CBD is getting a lot of press for its anti-anxiety effects. Here is the scientific evidence, mechanisms behind how it works, and upcoming clinical trials.

Anxiety disorders such as generalized anxiety disorder (GAD) and social anxiety disorder (SAD) affect a large proportion of the population. Even many people that are not diagnosed with a specific condition suffer from impairing levels of anxiety due to chronic stress.

Cannabidiol (CBD) is getting a lot of press these days for its anxiolytic (anxiety-reducing) properties. But what do we really know about the effects of CBD on anxiety? My opinion is that although we know a lot about the effects of a single CBD dose in acute anxiety, we still have a lot to learn about repeated CBD doses in chronic anxiety.

Most of what we know about the effects of CBD in chronic anxiety is anecdotal, but as I will show below, the scientific studies we do have so far are encouraging.

[Note: although panic disorders and PTSD fall under the spectrum of anxiety disorders, I will focus on these in a different article.]

 

Can CBD Reduce Anxiety?

Anti-anxiety effects of CBD

[Pexels]

Acute Anxiety

CBD has anxiolytic properties in many different rodent models of anxiety. There is also strong evidence that CBD helps with acute anxiety in humans.

If you are not stressed or anxious to begin with, single CBD doses will not necessarily make you feel more relaxed. Several studies of single dose CBD have been performed in healthy, non-anxious people and CBD did not do very much to their mental state (a few examples: 2012 study, 2015 study, 2017 study).

However, when acute anxiety was induced, CBD did show a significant anxiety-reducing effect. For example:

Chronic Anxiety

What all of the above studies have in common is that they are single dose studies in experimentally-induced anxiety. What is missing is a study of chronic CBD dosing in chronically stressed people or patients with a clinical anxiety disorder such as GAD or SAD (but wait until the last section, the answer may be on its way!)

Although animal models aren’t always predictive of humans, some studies have indicated that CBD is useful for chronic anxiety. In chronically-stressed mice, repeated CBD administration had an anxiolytic effect.

 

What is the Right Dose of CBD to Reduce Anxiety?

Dose of CBD for anxiety

This is where things get tricky. There is not yet a commonly accepted dose of CBD to treat anxiety. However, the data that we do have so far shows that it could be easy to get the dose wrong.

In animals, CBD shows a bell-shaped dose-response curve. Moderate doses are anxiolytic, but this effect is actually lost at higher doses. (Side note: THC also shows a complex dose-response curve, where lower doses are anxiolytic, but higher doses cause anxiety.)

Acute Stress-Induced Anxiety

Until recently, most human studies of CBD and anxiety have only tested a single dose level. This always left me wondering whether the optimal dose of CBD was used in many of these studies. However, a recent 2017 study of public speaking-related anxiety confirmed the bell-shaped dose-response in humans. This study showed that a 300 mg dose of CBD effectively reduced subject’s anxiety, but not a 100 mg or 900 mg dose.

The studies that showed an effect of CBD in experimentally-induced anxiety (listed in previous section) used doses of 300 mg, 400 mg, or 600 mg. So it appears that they were in the right range. However, with hemp oil costing around $0.15 per mg of CBD, even a single 300 mg dose could cost $45!

THC-Induced Anxiety

CBD may counteract THC-induced anxiety at lower doses than those needed to reduce anxiety from acute stress. For example, doses of 15-60 mg (1976 study) and ~70 mg (1982 study) were able to reduce THC-induced anxiety. Perhaps an even lower dose may be effective, but 15 mg of CBD was the lowest dose that I found tested.

Chronic Anxiety

As I mentioned previously, all of the above studies were single-dose studies of acute anxiety. So far, no clinical studies have been performed to establish a regular dosing regimen for chronic anxiety. I do realize there is a wealth of anecdotal data around this, but you can google that for yourself. Overall though, repeated doses of CBD for chronic anxiety are probably much lower. This is potentially related to changes in the endocannabinoid system in people with chronic anxiety (a separate article on this is on it’s way!).

