Psychology

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ANXIETY

Summaries of the available clinical evidence for the use of medicinal cannabis in addressing anxiety disorders can be found below.

EFFICACY AND EXPECTED BENEFITS

While larger scale, high quality double-blind, randomised, controlled trials are eagerly awaited and critically required, the available evidence of smaller controlled trials and case studies suggests that cannabidiol (CBD) may be an effective and well-tolerated treatment option for anxiety disorders – especially social anxiety disorder.

EVIDENCE REVIEWS

Black et al., 2019

A systematic review and meta-analysis of medicinal cannabis for the treatment of mental disorders and symptoms of mental disorders was conducted and published in the journal, the Lancet Psychiatry. It included any type and formulation of a medicinal cannabinoid in adults and for anxiety disorders, 31 eligible studies were included with 17 being randomised controlled trials; n=605.

The review determined pharmaceutical tetrahydrocannabinol (THC) with or without cannabidiol (CBD) content (eg, THC, CBD extract, or THC–CBD combinations such as nabiximols) improved anxiety symptoms among individuals with other medical conditions, primarily chronic non-cancer pain and multiple sclerosis. Changes in symptoms were pooled as standardised mean differences and were determined to be -0·25 [95% CI -0·49 to -0·01]; seven studies; n=252. However, the evidence GRADE was deemed very low due to none of the studies including participants with a primary diagnosis of anxiety and partly due to reporting bias.

In conclusion, there is very low quality evidence that pharmaceutical THC (with or without CBD) leads to a small improvement in symptoms of anxiety among individuals with other medical conditions. Further high-quality studies directly examining the effect of cannabinoids in patient populations with anxiety disorders are required.

Chadwick et al., 2020

This review examined evidence for the use of cannabis and cannabinoid in anxiety, depression and bipolar disorder, PTSD and emotional dysregulation from the 18 months prior to publication.

Authors wrote that RCTs in patients are rare, and a long-term therapeutic effect has not been investigated using RCTs

Stockings et al., 2018

A systematic review of cannabinoids as add-on therapy for treatment-resistant epilepsy included six randomised controlled trials (RCTs) and 30 non-RCTs of varying quality. The RCTs all studied CBD versus placebo in paediatric populations with rare and serious forms of disease; while the non-RCT studies studied a range of cannabinoids: CBD (n = 15), CBD:THC extract (n = 4); Cannabis sativa (n = 6) and various other cannabinoid formulations (n = 5).1

The authors concluded that pharmaceutical-grade CBD as adjuvant treatment in paediatric-onset drug-resistant epilepsy may reduce seizure frequency and has an acceptable safety profile. However, they noted that there is insufficient evidence from moderate-quality or high-quality studies to assess whether there is a treatment effect of Cannabis sativa, CBD:THC combinations or oral cannabis extracts.1

PRIMARY LITERATURE

Hurd et al., 2019

A randomised double-blind placebo-controlled clinical study was used to investigate the potential of CBD to reduce drug cue-induced craving and anxiety in drug abstinent individuals with heroin use disorder.

Participants were given either a placebo (n=15), 400 mg CBD (n=14) or 800 mg CBD (n=13) (oral solution 100 mg/mL; Epidiolex) once daily for 3 consecutive days. The acute (1 hour, 2 hours, and 24 hours), short-term (3 consecutive days), and protracted (7 days after the last of three consecutive daily administrations) effects of CBD administration (400 or 800 mg,) on drug cue-induced craving and anxiety was assessed by showing participants drug-related cues and measuring opioid cravings using the visual analogue scale for craving [VAS-C] and anxiety using the visual analogue scale for anxiety.

Efficacy

In session 1 (1-2 hr after CBD or placebo), participants exposed to the drug cue had significantly higher anxiety scores (mean difference score=1.37) than when they were exposed to the neutral cue (mean difference score=−0.65). The interaction between the cue condition and drug group was also significant (F=3.98, df=2, 38, p=0.0270). After experiencing the drug cue, there was a significant increase in anxiety (mean difference score=2.78) for participants in the placebo group, followed by participants who received 400 mg of CBD (mean difference score=0.99) and then those who received 800 mg of CBD (mean difference score=0.33). For the neutral cue, the mean difference score for all three drug groups indicated decreased anxiety after viewing the cue.

A similar pattern was evident in session 2 (24 h after CBD or placebo), where anxiety scores were significantly higher after experiencing the drug cues (mean difference score=1.16) than after exposure to the neutral cue (mean difference score=−0.07), although there was not an overall significant drug group difference.

