Loading...
Visit our Evidence-Based Covid-19 Website and Stay Up to Date with the latest Research.
Volume:3 Issue:12 Number:3 ISSN#:2563-559X
OE Original

The Truth About Cannabis Effects on Anxiety: A Meta-analysis of Randomized Trials

Authored By: OrthoEvidence

December 16, 2020

How to Cite

OrthoEvidence. The Truth About Cannabis Effects on Anxiety: A Meta-analysis of Randomized Trials. OE Original. 2020;3(12):3. Available from: https://myorthoevidene.com/Blog/Show/107

Studies show that many people report using cannabis to relieve anxiety as one of the novel ‘self-medication’ options, especially those with anxiety-related disorders [1-3]. Medical cannabis has potential anxiolytic effects through the modulation of functional activity of the limbic and paralimbic brain regions as well as the endocannabinoid systems [4-6]. Human experimental studies have shown that acute dosing of cannabidiol (CBD) is effective for treating multiple anxiety conditions, including social anxiety disorder, generalized anxiety disorder, post-traumatic stress disorder and obsessive-compulsive disorder [5,6].


We conducted a systematic review of randomized clinical trials (RCTs) evaluating the efficacy and safety of medical cannabis for relieving anxiety (Scoping the Evidence) by searching Ovid Medline, Embase, and PsychInfo databases. In this OE Original, we present results of a meta-analysis outlining the evidence from a total of 19 eligible RCTs with 462 participants that provided an anxiety outcome measured on a standardized scale [6-24]. Table 1 shows the characteristics of the various types of cannabis products identified in the included studies, by their routes of administration and specific formulations.


Table 1. Characteristics of Treatments in the Included Studies


Treatment

Route of Administration

Formulation / Dose

Number of Studies

THC

Oral capsules

5 to 10 mg, single dose

2

Smoked

THC concentration of 1.4%

1

THCV

Oral capsules

10 mg, single dose

1

CBD

Oral capsules

300 to 600 mg, single dose

7

THC & CBD

Oromucosal spray

2.7mg THC:2.5mg CBD/actuation. The maximum permitted dose was 129.6mg THC:120mg CBD/day.

2

Nabilone*

Oral capsules

0.5 to 5 mg/day

5

Dronabinol*

Oral drops

10 mg/day

1

Notes: THC = delta-9-tetrahydrocannabinol; THCV = Tetrahydrocannabivarin; CBD = cannabidiol.

* A synthetic form of THC



What Does the Evidence Show?


The outcome of anxiety was measured on a 0-100 visual analogue mood scale (VAMS) anxiety subscale, 0-10 visual analogue scale for anxiety, 20-80 Zung anxiety scale (ZAS) and the state trait anxiety inventory (STAI) anxiety subscale, 0-4 Hamilton anxiety scale, 0-36 profile of mood states (POMS) anxiety subscale, 0-24 Hopkins symptom checklist (HSCL) anxiety subscale, 0-21 hospital anxiety and depression scale (HADS) anxiety subscale and 0-63 Beck anxiety inventory. We converted the scores from different scales to the 0-100 numeric rating scale for level of anxiety (0 = no anxiety, 100 = highest level of anxiety). No statistically significant differences were detected between cannabis and control groups on the effect of anxiety relief by the separate meta-analyses for different durations of follow-up (Table 2).



Table 2. Effects of Medical Cannabinoids for Anxiety Relief


Follow-up

Treatment effects [95% CI]

Treatment

Control

Quality of Evidence

Number of subjects

Within 4 hours

Mean difference: -5.18 [-12.22, 1.85]. Based on data from 11 trials.

109

111

Very low

1-8 weeks

Mean difference: -2.42 [-9.65, 4.80]. Based on data from 8 trials.

121

121

Very low

Notes: CI = confidence interval.


