,51,57,58} 2-AG is increased by acute stress in the prefrontal cortex and hippocampus, but not the amygdala.

Chronic exposure to the same type of stress increases 2-AG; however, chronic exposure to different types of stressors reduces 2-AG.^{49,57,59–62} Chronic repeated restraint or foot shock stress also alters CB1R signaling, creating deficits in learning, memory, and coping behaviors.^63,64

Further studies indicate that trauma-induced eCB alteration is dependent on the age of exposure and that early life trauma is distinct from trauma experienced in adulthood.^65,66 Importantly, the eCB system undergoes significant alterations during typical development. During early life, there is higher abundance of prefrontal cortex CB1R compared with adulthood.^63,67

Since CB1R activation can extinguish fear memory and reduce aversive memories,⁶⁸ stress-induced inhibition of CB1R signaling may increase the risk of PTSD and phobias.⁶⁹ Conversely, repeated exposure to the same stressor can progressively increase 2-AG levels, likely by reduced MAGL expression, which causes progressively increased frequency of signaling through CB1Rs, leading to stress habituation.⁶²

Additional pre-clinical research has found that maternal separation stress in rat pups resulted in decreased AEA levels and increased 2-AG levels in the amygdala and hippocampus.^62,70 This early life stress can lead to long-term reductions in hippocampal AEA and 2-AG levels, compromising the eCB system into adulthood.

Early life stress in male mice impacts the eCB system by reducing CB1Rs across regions such as the prefrontal cortex, striatum, and amygdala.^63,71 At the same time, maternal separation can lead to increased gene expression of FAAH and MAGL, further decreasing AEA and 2-AG levels in the amygdala, hippocampus, prefrontal cortex, and striatum.⁷²

Results in female rodents have been mixed, with some studies indicating an increase in eCB degradation enzymes within the frontal cortex, striatum, hippocampus, and amygdala, while in other studies, these changes were restricted to just the hippocampus.^72,73

During adolescence, the development of eCB activity parallels development of the HPA axis, resulting in changes that can influence fear learning and stress sensitivity.^63,74 As discussed above, eCB signaling regulates HPA axis function, restricting its activity to short-term stress and maintaining low basal levels of glucocorticoids.¹⁸ Studies have emphasized the effects of stress and trauma over varying periods of time on the eCB system.^75,76

Overall, both clinical and pre-clinical studies show that early life trauma leads to eCB system changes that can last into adulthood. Such alterations have strong implications for the possibility of subsequent development of PTSD and other stress-related disorders, as lifelong dysregulation of the eCB system by early life trauma may increase the risk that any future traumatic event would induce development of PTSD or reinforce existing PTSD symptoms.

CBD Effects on Stress Neurocircuits and Stress Behavior

CBD may reduce the severity of PTSD-related symptoms by interacting with the HPA-eCB system.^77,78 Rather than binding directly to CB1R and CB2R, as is the case with THC, CBD is a competitive inhibitor of FAAH and MAGL, binding to both enzymes at a higher affinity than either AEA or 2-AG.^77,78 The resulting inhibition reduces the hydrolysis of eCBs, increasing circulating AEA and 2-AG levels throughout the body (Fig. 2).

FIG. 2.

CBD inhibition of synaptic signaling. CBD inhibits hydrolysis of AEA and 2-AG in the postsynaptic terminal by competitively binding to FAAH and MAGL, respectively. AEA and 2-AG then activate CB1R and CB2R on the presynaptic terminal, leading to suppression of neurotransmitter release. CBD can also act on the TRPV1 receptor, desensitizing TRPV1 channels and increasing Ca²⁺ concentrations in the presynaptic neuron. Created with BioRender.com. CB1R, cannabinoid receptor type 1; CB2R, cannabinoid receptor type 2; MAGL, monoacylglycerol lipase; TRPV1, transient receptor potential of vanilloid subtype 1.

This, in theory, means that CBD can combat dysregulation of the eCB system caused by trauma or prolonged stress and restore proper negative feedback of the HPA axis. Currently, limited clinical literature is available on utilization of CBD as a potential treatment for PTSD or other stress/anxiety-related disorders, particularly in patients who have experienced early life stress or traumas. However, some clinical studies have examined the utility of CBD in related contexts.

