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Anxiety

There is limited evidence that cannabis compound cannabidiol (CBD) is effective in the treatment of anxiety symptoms.1 Researcher Bergamaschi and colleagues showed that patients with social anxiety disorder treated with oral capsules of 600mg of CBD had lower anxiety, measured by a reduction of 16.5 on a 100 point scale in a simulated public speaking test.2 Other studies that looked at the effect of oral CBD (400 mg or 600 mg) on anxiety using brain imaging studies and subjective measures of anxiety symptoms found that, compared to placebo, CBD isolated from cannabis decreased subjective anxiety that was caused by THC.3, 4, 5 Research with doses that were lower and higher than the dosages in the previously mentioned studies, e.g. 100 or 900mg, have not shown to be efficacious against certain types of anxiety.6 Also, studies so far have only investigated single doses instead of taking multiple doses over a longer period of time, and therefore long-term effects of CBD on anxiety are unknown. Zuardi and colleagues showed that when testing three different doses of CBD, 100 mg, 300 mg and 900 mg, only the 300 mg dose attenuated the anxiety in the post-speech phase. Note that this was seen in healthy subjects in a simulated public speaking test, and that the results will need to be replicated in clinical patients.6 Although it seems strange that a high dose of an effective compound can counteract the beneficial effect, there are pharmacological explanations for this phenomenon. Also, this phenomenon is not exclusive to anxiety-related effects: similar effects have been observed in animals and humans in, for example, pain.7 The mechanisms of how CBD works on anxiety are not fully understood, but there are some interesting players in this area:
  • CB1 receptor – CBD may decrease the breakdown, and therefore the presence of the endocannabinoid anandamide in a brain area that is involved in anxiety and fear. This way, anandamide could influence emotional states via the CB1 receptor.5, 8
  • Serotonin receptor – “…another possibility is that CBD directly acts on the receptors that are involved with anxiety. These receptors are referred to as serotonin receptors, and are also called 5-HT1A.”9, 10
  • Capsaicin receptor – The question arises: Why does CBD show anxiety relief at 300 and 400mg, but not at 900mg? This is thought to happen in the following. manner: Higher doses of CBD start activating an additional type of receptor, called capsaicin receptor, or TRPV1. Upon activation, these receptors release a compound (called glutamate) that counteracts anxiety relieving effects caused by CB1 and serotonin receptor activation.11 This theory has been affirmed by the observation that blocking the capsaicin receptor in mice, induces anxiety-relieving effects for a CBD dose that would otherwise have been too high to be effective.12
Furthermore, neuroimaging studies in humans indicate that CBD acts on the brain areas involved with anxiety.5, 13 Δ9-Tetrahydrocannabinol (THC) has been shown to induce anxiety in both naïve users and in experienced users that consume relatively high doses of THC.14, 15, 16, 17, 18 Recently, one study has shown that low doses of cannabis, and THC in particular, had “subjective stress-relieving effect,” but more studies need to be done.19 It is important to note that if you are seeking treatment for anxiety, using products containing THC might give the opposite effects than the ones you were looking for due to THC’s anxiety-inducing properties. The illustration below gives a schematic idea of how a potentially effective THC dose could imply precision work, but the exact doses are different for every individual. In summary, there are more scientific publications on CBD than on THC that observed anxiety-lowering effects. For both CBD and THC, certain ranges within the beneficial effects have been found, with CBD’s range being wider than THC’s range. THC can induce anxiety, with risk increasing as dose increases. All in all, more studies need to be done to unravel more about the effects of CBD and THC on anxiety. Illustration: Schematic visualization as a warning that THC dosing is precision work. THC could help, but at the same time be cautious: a ‘low dose’ of THC might be helpful with decreasing symptoms of anxiety, whereas a higher dose can induce anxiety. Very high levels of THC can result in serious panic attacks. The dose ranges for all effects are different per individual and can be related to genetic predisposition and cannabis experience, among other factors. Precision work illustration of CBD effects on anxiety References:
  1. National Academies of Sciences, Engineering, and Medicine (2017). The Health Effects of Cannabis and Cannabinoids. Nap 24625 (440). National Academies Press.
  2. Bergamaschi, M. M.; Queiroz, R. H. C.; Chagas, M. H. N.; de Oliveira, D. C. G.; De Martinis, B. S.; Kapczinski, F.; Quevedo, J.; Roesler, R.; Schröder, N.; Nardi, Antonio E.; Martín-Santos, R.; Hallak, J. E. C.; Zuardi, A. W.; Crippa, J. A. S. (2011). Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naïve social phobia patients. Neuropsychopharmacology, 36(6), 1219--26.
  3. Bhattacharyya, S.; Morrison, P. D.; Fusar-Poli, P.; Martin-Santos, R.; Borgwardt, S.; Winton-Brown, T.; Nosarti, C.; C. M., O' Carroll; Seal, M.; Allen, P.; Mehta, M. A.; Stone, J. M.; Tunstall, N.; Giampietro, V.; Kapur, S.; Murray, R. M.; Zuardi, A. W.; Crippa, J. A.; Atakan, Z.; McGuire, P. K. (2010). Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology. Neuropsychopharmacology, 35(3), 764--774.