Below we present the effects by the different types of cannabinoids, when possible, at the two follow-up durations (Tables 3-4). Compared to placebo, CBD demonstrated acute effects of anxiety relief (mean difference, -12.02; 95% CI, -18.34 to -5.70; low quality of evidence); tetrahydrocannabivarin (THVC) increased level of anxiety (mean difference, 18.50; 95% CI, 10.06 to 26.94; low quality of evidence) within 4 hours’ follow-up. Based on the recommended minimum important difference (MID) of 10mm on a 0-100mm anxiety measurement scale [25], the short-term point estimates of difference in our findings reached the threshold of MID for CBD and THCV (Table 3).



Table 3. Differences in Level of Anxiety Compared to Placebo Within 4 Hours


Treatment

Mean difference [95% CI]

Interpretation

Quality of Evidence

THC

0.74 [-7.89, 9.37] based on data from 73 subjects in 3 trials.

NS

Very low

THCV

18.50 [10.06, 26.94] based on data from 20 subjects in 1 trial.

Difference > 10 points

Low

CBD

-12.02 [-18.34, -5.70] based on data from 103 subjects in 6 trials.

Difference > 10 points

Low

Nabilone

-5.84 [-15.20, 3.52] based on data from 24 subjects in 1 trial.

NS

Very low

Notes: NS = not significant.




Table 4. Differences in Level of Anxiety Compared to Placebo (1 to 8 weeks)


Treatment

Mean difference [95% CI]

Interpretation

Quality of Evidence

THC & CBD

-1.79 [-6.63, 3.05] based on data from 83 subjects in 2 trials.

NS

Moderate

CBD

3.11 [-6.64, 12.86] based on data from 32 subjects in 1 trial.

NS

Very low

Nabilone

-6.51 [-19.20, 6.17] based on data from 114 subjects in 4 trials.

NS

Very low

Dronabinol

7.62 [-9.60, 24.84] based on data from 13 subjects in 1 trial.

NS

Low

Notes: NS = not significant.



There is a lack of evidence between acute examination and six days’ follow-up, and longer than two months’ follow-up. During a follow-up period of 1 to 8 weeks, no significant differences were found for any types of medical cannabis compared to placebo (Table 3). Unfortunately, there was insufficient data for us to conduct any other subgroup analyses by dose or patient condition.


Adverse event (AE) data were available from 5 trials. Overall, the risk ratio was 1.28 (95% CI, 1.00-1.63) for medical cannabis relative to placebo, with the medical cannabis group having 41 / 76 (53.9%) and the placebo group having 30 / 73 (41.1%) patients report an AE. In one study following patients 2.5 hours after taking a single dose of 300 mg CBD, no AEs were reported [9]. The most commonly reported AEs after treatment with cannabis included dizziness (30%), dry mouth (9%), nausea (6%) and fatigue (6%). Most of these symptoms were mild or moderate and subsided over time after stopping medication.



What’s the Bottom Line?


Our analysis showed acute anxiolytic effects with a single dose of 300mg to 600mg oral CBD, one of the major compounds from the Cannabis sativa L. plant (12.0 points less anxiety than placebo with 95% CI of 18.3 less to 5.7 less points on a 0-100 anxiety measurement scale, within 4 hours’ follow-up). The size of effects reached the threshold of MID. The result is consistent with findings from previous studies in both animals and humans indicating that CBD has anxiolytic properties [4-6].


On the contrary, our analysis showed anxiogenic effects with a single dose of 10mg oral THCV (18.5 points more anxiety than placebo with 95% CI of 10.1 more to 26.9 more points, within 4 hours’ follow-up) based on data from 1 trial [14]. THCV is similar to THC by its molecular structure but not as much studied as THC because of the low concentration of THCV in a cannabis plant [1,26]. It will require more laboratory and clinical studies to explore THCV’s effects on anxiety. In our analysis, no significant differences were found for THC at short or longer durations of follow-up. Previous non-randomized studies suggest that THC might have anxiolytic effects at lower doses but lead to anxiogenic effects at higher doses; however, the threshold of high and low doses for THC of such different dose-dependent “biphasic” effects was not clearly reported [1,5,6,26,27]. One three-arm trial that enrolled a total of 42 participants with current or past cannabis use showed non-significant increase in anxiety with a single dose of 7.5 mg oral THC and significant increase in anxiety with 12.5 mg THC at 2.5 hours follow-up, compared to placebo [8]. Due to an insufficient number of studies, we were not able to conduct a subgroup analysis for THC by dose.