For example, CBD was shown to be effective in reducing anxiety in patients at high risk for psychosis, with a 600-mg dose of CBD every day for a week reducing anxiety from acute stress as well as attenuating abnormally low cortisol levels found in these patients, likely from a dysregulated HPA axis.⁷⁹ Bergamaschi et al. found that a 600-mg dose of CBD reduced anxiety in participants with social anxiety disorder before they gave a public speech, compared with placebo.⁸⁰

Another study found a similar reduction in anxiety in individuals with social anxiety disorder when treated with 400 mg of CBD for over 2 h.²³ This reduction in anxiety correlated with decreased blood flow to brain regions associated with fear and anxiety.

While both these studies examined the effects of short-term CBD on anxiety, a longer study has also been conducted in which adolescents with social anxiety disorder received either placebo or 300 mg of CBD daily for 4 weeks.⁸¹ This study found that CBD significantly reduced anxiety symptoms compared with placebo, and self-reported levels of anxiety in the patients receiving CBD were similar to those reported in a separate study of patients taking paroxetine.⁸²

More closely related to PTSD specifically, clinical studies into the effectiveness of CBD in fear extinction show promise, as a single dose of CBD (32 mg) given to healthy subjects postextinction significantly enhanced consolidation of extinction learning from conditioned shock.⁸³

Given that the eCB system and fear extinction are altered in patients with PTSD, additional research will be needed to determine if CBD, potentially in conjunction with other phytocannabinoids (both synthetic and from plant extracts), may be effective in improving outcomes in PTSD patients.

Several pre-clinical studies have been conducted examining potential anxiolytic effects of CBD. A study by Uribe-Mariño et al investigated the effect of intraperitoneal administration of CBD in male Swiss mice exposed to an ethological model of panic attack caused by threatening stimuli from wild constrictor snakes.⁸⁴ The results showed that pretreatment with CBD lowered active avoidance of the snake predator, indicating that CBD can reduce behavioral responses in environments containing clear and perceived danger following identification of threatening stimuli.

Bitencourt et al tested the effects of CBD on extinction of contextual fear memories in 3-month-old Wistar rats, using a conditioned foot shock model with 24-h intervals between each extinction event, and found that treatment with CBD before the extinction trials produced anxiolytic effects.⁸⁵ Similar experiments were conducted by Lemos et al, with additional testing of neuronal activity in various brain regions.⁸⁶

Between both these studies, mice given i.c.v. or i.v. injections of CBD (0.2, 1.0, and 2.0 μg/μL [1 μL injection volume] for Bitencourt et al; 10 mg/kg for Lemos et al) 5–30 min before an extinction trial displayed persistent reductions in percentage of freezing time compared with control mice with each successive extinction trial, with higher CBD dosages producing greater effects.^85,86

The effects of CBD on fear memory extinction were antagonized by administration of a CB1 receptor antagonist 20 min before treatment, but not by a TRPV1 vanilloid receptor antagonist 5 min prior, indicating that CBD relies heavily on the CB1 receptor pathway to produce anxiolytic effects.⁸⁶ Significant reductions in c-Fos expression were observed in the prelimbic and infralimbic regions of the prefrontal cortex and ventral bed nucleus of the stria terminalis, indicating reduction in neuronal activity.⁸⁶

Direct microinjection of CBD into the prelimbic prefrontal cortex also reduced freezing behavior while inducing the opposite when injected into the infralimbic prefrontal cortex.⁸⁶ These findings support the notion that the prelimbic prefrontal cortex is important in activation of contextual fear and represents a possible target for treatment.⁸⁶

Another contextual fear memory paradigm conducted by Stern et al. found that CBD at a dose of 1.0 mg/kg i.p. administered immediately after memory retrieval could block reconsolidation of fear memories from 1 to 7 days prior, producing reduction in freezing behavior during reexposure to a foot shock-paired context.⁸⁷ The same effect could not be achieved when CBD was administered 6 h or more after retrieval, nor did reduction in freezing behavior occur in the absence of memory activation, showing that the anxiolytic effects of CBD in this model are specific to reconsolidation of fear memory.

Furthermore, reconsolidation is permanently disrupted even 22 days later without reinstatement, indicating the long-term benefits of CBD treatment for fear memory extinction. The mechanisms for why this occurs are not fully understood, but may be related to increased neurogenesis in the hippocampus.^88–91

Such findings are highly relevant to PTSD as PTSD patients have difficulty in extinction of fear memories related to the trauma exposure, suggesting that CBD may be an effective adjunctive to current psychiatric treatments for PTSD such as trauma-based cognitive-behavioral therapy.