 

Mechanisms Behind CBD Anxiolytic Effect

5-HT1A agonist anti-anxiety mechanism CBD

Acute Anxiety

The primary mechanism of the acute anti-anxiety effect of CBD is through the serotonin 5-HT1A receptor. CBD is an agonist of the 5-HT1A receptor. I won’t get into all the details of why stimulating this receptor is anxiolytic. I will say that it is a well validated anti-anxiety target with decades of study. Another 5-HT1A agonist, called buspirone, is FDA-approved for treating GAD.

So why does CBD show the bell-shaped dose-response curve, with higher doses not having any anti-anxiety effect? This appears to be related to another receptor, called TRPV1. TRPV1 is expressed in a part of the brain called the periaqueductal gray area (PAG), where its activation produces anxiety. There is evidence that at higher doses, CBD activates the TRPV1 receptor in the PAG, masking its anxiolytic effect at the 5-HT1A receptor.

Is CBD Just Another Buspirone?

Buspirone shares a mechanism of action with CBD (both are 5-HT1A agonists) . This brings up the question: is CBD just a natural version of buspirone when it comes to anxiety?

Buspirone is approved by the FDA for use in GAD and has also shown some efficacy in social phobia. It is safe and generally well-tolerated, with decades of study behind it (it was approved by the FDA in 1986). It has generic versions available (i.e. it is cheaper than CBD). The appropriate dosing regimen for anxiety is well-established. It’s absorption is less variable than CBD and there is not the same risk that it’s anxiolytic effect is lost with too high of a dose. It’s manufacturing is controlled per FDA regulations, so you know exactly what you’re getting (not always the case with CBD, since it has fewer regulations).

I’m not trying to convince anyone that buspirone is a better choice than CBD, but it definitely has its advantages. So could there be more to CBD than agonism of 5-HT1A receptors? Something that differentiates it from buspirone and makes it worthy of further study? The next section on repeated CBD dosing shows that the answer may be yes.

Chronic Anxiety

Although 5-HT1A agonism by CBD may contribute to its (still unproven) efficacy in chronic anxiety, there are other mechanisms of action. Chronic anxiety can be driven by stress, which dysregulates the endocannabinoid system (here is a 2017 open-access review with more detail). CBD may be able to restore “endocannabinoid tone” and normalize the function of brain areas impacted by stress.

A 2013 study looked at the anti-anxiety mechanisms of CBD in mice subjected to 14 days of stress. In this study, the anti-anxiety effect did not depend on CBD activating the 5-HT1A receptor. Instead, the anti-anxiety effects were due to CBD doubling the levels of the endocannabinoid anandamide in the brain. The higher anandamide levels activated CB1 and CB2 receptors, leading to neurogenesis in the hippocampus. This neurogenesis was critical to reducing anxiety behavior of the mice.

Yet another mechanism of anti-anxiety effects is through reduction of inflammation. Neuroinflammation has been linked to anxiety, and this may be reduced by CBD. This may be a particularly important anti-anxiety mechanism in specific brain diseases such as multiple sclerosis.

 

Ongoing Trials of CBD and Anxiety

[Pixabay]

I searched clinicaltrials.gov for ongoing or recently completed studies of CBD and anxiety. Surprisingly, there was only one upcoming study where the main focus was on anxiety.

This study has two phases. The first is an open-label assessment of 4 weeks of CBD treatment in adults with anxiety (dosing 9.4 mg three times daily for a total of 28 mg per day). The second phase is similar, but will be double-blind and placebo-controlled. This study will start in March 2018.

There were several other studies where anxiety is not the main focus, but assessing anxiety is a secondary objective of the study. These include several diseases where anxiety is a component, such as drug dependence or psychiatric diseases:

Studies in patients with drug dependence:

Studies in patients with psychiatric and neurodegenerative diseases:

As the results of these studies are published, I will report them in the weekly update!

 

[Featured image: Pexels]

Last modified: February 4, 2018

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