  4. Crippa, José Alexandre de Souza; Zuardi, Antonio Waldo; Garrido, Griselda E. J.; Wichert-Ana, Lauro; Guarnieri, Ricardo; Ferrari, Lucas; Azevedo-Marques, Paulo M.; Hallak, Jaime Eduardo Cecílio; McGuire, Philip K.; Busatto, Geraldo Filho (2004). Effects of Cannabidiol (CBD) on Regional Cerebral Blood Flow. Neuropsychopharmacology, 29(2), 417--426.
  5. Crippa, J. A. S.; Derenusson, G. N.; Ferrari, T. B.; Wichert-Ana, L.; Duran, Fabio L. S.; Martin-Santos, R.; Simoes, M. V.; Bhattacharyya, S.; Fusar-Poli, P.; Atakan, Z.; Filho, A. S.; Freitas-Ferrari, M. C.; McGuire, Philip K.; Zuardi, A. W.; Busatto, G. F.; Hallak, J. E. C. (2011). Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. Journal of Psychopharmacology, 25(1), 121--130.
  6. Zuardi, A. W.; Rodrigues, N. P.; Silva, A. L.; Bernardo, S. A.; Hallak, J. E. C.; Guimaraes, F. S.; Crippa, J. A. S. (2017). Inverted U-Shaped Dose-Response Curve of the Anxiolytic Effect of Cannabidiol during Public Speaking in Real Life. Frontiers in Pharmacology (259).
  7. Genaro, Karina; Fabris, Débora; Arantes, Ana L. F.; Zuardi, Antônio W.; Crippa, José A. S.; Prado, Wiliam A. (2017). Cannabidiol Is a Potential Therapeutic for the Affective-Motivational Dimension of Incision Pain in Rats. Frontiers in Pharmacology, 8, 391.
  8. Casarotto, Plinio C.; Gomes, Felipe V.; Resstel, Leonardo B. M.; Guimarães, Francisco S. (2010). Cannabidiol inhibitory effect on marble-burying behaviour: involvement of CB1 receptors. Behavioural Pharmacology, 21(4), 353-358.
  9. Zanelati, T. V.; Biojone, C. Moreira, F. A.; Guimarães, F. S.; Joca, S. R. L. (2010). Antidepressant-like effects of cannabidiol in mice: possible involvement of 5-HT1A receptors. British Journal of Pharmacology, 159(1), 122-128.
  10. Campos, Alline Cristina; Guimarães, Francisco Silveira (2008). Involvement of 5HT1A receptors in the anxiolytic-like effects of cannabidiol injected into the dorsolateral periaqueductal gray of rats. Psychopharmacology, 199(2), 223-230.
  11. Campos, Alline Cristina; Moreira, Fabricio Araújo; Gomes, Felipe Villela Del; Bel, Elaine Aparecida; Guimarães, Francisco Silveira (2012). Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 367(1607), 3364-3378.
  12. Campos, A. C.; Guimaraes, F. S. (2009). Evidence for a potential role for TRPV1 receptors in the dorsolateral periaqueductal gray in the attenuation of the anxiolytic effects of cannabinoids. Progress in Neuro-Psychopharmacology and Biological Psychiatry, 33(8), 1517--1521.
  13. Fusar-Poli, Paolo; Crippa, José A.; Bhattacharyya, Sagnik; Borgwardt, Stefan J.; Allen, Paul; Martin-Santos, Rocio; Seal, Marc; Surguladze, Simon A.; O’Carrol, Colin; Atakan, Zerrin; Zuardi, Antonio W.; McGuire, Philip K. (2009). Distinct Effects of Δ9-Tetrahydrocannabinol and Cannabidiol on Neural Activation During Emotional Processing. Archives of General Psychiatry, 66(1), 95.
  14. Hall, Wayne; Solowij, Nadia (1998). Adverse effects of cannabis. The Lancet, 352(9140), 1611--1616.
  15. Hall, Wayne (2009). The adverse health effects of cannabis use: What are they, and what are their implications for policy?. International Journal of Drug Policy, 20(6), 458--466.
  16. Hollister, Leo E. (1986). Health aspects of cannabis. Pharmacological reviews, 38(1), 1--20.
  17. Johns, A. (2001). Psychiatric effects of cannabis. The British journal of psychiatry : the journal of mental science, 178, 116--122.
  18. Karila, Laurent; Roux, Perrine; Rolland, Benjamin; Benyamina, Amine; Reynaud, Michel; Aubin, Henri-Jean; Lancon, Christophe (2014). Acute and long-term effects of cannabis use: a review. Current pharmaceutical design, 20(25), 4112--4118.
  19. Childs, Emma; Lutz, Joseph A.; de Wit, Harriet (2017). Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug and Alcohol Dependence, 177, 136--144.