Anxiety disorders, the most common of which are generalized anxiety disorder (GAD), panic disorder (PD), and social anxiety disorder (SAD), are the most prevalent mental illnesses in the world1. It has been estimated that 28% of Americans will suffer from an anxiety disorder at some point in their life, with an economic cost of 42.3 to 46.6 billion dollars2. Post-traumatic stress disorder (PTSD), although not classified as an anxiety disorder in the DSM-IV, is also characterized in part by anxiety.
Anxiety disorders are widely treated with antidepressants and benzodiazepines, but 40-60% of patients do not get full relief from their symptoms with these drugs3. Side effects are common, and include sexual dysfunction, nausea/vomiting, weight changes, and sleep disturbances4. These drugs also have a delayed effect, taking weeks to achieve full efficacy, which can lead to poor compliance4. Alternative treatments that are more effective, have fewer side effects, and act quickly are desperately needed.
Anxiety and Cannabis
It has been well documented that people suffering from anxiety self-medicate with cannabis to improve their symptoms5. Medical cannabis users are also widely using cannabis to treat anxiety. In a recent review study exploring reasons for the use of medical cannabis, more than half of users reported using it for anxiety, second only to pain, with many reporting substituting medical cannabis for anxiety medication6.
While these statistics show that people are widely using cannabis to treat anxiety, they appear to be at odds with the National Academy of Sciences, Engineering, and Medicine, who noted in 2017 that regular cannabis use is associated with the incidence of social anxiety disorder7. The reason for this inconsistency might be due to the fact that cannabis has the ability to both increase and decrease anxiety, depending on dose. This is known as a “biphasic” effect, and it has been demonstrated in research studies using both animals and humans.
The Biphasic Effect of Cannabis
Cannabis consumption in humans affects anxiety in a dose-dependent manner, with only low doses reducing anxiety and high doses increasing anxiety and panic5,6,8.This effect is due to actions of THC, the psychoactive cannabinoid, in the brain. In rodent studies, the doses of THC that reduce anxiety are less than 1mg/kg of body weight, while the doses that increase anxiety are up to 10mg/kg of body weight9. In humans, this dose distinction is less clear. One study found that treatment with 12.5mg of THC resulted in higher anxiety and anticipatory distress than either placebo or 7.5mg of THC, leading the authors to suggest that a lower dose of THC could improve the negative psychological consequences of stress, but not a higher dose10. In contrast, a review article suggested that more than 5mg of oral THC can cause intense fear and anxiety in some cases11. It is especially difficult to predict dose responses to cannabis and THC in humans, as the same dose may affect people differently depending on factors such as body composition, age, and history of cannabis use. When co-administered with THC, CBD can reduce the increase in anxiety seen with higher doses of THC12,13,14.
Consumption of cannabis in its different forms results in a wide range of THC intake. Smoked cannabis will contain approximately 60 to 150mg of THC per cigarette, while commercially sold edibles can range as high as several hundred milligrams. The pharmaceutical THC medications Dronabinol (Marinol, Syndros) and Nabilone (Cesamet) come in doses of 4, 6 or 8mg of synthetic oral THC, while Nabiximol (Sativex) contains 2.7mg THC and 2.5mg CBD per spray. As well, each strain of cannabis has a unique chemical composition, resulting in a wide variation of intake of cannabinoids and terpenes which may have different effects15. Compounding this issue further is that the pharmacokinetics, or the rate at which ingested cannabinoids end up in the bloodstream, is highly variable. Cannabis absorption is approximately 20-30% with oral ingestion and 10-60% for inhalation16. This is speculative, but it is possible that these differences factor heavily into the outcomes observed in cannabis and anxiety research.
Most medical cannabis users report experiencing reductions in anxiety following cannabis use. In a recently published study, 93.5% of cannabis users tracking symptoms using a smartphone app reported lower anxiety levels after intake17, while another study found that 71.8% of users reported reducing their use of prescription medication for anxiety18. However, the use of cannabis may not provide a dramatic improvement in symptoms: while 93% of medical cannabis users reported that cannabis use reduced their symptoms, scores remained moderate to high on self-reported anxiety questionnaires19.
Although not technically an anxiety disorder, PTSD often involves symptoms of severe anxiety, and since it has received the most research attention, is worth mentioning here. Cannabis has been shown to reduce symptoms of PTSD, including quality of life, sleep quality, and hyperarousal20,21. However, not all studies have shown benefit. For example, another study found that when veterans initiated cannabis use after treatment for PTSD that symptoms worsened compared to those who stopped using or who never used22. A recent review article noted that there is “potential” for cannabis to be used to treat PTSD23, but the National Academy of Sciences, Engineering and Medicine found that there is also some evidence to suggest that near daily cannabis use may increase severity of PTSD symptoms7. It isn’t clear whether the biphasic effect of cannabis on anxiety underlies these contradictory results, but it may be a factor.