Perspective: Is eCB a Viable Target for PTSD Treatment?

There has been a lot of concern regarding cannabinoids and their impact and long-term consequences on developing brains of children. Both CBD and THC are often purified from plant materials and utilized in clinical and pre-clinical studies.⁸¹ However, THC is the main euphorigenic component of cannabis and can produce negative psychotropic and anxiogenic effects, particularly at high doses.⁹² This may be due to THC increasing activation of the HPA axis, which results in increased levels of basal and stress-induced cortisol.¹⁸

There is especially a risk of adverse effects when administering treatments containing THC to pediatric patients as research has shown that THC administration in children reduces cognitive ability, object recognition memory, and spatial learning.^93–95 CBD has been shown to counteract the negative effects of THC, such as memory impairment, anxiety, and psychotic-like symptoms, and is thought to produce stronger anxiolytic effects when in combination with THC.⁹² CBD may also be beneficial for healthy sleep patterns.^96,97 Sleep is disrupted in PTSD, which may exacerbate symptoms, and may be worsened by THC.^1,98

It should be noted that treatments utilizing purified CBD (without THC present) have been used clinically in pediatric patients with severe seizure-related disorders with minimal adverse side effects.^99,100 Purified CBD has a very high safety profile and can be tolerated in doses of up to 6000 mg with minimal side effects when treating common ailments such as diarrhea, headaches, and nausea.¹⁰¹

CBD has also been shown to provide both antioxidant and anti-inflammatory effects, and in pre-clinical studies, it was found to work in combination with other phytocannabinoids and even different medications.^102–105 However, many CBD-predominant preparations are largely unregulated and may contain THC at amounts above the lowest observed adverse effect level of 2.5 mg/day.^106,107

Even a relatively low dosage of 50 mg of CBD, if given in a THC-to-CBD ratio of 1:20, can lead to undesirable side effects in patients.¹⁰⁶ Any CBD-marketed treatment needs to be scrutinized for the presence of THC-like compounds, and treatments using both CBD and THC must consider the ratio of these two compounds to avoid the negative effects of THC while emphasizing the benefits from CBD, particularly if utilized in pediatric patient populations.

However, since early life trauma can inhibit eCB function, targeting this system using CBD or by other means may be of clinical benefit.

Summary

While much pre-clinical work has examined the effectiveness of CBD in treatment of PTSD-related behaviors, as well as in models for other psychiatric and neuropsychiatric disorders, there is a considerable dearth of clinical research in this area. Even less research has been conducted into any possible anxiolytic effects that CBD could have on symptoms caused by early life stress.

However, the research that has been performed indicates that CBD is likely to be an efficacious treatment that reduces avoidant and stress-related symptoms of PTSD while potentially minimizing adverse side effects of THC. There is more than sufficient evidence to show that the eCB system is intrinsically linked to regulation of stress responses and the associated brain regions.

Overall, pre-clinical evidence has demonstrated the need for further clinical trials into CBD as a potential treatment for PTSD and other psychiatric conditions that may be associated with disruption of the eCB system.

Abbreviations Used

1-AG

1-arachidonoylglycerol

2-AG

2-arachidonoylglycerol

ACTH

adrenocorticotropic hormone

AEA

N-arachidonoylethanolamine

CB1R

cannabinoid receptor type 1

CB2R

cannabinoid receptor type 2

CBD

cannabidiol

CRH

corticotropin-releasing hormone

eCB

endocannabinoid

FAAH

fatty acid amide hydrolase

HPA

hypothalamic–pituitary–adrenal

MAGL

monoacylglycerol lipase

OEA

N-oleoylethanolamide

PEA

N-palmitoylethanolamine

PTSD

post-traumatic stress disorder

PVN

paraventricular nucleus

SEA

N-stearoylethanolamine

SSRIs

selective serotonin reuptake inhibitors

THC

delta-9-tetrahydrocannabinol

Author Disclosure Statement

The authors have no significant conflict of interests. Y.S. has minimal ownership of FLORA, a Vermont adult-use cannabis retailer.

Funding Information

This work was funded, in part, by an NIH grant, AA026865.

Cite this article as: Lookfong NA, Raup-Konsavage WM, Silberman Y (2023) Potential utility of cannabidiol in stress-related disorders, Cannabis and Cannabinoid Research 8:2, 230–240, DOI: 10.1089/can.2022.0130.