Cannabidiol (CBD), the Endocannabinoid System, and Regulation of Everyday Stress and Anxiety
For many, the demands of daily life can become overwhelming, gradually chipping away at inner peace and joy. The hypothalamic-pituitary-adrenal (HPA) axis and sympathetic nervous system (fight-or-flight response) are well-known regulators of the stress response.
Fewer people realize the body’s endocannabinoid system (ECS) also plays a major role. Cannabidiol (CBD), a non-psychoactive component of the Cannabis plant, is a phytocannabinoid that interacts with the ECS. Studies show that CBD is effective in regulating the body’s stress response and its manifestations of anxiety, fear, depression, and burnout.1
The Endocannabinoid System (ECS) and HPA Axis Regulation
The ECS regulates mood, sleep, appetite, memory, pain, and other important functions. The ECS is composed of endogenous ligands called endocannabinoids that interact with cannabinoid receptor 1 (CB1) and CB2. These receptors are present in the hypothalamus, pituitary, and adrenal glands, acting as a “gatekeeper” of the HPA axis and playing a role in stress resilience and homeostasis. It can prevent the HPA axis from becoming over- or underactive, especially in states of chronic stress.2,3 The sympathetic nervous system is also regulated by the ECS via CB1.1
ECS dysfunction may contribute to chronic stress complications such as learning and memory deficits, changes in coping behaviors, post-traumatic stress disorder (PTSD), anxiety disorders, depression, psychosis, and pain syndromes.1
How Does CBD Alleviate Stress and Anxiety?
CBD increases CB1 and CB2 signaling, and interacts with other systems that help regulate the stress response.1 CBD is a partial 5-HT1a receptor agonist, modulates GABAA receptors, increases PPARγ signaling, and desensitizes TRPV1, which supports anxiolytic, antidepressant, and stress-reducing effects. These mechanisms also inhibit neuroinflammation and gastrointestinal tract dysfunction caused by stress.1, 4
A study using regional cerebral blood flow (rCBF) SPECT imaging examined the effects of CBD on the brain in 10 healthy male volunteers. In a double-blind crossover design, participants received either 400 mg of CBD or a placebo, followed by brain imaging 90 minutes later. Imaging after CBD showed reduced activity in the limbic and paralimbic regions, which are involved in stress and anxiety. Reduced hypothalamic activity suggests CBD may modulate the HPA axis, contributing to its anxiolytic effects. CBD decreased subjective anxiety and improved mental sedation compared to placebo.5
CBD Improves Stress, Anxiety, and Sleep
In a 20-question online survey, 387 adults were asked about CBD use. The top 4 reasons for using CBD were self-perceived anxiety (42.6%), sleep problems (42.5%), stress (37%), and general health and wellbeing (37%). Most participants reported that CBD was effective in managing stress, improving sleep, and reducing anxiety. Among those using CBD for stress, 92.2% reported feeling less stressed, and no respondent experienced an increase in stress levels.4
Public speaking simulations are often used in studies to induce stress. Studies on healthy participants without any psychiatric diagnoses show that acute CBD dosing reduces stress-response-associated anxiety caused by public speaking. Studies show that 300 mg of CBD is comparable to 10 mg diazepam, 5 mg ipsapirone (5-HT1a agonist), and 1 mg clonazepam in reducing stress-induced anxiety.6, 7
Another study evaluated one week of 600 mg of daily CBD treatment on serum cortisol and anxiety in healthy people at clinical high risk for psychosis (CHR). Public speaking stress was highest in CHR patients on placebo and lowest in healthy controls. CHR participants on CBD had decreased anxiety and a more normalized cortisol response compared to placebo.8
CBD Reduces Fear Conditioning
Fear is another behavioral manifestation of stress. Fear conditioning is a form of associative learning in which a neutral stimulus becomes linked to an aversive event, triggering a fear response. The ECS plays a role in adaptive processes related to aversive memory consolidation and fear conditioning.3 CB1 signaling is important for minimizing fear after stress; lack of this signaling is thought to contribute to fear and anxiety disorders.3
CBD influences CB1 signaling. A study investigated how fear and aversive memories induced by electric shock persist in healthy individuals and found that a 32 mg dose of CBD effectively facilitated the extinction of these memories.9
How Much CBD is Needed for Stress Relief?
Survey data shows that individuals independently using CBD are generally dosing lower than what is prescribed in clinical studies on stress and anxiety.4 One of the public speaking studies showed that 300 mg was effective, while doses of 100 mg and 900 mg were less effective for stress-induced anxiety.7 CBD does not have the potential for abuse or dependence, which is important when prescribing for mood disorders and chronic stress. Reviews of 49 clinical trials showed that doses ranging from 10-1500 mg daily were safe and well-tolerated.1
CBD to Relieve Everyday Stress
A growing body of research suggests CBD decreases neuroinflammation and excitotoxicity associated with stress, easing everyday tension and anxiety, not only in the moment, but also long-term. Unlike benzodiazepines and other anxiety medications, CBD is generally well-tolerated, non-habit forming, and has few to no side effects at moderate doses. This makes CBD an appealing therapeutic option for those seeking sustained stress relief.
References:
1. Henson JD, Vitetta L, Quezada M, Hall S. Enhancing Endocannabinoid Control of Stress with Cannabidiol. Journal of clinical medicine. 2021;10(24).
2. Gorzalka BB, Hill MN. Integration of endocannabinoid signaling into the neural network regulating stress-induced activation of the hypothalamic-pituitary-adrenal axis. Current topics in behavioral neurosciences. 2009;1:289-306.
3. Hill MN, Patel S, Campolongo P, Tasker JG, Wotjak CT, Bains JS. Functional interactions between stress and the endocannabinoid system: from synaptic signaling to behavioral output. The Journal of neuroscience : the official journal of the Society for Neuroscience. 2010;30(45):14980-14986.
4. Moltke J, Hindocha C. Reasons for cannabidiol use: a cross-sectional study of CBD users, focusing on self-perceived stress, anxiety, and sleep problems. Journal of cannabis research. 2021;3(1):5.
5. Crippa JA, Zuardi AW, Garrido GE, et al. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology. 2004;29(2):417-426.
6. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. Journal of psychopharmacology (Oxford, England). 1993;7(1 Suppl):82-88.
7. Zuardi AW, Rodrigues NP, Silva AL, et al. Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Frontiers in pharmacology. 2017;8:259.
8. Appiah-Kusi E, Petros N, Wilson R, et al. Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis. Psychopharmacology. 2020;237(4):1121-1130.
9. Das RK, Kamboj SK, Ramadas M, et al. Cannabidiol enhances consolidation of explicit fear extinction in humans. Psychopharmacology. 2013;226(4):781-792.