In session 4 (7 days after CBD or placebo), the main effect of drug group was significant (F=3.64, df=2, 36, p=0.0363), with participants receiving placebo reporting significantly greater anxiety (mean difference score=0.53) than those receiving 400 mg of CBD (mean difference score=−0.14) or 800 mg of CBD (mean difference score=−0.03). There was no significant difference in anxiety between participants in the two CBD groups.

Additionally, CBD also tended to reduce physiological measures of stress reactivity, such as increased heart rate and cortisol levels that were induced by salient drug cues.

The results of this double-blind randomized placebo-controlled trial indicated that administration of 400 mg or 800 mg of CBD reduced cue-induced craving and anxiety in heroin-abstinent individuals, suggesting a potential role for CBD to alleviate clinical signs and symptoms critical to the continued cycle of addiction.

Safety, risks and adverse effects

CBD treatment was well tolerated. There were no serious adverse events noted in association with CBD administration throughout the duration of the trial. Mild diarrhea was reported in three participants, headache in three (two of whom had received placebo), and tiredness or fatigue was reported by two participants (one had received placebo; the other, 800 mg of CBD).

Masataka, 2019

The efficacy of CBD on symptoms of Social Anxiety Disorder (SAD) was investigated using a randomised double-blind placebo-controlled clinical study. The study was conducted in thirty-seven Japanese teenagers aged 18 to 19 with SAD and avoidant personality disorder. 17 paticpants were given 300 mg of CBD orally in oil while the other 20 teenagers were given a placebo daily for 4 weeks. Participants had been symptomatic for at least 6 months and were psychological or drug treatment-naïve and cannabis-naïve. SAD symptoms were measured at the beginning and end of the treatment period. CBD significantly decreased anxiety as measured by Fear of Negative Evaluation Questionnaire and the Liebowitz Social Anxiety Scale.

Using the FNE, the mean score of the CBD group went from 24.4 (2.7) to 19.1 (2.1), which was significantly lower (p = 0.02). Whereas the mean scores for the placebo group went from 23.5 (2.1) to 23.3 (2.9), which was not significantly different (p = 0.29). When anxiety was measured using the LSAS, the mean difference in scores for the CBD group from preintervention to postintervention were 74.2 (7.5) to 62.1 (8.7), which was deemed significantly different (p = 0.03). While the change in scored in the placebo group from 69.9 (10.3) to 66.8 (11.2) was not significantly different (p = 0.42).

In summary, in children and adolescents, SAD is known to be among the most common mental disorders. In all, the results of the current study provide evidence for anxiolytic effects of repeated CBD administration in teenagers with SAD.

Safety, risks and adverse effects

Laczkovics et al., 2020

A case study reports that daily CBD (100 mg up to 600 mg over 8 weeks given orally as capsules) improved anxiety symptoms in a 16.9-year-old patient with multiple substance use disorder after unsuccessful treatment with antidepressants.

Upon treatment with CBD and cessation of the antidepressant medication, improvements in depressive and anxiety symptoms (including simple phobias, symptoms of paranoia and dissociation) were observed. Furthermore, the patient quit abusing illegal drugs including THC without showing withdrawal symptoms.

CBD was a safe and well tolerated medication for this patient.

Klier et al., 2020

This case study reports CBD (100 mg/d to 600 mg/d over 19 weeks given orally as capsules) eased the anxiety symptoms seen in a female adolescent patient aged 14 years with Crohn’s disease. Cannabidiol showed an effect on symptoms of needle phobia, fear of medical interventions, and social phobia as shown by changes in symptom expression as well as in Clinical Global Impression Severity Scale score, but no remission of the anxiety disorder was achieved. The improvement to her comorbid anxiety, resulting from CBD, allowed her to receive better clinical care for her IBD symptoms, which in turn improved her overall condition.

Gulbransen, Xu & Arroll, 2020

An audit of the first 400 patients to attend the Cannabis Care in New Zealand, between 7 December 2017 and 7 December 2018 seeking CBD prescriptions assessed self-reported quality of life measures at baseline and after 3 weeks of use, patient-reported satisfaction, incidence of side effects, and patient-titrated dosage levels of CBD.

Of the 400 attending patients, 397 received a prescription for CBD oil and a follow-up assessment was completed on 253 patients (63.3%). Quality of life measures (mobility, self-care, usual activities, pain or discomfort, anxiety or depression) were assessed using the EQ-5D-5L. Results from Wilcoxon rank sum tests for EQ-5D-5L domains found that patients experiencing non-cancer pain symptoms had a significant improvement of self-reported anxiety or depression (P = 0.017). Patients with mental-health related symptoms also experienced significant improvements to their anxiety or depression symptoms (P = 0.02). There were no significant differences in anxiety/depression symptoms determined for patients attending for neurological or cancer symptoms.

