Cannabis, CBD & Anxiety

We are currently living through anxiety provoking times. The coronavirus is the perfect recipe to turn even the most laid back and centered among us into worrying wrecks, imagining the most catastrophic (although unlikely) outcomes for ourselves and our loved ones.

And that, dear friends, is the day-to-day life of someone living with anxiety. I know because for the last fifteen years it’s an inner world I’ve inhabited. Only for me, it’s not a pandemic I’m freaking out about, but lesser evils such as whether I’m going to make a complete idiot of myself in some social gathering or my own favorite anxiety rabbit hole – feeling anxious about feeling anxious.

While there’s no magic bullet to banish anxiety for good, managing anxiety symptoms is a commonly stated reason why people take cannabis – medical or otherwise – with CBD showing particular promise in preliminary studies.

Anxiety Disorders

Anxiety disorders are a collection of mental health conditions characterized by disproportionate worrying about future events that brings about physiological responses in the body such as tightness in the chest, shortness of breath, muscle tension, sleep disturbance, excessive sweating, agitation, restlessness, irritability, and difficulty concentrating.

Avoidance behavior are common strategies amongst anxiety sufferers. If you’ve had a panic attack crossing a bridge, there’s a fair chance you’ll never make it to the other side of that river again. And for the socially anxious amongst us, myself included, not turning up to that party or after work drinks or a friend’s wedding are tactics regularly employed.

However, the more situations we avoid, the smaller our worlds eventually become, and it’s often at this point when an anxiety disorder is diagnosed. Right now, it’s estimated 264 million¹ people worldwide have some kind of anxiety disorder, with approximately 40 million² of them residing in the United States.

Anxiety disorders include generalized anxiety disorder (GAD) when anxiety is felt about a wide range of situations or issues; social anxiety disorder (SAD) – the fear of being negatively judged or rejected in social situations; panic disorder – sudden feelings of terror resulting in panic attacks; obsessive compulsive disorder (OCD) – unwelcomed repetitive thoughts and behavior; phobias – an extreme fear triggered by a situation or object; and post-traumatic stress disorder (PTSD) – anxiety including flashbacks that develop after some kind of traumatic event.

Due to their complex and often individualized nature, there’s no one-size-fits-all approach to treating anxiety disorders. Talking therapies, such as cognitive behavioral therapy (CBT), are often combined with anti-anxiety drugs like SSRI antidepressants or benzodiazepines for a more immediate calming effect. Also known as tranquilizers, benzodiazepines include the likes of Xanax and Valium, and while they may lull patients into a state of anxiety-free calm, taken long term they can result in addiction. 

It’s clear, therefore, that a new class of anti-anxiety medication, without risk of abuse or dependence and free from side effects, must be developed. And the big ‘green’ hope is that the cannabis plant might hold the key.

Stress, Anxiety & the Endocannabinoid System

Coping with stress or unwinding from a hectic day, is one of the major reasons millions of people consume cannabis. While your average recreational user isn’t interested in the biological mechanisms behind why they feel more relaxed after smoking a joint, the reason is almost certainly due to the direct activation of their endocannabinoid system (ECS).

The ECS comprises fatty ligands called endocannabinoids which bind to a vast network of cannabinoid receptor sites (CB1 and CB2) throughout the brain, central nervous system, immune system, and organs. Dynamic in nature, it is constantly working to ensure all our physiological systems remain in balance.

Life is filled with external stressors – pollution, poor sleep, that argument with your boss, the 24/7 news reports about the millions of people dying worldwide from the coronavirus. Thankfully the ECS works as a buffer to ensure our organisms don’t develop some kind of illness as a result. It also plays a crucial role in regulating fear, anxiety and how we cope with stress.³

Activating CB1 receptors in the brain and central nervous system has been found to calm feelings of anxiety, which explains why consuming cannabis tends to chill people out.⁴ However, it’s not a case of the more you smoke, the less anxious you feel as higher doses of THC, the main psychoactive compound in cannabis, can actually be anxiety-inducing.⁵

Enhanced signaling between CB1 receptors and the endocannabinoid anandamide in the amygdala, an area of the brain key to processing fear, has been shown to help mice forget frightening experiences.⁶ That’s something of clinical interest for the treatment of anxiety disorders where frightening events of the past become indelibly marked in a patient’s memory, fueling future feelings of anxiety.

