What is it?

Anxiety disorders have the highest lifetime prevalence of any mental illness worldwide, affecting individuals of all ages and backgrounds. In today’s fast-paced and demanding world, with its constant stimuli, many factors contribute to the increased prevalence of anxiety. Work pressures, financial responsibilities, social expectations, lack of contact with nature, poor health habits, and constant exposure to information through technology can all contribute to elevated stress and anxiety levels. The available medications for anxiety have low efficacy and many adverse effects. The current literature indicates cannabinoids can be a viable and safe alternative to address this relevant and urgent issue in modern society.

Synopsis of Research on Cannabis for Anxiety Disorders:

133 primary studies

3 clinical meta-analyses

19 double-blind human studies

12 clinical human studies

55 reviews

43 animal studies

1 laboratory study

The current literature confirms that the endocannabinoid system (ECS) is involved in modulating the biological foundations and emotional states relevant to the experience and processing of anxiety. A 2018 study published in the Journal Psychoneuroendocrinology examined the relationship between circulating endocannabinoids (AEA and 2-AG) and affect and emotionality in 175 individuals with (n=115) and without (n=60) mood, anxiety, and/or personality disorders, showing that circulating levels of AEA had a significant and inverse relationship with affect regulation. That indicates that endocannabinoids in the bloodstream may play a role in influencing emotional responses in individuals, regardless of specific psychiatric diagnosis.

Preclinical and human studies show that the phytocannabinoids THC and CBD activate different parts of the brain’s architecture, producing opposing effects that reduce anxiety. CBD has been shown to reduce the affective aspects of anxiety without producing cognitive changes or sedation, both highly desirable. Within the broader spectrum of CBD’s action, multiple mechanisms can modulate anxiety symptoms, such as its interactions with G protein-coupled receptors (GPCRs) and ion channels, including the transient receptor potential (TRP) calcium channel, neurotransmitter transporters, membrane receptors, and serotonin receptors (5-HT1a).

Several animal studies suggest that CBD has anxiolytic properties. A recent 2023 study published in Neuropharmacology investigated the effects of CBD on aversive memories and anxiety-related responses in adult female rats. The study aimed to fill the knowledge gap regarding the treatment of anxiety and stress disorders in females. The study found that CBD attenuated the behavioral manifestation of learned fear and anxiety in female rats, as well as reduced anxiety-related responses evaluated in the elevated plus maze test, concluding that CBD has the potential to be a safe and effective treatment for anxiety and stress disorders in females.

A 2017 study published in the British Journal of Pharmacology delved deeper into the cannabidiol mechanisms of action, revealing that it reduces anxiety through the activation of 5-HT1A receptors and cannabinoid receptors (indirectly), potentially regulating the processing of emotional memory in humans and animal models. CBD inhibits FAAH and FABPs, resulting in an indirect activation of CB1 and/or CB2 receptors. Additionally, CBD activates the 5-HT1A receptor, PPARγ, TRPV1, TRPA1, and TRPV2. It also inhibits adenosine reuptake and antagonizes GPR55, TRPM8, and T-type calcium channels.

A review of human studies conducted in 2015 and published in Neurotherapeutics found that CBD can be useful in treating anxiety disorders in different contexts. According to the reviewed studies, it can reverse the anxiogenic effects of THC, reducing experimentally induced or fear-related anxiety. In healthy individuals and people with social anxiety disorder, CBD effectively reduced anxiety associated with simulated public speaking tests. Additionally, research has found CBD effective in enhancing fear memory extinction in healthy volunteers.

Published in 2022 in Frontiers in Pharmacology, a study conducted with frontline healthcare professionals in Brazil during the COVID-19 pandemic found that, compared to the control group, there was a significant reduction in the Generalized Anxiety Disorder-7 (GAD-7) questionnaire scores compared to baseline in the group that received CBD. The anxiolytic effects of CBD were maintained up to one month after treatment discontinuation, suggesting a persistent decrease in anxiety in this real-world group. Furthermore, a clinical trial published in the Journal of Clinical Psychiatry in 2022 investigated the safety and efficacy of cannabidiol for anxiety disorders in young individuals who did not respond to previous standard treatment. The study included 31 participants aged 12 to 25 years with a DSM-5 anxiety disorder and no clinical improvement despite treatment with cognitive-behavioral therapy and/or antidepressant medication. All participants received additional CBD for 12 weeks on a fixed-flexible schedule, titrated up to 800 mg/day. The primary outcome was an improvement in anxiety severity measured by the Overall Anxiety Severity and Impairment Scale (OASIS) at week 12. The study found that the mean OASIS score decreased from 10.8 at baseline to 6.3 at week 12, corresponding to a -42.6% reduction. The study concluded that CBD can reduce the severity of anxiety and has an appropriate safety profile in youth with treatment-resistant anxiety disorders.