Unlike THC, CBD does not exhibit a biphasic effect on anxiety, and there is not a dose of CBD that increases anxiety the way high doses of THC do. However, the effect of CBD on anxiety may also not be entirely straightforward. This is because CBD does not appear to display a linear dose response, meaning that as dose increases, there may not be a consistently greater benefit. Studies in animals suggest that although CBD doesn’t increase anxiety at any doses, the therapeutic curve may be U shaped, with efficacy at intermediate but not low or high doses24. However, there are also animal studies that suggest that CBD most effectively reduces anxiety at lower doses25M. A 2015 review of human research also supported the possibility of a U shaped curve, although they did note that high doses did reduce anxiety in some studies26.
Several studies have demonstrated CBD’s ability to reduce anxiety in healthy subjects. CBD effectively reduced anxiety in healthy adults placed in a simulated public speaking environment at a dose of 300mg27,28. Two other studies in healthy subjects found that 400mg CBD decreased anxiety, while at the same time showing changes in brain areas involved in the control of emotions29,30. These studies all used a single, or acute, dose of CBD which may be different than when CBD is taken regularly across an extended period of time.
Human studies that have used CBD to treat anxiety disorders also have shown benefit. CBD used at 300mg per day over four weeks reduced anxiety in adolescents with SAD31, while 600mg of CBD reduced anxiety in adults with social phobia in a simulated public speaking environment32. Similarly, CBD combined with medication and psychotherapy reduced the severity of PTSD symptoms in adults after eight weeks33, and PTSD anxiety was also reduced in a 10-year old child treated with 25mg of CBD for four months34. And, in a study of psychiatric patients experiencing both anxiety and sleep concerns, nearly 80% showed a reduction in anxiety within the first month that was sustained over several months35.
The doses of CBD used in most of these studies is quite high. This raises two important considerations. First, most studies did not assess a range of doses, particularly not at the lower range. While higher levels of CBD have been shown to reduce anxiety, it is possible that lower doses may also be effective. The case study of pediatric PTSD that used a 25mg daily dose supports this possibility. Second, studies used an oral dose of lipid soluble CBD, which has poor bioavailability. In fact, it’s been found that only about 6 to 24% of fat soluble CBD ends up in the bloodstream36. Other forms of CBD, such as water soluble, are absorbed much faster and have been found to be 4.5 times more bioavailable than the fat soluble CBD37. Lower doses of more bioavailable CBD would be needed in comparison to lipid soluble products.
There are several ongoing clinical trials that should help to better understand CBD’s role in anxiety treatment. A small open-label clinical trial is evaluating the effects of CBD to reduce anxiety in adults at a total daily dose of 30mg for 4 weeks, which will be followed by a larger phase 2 trial; this daily dose is comparable to what consumers usually consume, so it will provide important insight into clinical relevance (Gruber, S., NCT02548559). A larger phase 3 trial is evaluating the effect of 200-800mg CBD per day for 4 weeks to reduce symptoms in patients with GAD, SAD, PD or agoraphobia (McMaster University, NCT03549819). And a small pilot study is evaluating the effect of 100mg CBD per day for 12 weeks to decrease anxiety and sleep disturbances in patients diagnosed with anxiety (CB2 Insights, NCT04267679). It is exciting that this clinical research is underway, and it speaks to the perception that CBD may be an important tool in the treatment of anxiety disorders, although it would be helpful to see a wider range of doses (especially at the lower range) being explored, as well as inclusion of more bioavailable CBD formulations.
There is a biphasic response to cannabis consumption whereby low doses of cannabis or THC reduce anxiety and high doses increase it, although it is not clear where the dose threshold is. The ability for cannabis to increase anxiety may be an important consideration in the interpretation of the cannabis and anxiety research evidence. CBD may also be able to reduce the anxiety induced by higher doses of THC, allowing for people to use THC at higher doses when indicated for other conditions safely. Observational studies often report a reduction in anxiety following cannabis use, and although the reduction in anxiety may be modest, people using cannabis to treat anxiety widely report experiencing a benefit. CBD also shows strong potential for being useful in the treatment of anxiety, both when taken by healthy adults in an anxiety provoking setting as well as by those with anxiety disorders such as SAD and PTSD. Several research studies using CBD to reduce anxiety are ongoing and will soon provide helpful information regarding efficacy and dosing.
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