However, chronic stress itself can eventually impair our endocannabinoid system. Prolonged exposure to stress downregulates CB1 receptor signaling in brain regions involved in emotional processing. Chronic stress also increases levels of fatty acid amide hydrolase (FAAH), the enzyme that breaks anandamide down in the body, resulting in lower concentrations of the feel-good endocannabinoid.⁷

With weakened endocannabinoid signaling, we are more vulnerable to developing anxiety and depression. Indeed, one study showed a clear inverse relationship between anandamide levels and anxiety severity in women with major depression;⁸ So in basic terms, the more anandamide deficient we are, the more anxious we may become.

Thus, boosting CB1 signaling could be a potential therapeutic target for both protecting against and treating anxiety disorders – a theory explored in a preclinical study on mice with low anandamide levels caused by stress-induced anxiety. Researchers observed how inhibiting FAAH reversed the animals’ anandamide deficiency, which in turn reduced their anxious behaviour.⁹

CBD: A Multi-Targeted Approach to Anxiety

While drug companies around the world are experimenting with synthetic FAAH inhibitors,¹⁰ hoping they’ll become the next big thing in anti-anxiety medication, cannabidiol (CBD), the non-intoxicating compound found in cannabis, has been shown to inhibit anandamide reuptake and delay its metabolism by FAAH.¹¹ Several studies confirm that administering CBD enhances CB1 signaling, in turn promoting the creation of new neurons in the hippocampus,¹² which scientists believe further contributes towards the compound’s anxiolytic effect.

However, CBD’s anti-anxiety action extends beyond increasing endocannabinoid signaling. Animal studies show how CBD interacts with serotonin 5-HT1A receptors in the brain, which are tried and tested targets for anti-anxiety medication.

In one study, administering CBD to rats submitted to 60 minutes of enforced restraint not only lowered their heart rate and mean arterial pressure, but also reduced anxiety levels. However, these results were not replicated when the rats were given a 5-HT1A antagonist, which blocked CBD from interacting with the serotonin receptors,¹³ What remains unclear is whether CBD elicits this effect by directly binding with 5-HT1A¹⁴ receptors or by indirectly facilitating 5-HT1A serotonin signaling.¹⁵

Neuroimaging in healthy subjects given 400mg of a CBD isolate suggested that the relaxation they reportedly experienced may have been caused by activity in the limbic and paralimbic brain system, areas of the brain associated with emotional processing, memory, and cognitive processes.¹⁶

CBD & Anxiety: Outside the Lab

While more still remains to be discovered about the mechanisms behind CBD’s anxiolytic effect, in certain US states and countries where medicinal use of cannabis is legal, doctors are treating their patients with CBD-rich cannabis strains for anxiety disorders. For the rest of us still condemned to the dark ages of prohibition, CBD oil derived from hemp has been our anti-anxiety salvation.

Consider the case of Emily Wilson, a 30-year-old British aid worker living in Greece. For the last three years, Emily has been education coordinator at a refugee camp on the outskirts of Athens, where 2800 displaced persons from countries like Syria, Afghanistan, Iraq, and Iran live side by side in converted shipping containers, many still suffering from severe trauma.

With limited resources, Emily was often left feeling stressed and frustrated by the limitations of the work she could do. After two years working at the refugee camp, her naturally buoyant and positive nature was no longer a protection against the physical and mental strain she endured on a daily basis.