Adverse effects such as sedation and vivid dreams were experienced by 25 out of 253 patients (9.9%). A worsening of a pre-existing condition was reported by 2 of 253 (0.8%) patients upon follow-up. Thirty-eight of followed-up patients (15.0%) reported positive side effects of CBD use, such as improved sleep or improved appetite. Negative side-effects reported by patients included sedation (2%), vivid dreams (2%), emotional disturbances (e.g. irritable, depressed, anxious; 2%), disorientation (1.2%) and others (0.4%).

CLINICAL CONSIDERATIONS

Dosing

Clinical prescriptive consideration involves caution in the use of high-THC formulations (avoidance in youth, and in people with anxiety or psychotic disorders), gradual titration, regular assessment, and caution in cardiovascular and respiratory disorders, pregnancy and breast-feeding.

Interactions with other drugs

Medicinal cannabis in the treatment of autism spectrum disorder (ASD) has been reported as an add-on therapy to existing medications, the most common including antipsychotics, antiepileptics, antidepressants, hypnotics and sedatives. The authors did not report any specific concerns regarding concomitant medication use in autism. However, all patients must be monitored for adverse events and tolerability when altering any therapeutic regimen (Bar-Lev Schleider et al., 2019).

References

  • Bar-Lev Schleider, L, Mechoulam, R, Saban, N, Meiri, G & Novack, V 2019, ‘Real life Experience of Medical Cannabis Treatment in Autism: Analysis of Safety and Efficacy’, Sci Rep, vol. 9, no. 1, pp. 200.
  • Black, N, Stockings, E, Campbell, G, Tran, LT, Zagic, D, Hall, WD, Farrell, M & Degenhardt, L 2019, ‘Cannabinoids for the treatment of mental disorders and symptoms of mental disorders: a systematic review and meta-analysis’, Lancet Psychiatry, vol. 6, no. 12, pp. 995-1010.
  • Chadwick, VL, Rohleder, C, Koethe, D & Leweke, FM 2020, ‘Cannabinoids and the endocannabinoid system in anxiety, depression, and dysregulation of emotion in humans’, Curr Opin Psychiatry, vol. 33, no. 1, pp. 20-42.
  • Gulbransen, G, Xu, W & Arroll, B 2020, ‘Cannabidiol prescription in clinical practice: an audit on the first 400 patients in New Zealand’, BJGP Open.
  • Hurd, YL, Spriggs, S, Alishayev, J, Winkel, G, Gurgov, K, Kudrich, C, Oprescu, AM & Salsitz, E 2019, ‘Cannabidiol for the Reduction of Cue-Induced Craving and Anxiety in Drug-Abstinent Individuals With Heroin Use Disorder: A Double-Blind Randomized Placebo-Controlled Trial’, Am J Psychiatry, vol. 176, no. 11, pp. 911-922.
  • Klier, CM, De Gier, C, Felnhofer, A, Laczkovics, C & Amminger, PG 2020, ‘A Case Report of Cannabidiol Treatment of a Crohn’s Disease Patient With Anxiety Disorder’, J Clin Psychopharmacol, vol. 40, no. 1, pp. 90-92.
  • Laczkovics, C, Kothgassner, OD, Felnhofer, A & Klier, CM 2020, ‘Cannabidiol treatment in an adolescent with multiple substance abuse, social anxiety and depression’, Neuropsychiatr.
  • Masataka, N 2019, ‘Anxiolytic Effects of Repeated Cannabidiol Treatment in Teenagers With Social Anxiety Disorders’, Front Psychol, vol. 10, pp. 2466.

Abbreviations

AE, adverse event; ASD, Autism Spectrum Disorder; APSI, Autism Parenting Stress Index; CBD, cannabidiol; CBG, cannabigerol; CBDV, cannabidivarin; ECS, endocannabinoid system; HSQ-ASD, Home Situations Questionnaire–Autism Spectrum Disorder; THC, ∆-9-tetrahydrocannabinol.

INSOMNIA

Summaries of the available clinical evidence for the use of medicinal cannabis in addressing insomnia and sleep disorders is being developed and will be available soon.

POST-TRAUMATIC STRESS DISORDER

Summaries of the available clinical evidence for the use of medicinal cannabis in addressing Post-traumatic Stress Disorder (PTSD) is being developed and will be available soon.