No significant differences in anxiety were detected for CBD and THC at longer duration of follow-up. For synthetic cannabis of nabilone and dronabinol, no significant differences were found at either short or long-time follow-up.



Hot Topic for Future Research


More high-quality trials are needed to answer the remaining questions including optimal dosing (e.g., lower than 300 mg single dose to minimize side effects) and route of administration (e.g., oromucosal spray or smoked) for CBD to play a role in reducing anxiety, and the dose threshold of THC for its anxiolytic or anxiogenic effects.




References


  1. Stoner SA. Effects of marijuana on mental health: anxiety disorders. Alcohol Drug Abus Inst. 2017(June):1-6.
  2. Buckner JD, Schmidt NB, Lang AR, Small JW, Schlauch RC, Lewinsohn PM. Specificity of social anxiety disorder as a risk factor for alcohol and cannabis dependence. Journal of psychiatric research. 2008 Feb 1;42(3):230-9.
  3. Sexton M, Cuttler C, Finnell JS, Mischley LK. A cross-sectional survey of medical cannabis users: patterns of use and perceived efficacy. Cannabis and cannabinoid research. 2016 Jun 1;1(1):131-8.
  4. Fusar-Poli P, Crippa JA, Bhattacharyya S, Borgwardt SJ, Allen P, Martin-Santos R, Seal M, Surguladze SA, O’Carrol C, Atakan Z, Zuardi AW. Distinct effects of ?9-tetrahydrocannabinol and cannabidiol on neural activation during emotional processing. Archives of general psychiatry. 2009 Jan 1;66(1):95-105.
  5. Blessing EM, Steenkamp MM, Manzanares J, Marmar CR. Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics. 2015 Oct 1;12(4):825-36.
  6. Crippa JA, Derenusson GN, Ferrari TB, Wichert-Ana L, Duran FL, Martin-Santos R, Simões MV, Bhattacharyya S, Fusar-Poli P, Atakan Z, Filho AS. Neural basis of anxiolytic effects of cannabidiol (CBD) in generalized social anxiety disorder: a preliminary report. Journal of Psychopharmacology. 2011 Jan;25(1):121-30.
  7. Bergamaschi MM, Queiroz RH, Chagas MH, De Oliveira DC, De Martinis BS, Kapczinski F, Quevedo J, Roesler R, Schröder N, Nardi AE, Martín-Santos R. Cannabidiol reduces the anxiety induced by simulated public speaking in treatment-naive social phobia patients. Neuropsychopharmacology. 2011 May;36(6):1219-26.
  8. Childs E, Lutz JA, de Wit H. Dose-related effects of delta-9-THC on emotional responses to acute psychosocial stress. Drug and alcohol dependence. 2017 Aug 1;177:136-44.
  9. de Faria SM, de Morais Fabrício D, Tumas V, Castro PC, Ponti MA, Hallak JE, Zuardi AW, Crippa JA, Chagas MH. Effects of acute cannabidiol administration on anxiety and tremors induced by a Simulated Public Speaking Test in patients with Parkinson’s disease. Journal of Psychopharmacology. 2020 Feb;34(2):189-96.
  10. Hundal H, Lister R, Evans N, Antley A, Englund A, Murray RM, Freeman D, Morrison PD. The effects of cannabidiol on persecutory ideation and anxiety in a high trait paranoid group. Journal of Psychopharmacology. 2018 Mar;32(3):276-82.
  11. Müller-Vahl KR, Koblenz A, Jöbges M, Kolbe H, Emrich HM, Schneider U. Influence of treatment of Tourette syndrome with ?9-tetrahydrocannabinol (?9-THC) on neuropsychological performance. Pharmacopsychiatry. 2001 Jan;34(01):19-24.
  12. Nakano S, Gillespie HK, Hollister LE. A model for evaluation of antianxiety drugs with the use of experimentally induced stress: comparison of nabilone and diazepam. Clinical Pharmacology & Therapeutics. 1978 Jan;23(1):54-62.