“I remember a few times,” Emily recounted, “where I’d just be walking and I’d start to think about work and my chest would tighten and I’d have to start taking deep breaths because my chest was tightening so much and my eyes were watering like I was crying. But it was tears of frustration and tears of panic. This happened about once or twice a week for about three or four weeks until I realized there was something really wrong. It was so crippling that I didn’t go to work because I couldn’t get out of bed.”

Emily started taking full spectrum CBD oil, and after gradually building up the dose from one drop to three drops, three times a day, she started to feel her anxiety levels subside.

“I think the major benefit of it for me,” says Emily, “was it prevented the anxiety from becoming all encompassing. It didn’t take away the problems, but meant that they were there, I acknowledged them, I knew that I had to work through them, but they weren’t in my chest, they weren’t in my throat, and weren’t stopping me doing things. So there was a distance from them. I also felt a deep sense of calm and a deep sense of, OK, well, everything can be solved.”

Evidence With Limitations

Thousands of glowing anecdotal accounts are one thing, but without some randomised clinical trials, mainstream medical institutions will never take CBD seriously as an anti-anxiety treatment. Unfortunately, as with most areas of cannabinoid research, clinical research into CBD for anxiety still falls rather short.

Because anxiety is such a broad term, most research conducted so far has concentrated on just one type of anxiety disorder, namely social anxiety disorder. A well-established protocol for measuring the effectiveness of an anti-anxiety drug is its administration to socially anxious individuals before they take part in a public speaking test.

In one study, healthy and socially anxious subjects were both asked to perform a simulated public speaking test.¹⁷ Those with social anxiety disorder were either given a one-off dose of 600mg pure CBD or a placebo. The healthy subjects performed the test without any medication.

This hefty dose of CBD allowed the socially anxious participants to perform the task with “significantly reduced anxiety, cognitive impairment and discomfort in their speech performance,” as well as reducing their stress levels prior to the test. In comparison, the placebo group fared less well experiencing high levels of anxiety. No difference in anxiety or performance was noted between the CBD group and the healthy subjects, suggesting a one-off, high dose of CBD before public speaking may allow the socially anxious to perform just as well as someone without social anxiety disorder.

However, giving a single 600mg dose of purified CBD does not reflect the clinical experiences of doctors recommending medical cannabis to patients with anxiety or that of the millions of people around the world taking hemp-based CBD oil for anxiety-related conditions.

Purified Versus Whole Plant CBD

With a race on to find a new anti-anxiety drug potentially worth billions of dollars,¹⁸ there’s little financial gain to be enjoyed from developing medication based on whole plant cannabis. But purified CBD, while potentially more lucrative and easier to study in clinical trials, has its own therapeutic drawbacks that aren’t present in full spectrum CBD-rich cannabis extracts.

Anyone who’s tried a CBD isolate will vouch for the fact that a high dose is generally needed to get any therapeutic effect. This common experience was confirmed in a meta-analysis comparing CBD-rich products with purified CBD in patients with epilepsy.¹⁹ The study found much lower doses of CBD-rich cannabis were taken by patients to successfully control their seizures compared to the high amounts of purified CBD used in Epidiolex clinical trials.

Not only that, animal studies demonstrate how purified CBD has a ‘bell shaped dose-response’,²⁰ whereby it only shows significant therapeutic benefit at a substantial dose, with little efficacy at lower or higher doses.

This inverted bell shaped dose-response was confirmed in the context of social anxiety when healthy volunteers undertaking a simulated public speaking test only experienced a reduction in anxiety when given 300mg of CBD, but no change with either 150mg or 600mg, suggesting a narrower therapeutic window compared to CBD-rich cannabis.²¹

Until recently, there’s been little evidence from human studies about the anti-anxiety effects of taking CBD over a prolonged period of time. However, just last year, a randomised placebo study was published in which Japanese teenagers with social anxiety and avoidant personality disorder were given 300mg of pure CBD or a placebo daily over four weeks.²² Not only did CBD significantly decrease their anxiety, but half of the participants given CBD expressed a wish to seek therapy or further treatment at the end of the study, while none of the placebo group mentioned such a desire.