In addition to CBD, THC can also help in specific anxiety conditions, causing a deep sense of relaxation and sedation. The THC effects on anxiety are believed to be mediated by CB1 receptor mechanisms. However, determining a safe and ideal dose of THC can be challenging due to its psychoactive effects, presenting with a narrow therapeutic window where the line between therapeutic and adverse effects is extremely delicate in individuals with high sensitivity.

Medical cannabis has demonstrated its significance as a valuable tool for addressing various anxiety disorders, especially for patients who do not respond to conventional pharmacological treatments, even when coupled with psychotherapeutic approaches. In association with psychotherapy, cannabis represents a new and promising therapeutic path with the potential to safely, effectively, and more naturally treat this increasingly prevalent issue in modern times.

References:

• Berger M, Li E, Rice S, Davey CG, Ratheesh A, Adams S, Jackson H, Hetrick S, Parker A, Spelman T, Kevin R, McGregor IS, McGorry P, Amminger GP. Cannabidiol for Treatment-Resistant Anxiety Disorders in Young People: An Open-Label Trial. J Clin Psychiatry. 2022 Aug 3;83(5):21m14130. doi: 10.4088/JCP.21m14130. PMID: 35921510.
• Blessing, E.M., Steenkamp, M.M., Manzanares, J. et al. Cannabidiol as a Potential Treatment for Anxiety Disorders. Neurotherapeutics 12, 825–836 (2015). https://doi.org/10.1007/s13311-015-0387-1
• Coccaro, E. F., Hill, M. N., Robinson, L., & Lee, R. J. (2018). Circulating endocannabinoids and affect regulation in human subjects. Psychoneuroendocrinology, 92, 66–71. https://doi.org/10.1016/j.psyneuen.2018.03.009
• Kwee CM, Baas JM, van der Flier FE, Groenink L, Duits P, Eikelenboom M, van der Veen DC, Moerbeek M, Batelaan NM, van Balkom AJ, Cath DC. Cannabidiol enhancement of exposure therapy in treatment refractory patients with social anxiety disorder and panic disorder with agoraphobia: A randomised controlled trial. Eur Neuropsychopharmacol. 2022 Jun;59:58-67. doi: 10.1016/j.euroneuro.2022.04.003. Epub 2022 May 10. PMID: 35561538.
• Lee, J. L. C., Bertoglio, L. J., Guimarães, F. S., and Stevenson, C. W. (2017) Cannabidiol regulation of emotion and emotional memory processing: relevance for treating anxiety-related and substance abuse disorders. British Journal of Pharmacology, 174: 3242– 3256. doi: 10.1111/bph.13724.
• Shannon S, Lewis N, Lee H, Hughes S. Cannabidiol in Anxiety and Sleep: A Large Case Series. Perm J. 2019;23:18-041. doi: 10.7812/TPP/18-041. PMID: 30624194; PMCID: PMC6326553.
• Souza JDS, Zuardi AW, Guimarães FS, Osório FL, Loureiro SR, Campos AC, Hallak JEC, Dos Santos RG, Machado Silveira IL, Pereira-Lima K, Pacheco JC, Ushirohira JM, Ferreira RR, Costa KCM, Scomparin DS, Scarante FF, Pires-Dos-Santos I, Mechoulam R, Kapczinski F, Fonseca BAL, Esposito DLA, Andraus MH, Crippa JAS. Maintained anxiolytic effects of cannabidiol after treatment discontinuation in healthcare workers during the COVID-19 pandemic. Front Pharmacol. 2022 Oct 3;13:856846. doi: 10.3389/fphar.2022.856846. PMID: 36263136; PMCID: PMC9574068.
• Stanley TB, Ferretti ML, Bonn-Miller MO, Irons JG. A Double-Blind, Randomized, Placebo-Controlled Test of the Effects of Cannabidiol on Experiences of Test Anxiety Among College Students. Cannabis Cannabinoid Res. 2022 Jul 20. doi: 10.1089/can.2022.0062. Epub ahead of print. PMID: 35861792.