  13. Pillard RC, McNair DM, Fisher S. Does marijuana enhance experimentally induced anxiety?. Psychopharmacologia. 1974 Sep 1;40(3):205-10.
  14. Rzepa E, Tudge L, McCabe C. The CB1 neutral antagonist tetrahydrocannabivarin reduces default mode network and increases executive control network resting state functional connectivity in healthy volunteers. International Journal of Neuropsychopharmacology. 2016 Feb 1;19(2).
  15. Zuardi AW, Cosme RA, Graeff FG, Guimarães FS. Effects of ipsapirone and cannabidiol on human experimental anxiety. Journal of Psychopharmacology. 1993 Jan;7(1_suppl):82-8.
  16. Zuardi AW, Rodrigues NP, Silva AL, Bernardo SA, Hallak JE, Guimarães FS, Crippa JA. Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Frontiers in pharmacology. 2017 May 11;8:259.
  17. Aragona M, Onesti E, Tomassini V, Conte A, Gupta S, Gilio F, Pantano P, Pozzilli C, Inghilleri M. Psychopathological and cognitive effects of therapeutic cannabinoids in multiple sclerosis: a double-blind, placebo controlled, crossover study. Clinical neuropharmacology. 2009 Jan 1;32(1):41-7.
  18. Ilaria RL, Thornby JI, Fann WE. Nabilone, a cannabinol derivative, in the treatment of anxiety neurosis. Current Therapeutic Research-Clinical And Experimental. 1981 Jan 1;29(6):943-9.
  19. Malik Z, Bayman L, Valestin J, Rizvi-Toner A, Hashmi S, Schey R. Dronabinol increases pain threshold in patients with functional chest pain: a pilot double-blind placebo-controlled trial. Diseases of the Esophagus. 2017 Feb 1;30(2).
  20. Pini LA, Guerzoni S, Cainazzo MM, Ferrari A, Sarchielli P, Tiraferri I, Ciccarese M, Zappaterra M. Nabilone for the treatment of medication overuse headache: results of a preliminary double-blind, active-controlled, randomized trial. The journal of headache and pain. 2012 Nov 1;13(8):677-84.
  21. Rog DJ, Nurmikko TJ, Friede T, Young CA. Randomized, controlled trial of cannabis-based medicine in central pain in multiple sclerosis. Neurology. 2005 Sep 27;65(6):812-9.
  22. Toth C, Mawani S, Brady S, Chan C, Liu C, Mehina E, Garven A, Bestard J, Korngut L. An enriched-enrolment, randomized withdrawal, flexible-dose, double-blind, placebo-controlled, parallel assignment efficacy study of nabilone as adjuvant in the treatment of diabetic peripheral neuropathic pain. PAIN. 2012 Oct 1;153(10):2073-82.
  23. Appiah-Kusi E, Petros N, Wilson R, Colizzi M, Bossong MG, Valmaggia L, Mondelli V, McGuire P, Bhattacharyya S. Effects of short-term cannabidiol treatment on response to social stress in subjects at clinical high risk of developing psychosis. Psychopharmacology. 2020 Jan 8:1-0.
  24. Skrabek RQ, Galimova L, Ethans K, Perry D. Nabilone for the treatment of pain in fibromyalgia. The Journal of Pain. 2008 Feb 1;9(2):164-73.
  25. Williams VS, Morlock RJ, Feltner D. Psychometric evaluation of a visual analog scale for the assessment of anxiety. Health and quality of life outcomes. 2010 Dec 1;8(1):57.
  26. Crippa JAS, Zuardi AW, Hallak JEC. Therapeutical use of the cannabinoids in psychiatry. Revista Brasileira de Psiquiatria. 2010;32(Suppl I):S56–S66.
  27. Viveros MP, Marco EM, File SE. Endocannabinoid system and stress and anxiety responses. Pharmacology Biochemistry and Behavior. 2005 Jun 1;81(2):331-42.

Please Login or Join to leave comments.