In an open label retrospective study also published in 2019, 72 psychiatric patients with anxiety or sleep disorders were given between 25-175mg of CBD a day, alongside existing psychiatric medications.²³ After two months of treatment, 78.1% of patients reported feeling less anxious and 56.1% experienced improved sleep.

A Clinician’s Experience

These encouraging results validate the experiences of clinicians who regularly prescribe medical cannabis to patients with anxiety. “For me, it’s a really good choice for treating anxiety in people,” says Dr. Rebecca Moore, a UK-based consultant psychiatrist who sees patients at The Medical Cannabis Clinics in London.

“I’ve seen some amazingly wonderful results. People who’ve had lifelong anxiety, who are doing all the right things in terms of their diet, their exercise, their supplements, but still have a fairly crippling anxiety, and within a couple of months they don’t have any anxiety at all and can’t quite believe what’s happened to themselves.

“One lady told me that she had been able to pick up a book and read for the first time in 20 years, focus and enjoy it. And another said she was planning her first holiday in 10 years. You know, it’s just life-changing differences for people.”

Dr. Moore has found medical cannabis – in particular CBD-rich oil, but also including small amounts of THC – to benefit patients with all types of anxiety disorders. In general, patients need far smaller doses than used in published preliminary studies, with some benefitting from as little as 30mg of CBD a day.    

Patients usually arrive at Dr. Moore’s clinic because they find the anti-anxiety drugs they have been prescribed over the years don’t work well, and they struggle with the harsh side effects. “I’ve had people come in,” says Dr Moore, “on four or five different medications, who have managed to stop them all and just be on CBD. People who were on two antidepressants, plus a benzodiazepine, plus a sleeping tablet at night, plus an anti-hypertensive, and they stopped all of them.”

It’s in her treatment of PTSD using cannabinoids where Dr. Moore has seen some of the most fascinating changes in patients: “I think particularly with trauma memories, it’s so interesting the way it seems to impact on people’s recollection of their memory. People talk about feeling like their trauma memories are being deleted. And then I’ve had lots of people say they actually then start to remember positive memories, which they weren’t able to access before.”

Clinical Trials

Right now, a number of clinical trials to study the effectiveness of CBD for anxiety are in the process of recruiting, including one using 25mg of full spectrum CBD soft gel capsules over a period of twelve weeks;²⁴ and a phase II clinical trial evaluating the efficacy of CBD for social anxiety, which will also measure changes in endocannabinoid levels.²⁵ And a Harvard Medical School research project will compare whole-plant and single-extract CBD solutions for anxiety.

Unfortunately, though, with clinical research moving at a slow pace, we’re a long way from official approval of CBD as an anti-anxiety medicine. 

In the meantime, in a bid to minimise any damage to our endocannabinoid system caused by current coronavirus stress which may make us more vulnerable to anxiety disorders now and in the future, we could do a lot worse than incorporating high quality, CBD-rich cannabis or a CBD oil into our self-care routine.

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Mary Biles, a UK-based journalist, educator, and Project CBD contributing writer, is the author of The CBD Book (Harper Collins, UK). © Copyright, Project CBD. May not be reprinted without permission.

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Footnotes

1. World Health Organization. Depression and Other Common Mental Disorders.
2. Anxiety and Depression Association of America. Facts and Statistics
3. Lutz, B et al. The endocannabinoid system in guarding against fear, anxiety and stress. Nat Rev Neurosci. 2015;16(12):705‐718.
4. Hillard C. J. Stress regulates endocannabinoid-CB1 receptor signaling. Seminars in immunology, 26(5), 2014, 380–388.
5. Lutz, J et al. Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug and Alcohol Dependence 177, 2017, 136-144.
6. Gunduz-Cinar, O et al. Convergent translational evidence of a role for anandamide in amygdala-mediated fear extinction, threat processing and stress-reactivity. Molecular psychiatry vol. 18,7 2013, 813-23.
7. Hillard C. J. Stress regulates endocannabinoid-CB1 receptor signaling. Seminars in immunology, 26(5), 2014, 380–388.
8. Hill, Matthew N et al. Suppression of amygdalar endocannabinoid signaling by stress contributes to activation of the hypothalamic-pituitary-adrenal axis. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 34,13 2009: 2733-45.
9. Hill, M N et al. Serum endocannabinoid content is altered in females with depressive disorders: a preliminary report. Pharmacopsychiatry vol. 41,2, 2008: 48-53.
10. Bluett, Rj et al. Central anandamide deficiency predicts stress-induced anxiety: behavioral reversal through endocannabinoid augmentation.Transl Psychiatry. 2014 Jul 8;4:e408.
11. Bedse, Gaurav et al. Therapeutic endocannabinoid augmentation for mood and anxiety disorders: comparative profiling of FAAH, MAGL and dual inhibitors. Translational psychiatry vol. 8,1 92. 26 Apr. 2018.
12. Elmes MW et al. Fatty acid-binding proteins (FABPs) are intracellular carriers for Δ9-tetrahydrocannabinol (THC) and cannabidiol (CBD). J Biol Chem. 2015;290(14):8711‐8721. doi:10.1074/jbc.M114.618447
13. Campos, AC et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol. 2013 Jul;16(6):1407-19.
14. Resstel, Leonardo B M et al. 5-HT1A receptors are involved in the cannabidiol-induced attenuation of behavioural and cardiovascular responses to acute restraint stress in rats. British journal of pharmacology vol. 156,1 (2009): 181-8.
15. Russo, EB et al. Agonistic properties of cannabidiol at 5-HT1a receptors. Neurochem Res. 2005 Aug;30(8):1037-43.
16. Rock, E M et al. Cannabidiol, a non-psychotropic component of cannabis, attenuates vomiting and nausea-like behaviour via indirect agonism of 5-HT(1A) somatodendritic autoreceptors in the dorsal raphe nucleus. British journal of pharmacology vol. 165,8, 2012, 2620-34.
17. Crippa, JA et al. Effects of cannabidiol (CBD) on regional cerebral blood flow. Neuropsychopharmacology. 2004 Feb;29(2):417-26.
18. Bergamaschi, Mateus M et al. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology : official publication of the American College of Neuropsychopharmacology vol. 36,6, 2011, 1219-26.
19. Crippa, JA et al. Cannabinoids for the Treatment of Mental Disorders. The Lancet. Correspondence Vol  7, Issue 2, 2020, 125-126. Some researchers, who’ve invented their own patented fluorinated CBD compounds, have agreements with a pharmaceutical company to develop a synthetic CBD product for anxiety disorders.
20. Pamplona, FA et al. Potential Clinical Benefits of CBD-Rich Cannabis Extracts Over Purified CBD in Treatment-Resistant Epilepsy: Observational Data Meta-analysis. Front Neurol. 2018 Sep 12;9:759.
21. Gallily, R et al. Overcoming the Bell‐Shaped Dose‐Response of Cannabidiol by Using Cannabis Extract Enriched in Cannabidiol. Pharmacology & Pharmacy, 2015, 6, 75‐85.
22. Crippa, JA et al. Cannabidiol presents an inverted U-shaped dose-response curve in a simulated public speaking test. Braz J Psychiatry. 2019 Jan-Feb;41(1):9-14.
23. Masataka, N et al. Anxiolytic Effects of Repeated Cannabidiol Treatment in Teenagers With Social Anxiety Disorders. Front Psychol. 2019 Nov 8;10:2466.
24. Shannon, Scott et al. Cannabidiol in Anxiety and Sleep: A Large Case Series. The Permanente journal vol. 23, 2019, 18-041.
25. ClinicalTrials.gov. Cannabidiol for Anxiety.
26. ClinicalTrials.gov. CHI-902 for Treatment of Social Anxiety Disorder.

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