Anxiety

Seriousness of medical condition(s)

Symptoms arising from excessive fear and anxiety occur in a number of neuro-psychiatric disorders, including generalized anxiety disorder (GAD), panic disorder (PD), post-traumatic stress disorder (PTSD), social anxiety disorder (SAD), and obsessive–compulsive disorder (OCD). These anxiety-related disorders are associated with a diminished sense of well-being, elevated rates of unemployment and relationship breakdown, and elevated suicide risk (Khan et al., 202; Kroenke et al., 2007; Olatunji et al., 2007). Together, they have a lifetime prevalence of 29% (Kessler et al., 2005), the highest of any mental disorder, and constitute an immense social and economic burden (Wang et al., 2005, Gustavsson et al., 2011). Evidence suggests that people with anxiety disorders are at greater risk for developing a number of chronic medical conditions, may have more severe symptoms and a greater risk of death. Importantly, anxiety is often a concomitant condition in chronic diseases such as migraine, IBS, chronic pain and cancer, to name a few.

Who could benefit from this treatment?

Intended for anxiety patients when other treatment and management strategies have not completely resolved symptoms, failed, are contraindicated or caused side effects.

Clinical justification for using Medicinal Cannabis

  1. The medicinal cannabis’s suitability for the intended indication and
  2. The medicinal cannabis’s efficacy and expected benefits

 

 

The substantial burden of anxiety-related disorders and the limitations of current treatments place a high priority on developing novel pharmaceutical treatment approaches. CBD has broad therapeutic properties across a range of neuropsychiatric disorders, stemming from diverse central nervous system actions (Izzo et al., 2009; Campos et al., 2012). Evidence from human studies supports an anxiolytic role of CBD, albeit with few studies performed in clinical populations. Overall, current evidence indicates CBD has considerable potential as a treatment for multiple anxiety disorders (SAD, GAD, Panic Disorder), with need for further study of chronic and therapeutic effects in relevant clinical populations (Blessing et al., 2015). Evidence from a small number of clinical studies of prescription cannabinoids containing small amounts of THC suggests that these drugs could improve symptoms of anxiety and depression in patients suffering from anxiety and/or depression secondary to certain chronic diseases (e.g. patients with HIV/AIDS, MS, and chronic neuropathic pain)(Health Canada, 2018).

 

NB: Anxiety, depression and cognitive states such as catastrophisation are also associated with a heightened experience of pain through inhibition of modulatory pathways

 

  1. any unknown or expected adverse effects, risks and safety issues & d. related toxicology:

A systematic review by Whiting et al. (2015) stated in their conclusions that “Cannabinoids were associated with an increased risk of short-term adverse effects”.

According to the Guidance for the Use of Medicinal Cannabis in Australia: Overview, Therapeutics Good Administration (2017):

Cannabis is not appropriate for patients who:

  • Are under the age of 25 (with the exception of intractable epilepsy or severe pain syndrome)
  • Have a personal history or strong family history of psychosis
  • Have a current or past cannabis use disorder, or active substance use disorder
  • Have unstable respiratory or cardiovascular disease (including angina, peripheral vascular disease, cerebrovascular disease, arrhythmias)
  • Are pregnant, planning to become pregnant, or breastfeeding

 

Cannabis should be authorized with caution in patients who:

  • Smoke tobacco
  • Have risk factors for cardiovascular disease
  • Are heavy users of alcohol
  • Are taking sedating medications or any other medication metabolized by the CYP450 pathway
  • At risk or have liver disease

 

Drug Interactions – CYP P450 Enzyme System

THC and CBD are metabolized by Cytochrome P450 enzyme system, including CYP1A2, CYP2C9, CYP2D6, CYP2C19 and CYP3A4. Based on in vitro and animal studies with cannabis, there is a potential for interactions with the medications metabolized by the P450 enzymes (2C9, 2C19, 3A4). It’s notable, however, that the inhibitory effects in vitro and in animal models were only seen at exposures significantly higher than the maximum observed in clinical trials. For instance, in clinical trials were Sativex® has been taken concomitantly with other drugs metabolized by the Cytochrome P450 enzyme system, no clinically apparent drug-drug interactions have been seen in these trials at clinical doses. In an in vitro study with 1:1% (v/v) THC botanical drug substance (BDS) and CBD BDS, no relevant induction of the Cytochrome P450 enzymes was seen for human CYP1A2, CYP2C9, CYP2C19 and CYP3A4 in human hepatocytes at doses of up to 1µM (314ng/mL) (Stout and Cimino, 2014).

 

Potential drug interactions

Increasing THC concentration:

Examples of inhibitors:

– Antidepressants (e.g. Fluoxetine, Fluvoxamine)

– Proton Pump Inhibitors (e.g. Omeprazole)

– Cimetidine

– Macrolides (Clarithromycin, Erythromycin)

– Antimycotics (e.g. Itraconazole, Fluconazole, Ketoconazole, Miconazole)

– Calcium Antagonists (e.g. Diltiazem, Verapamil)

– HIV protease inhibitors (e.g. Ritonavir)

– Amiodarone

– Isoniazid

– Grapefruit juice

 

Increasing CBD concentration:

– Metabolized by CYP 2C19 and CYP 3A4

– Bioavailability could be increased by many of the same substances as for THC

 

Decreasing THC and CBD concentration:

  • CYP 2C9 and 3A4 Inducers accelerate THC and CBD metabolism
  • Examples of inducers:

– Rifampicin

– Primidone

– Carbamazepine

– Phenobarbital

– Phenytoin

– Rifabutin

– Saint John’s Wort

 

Significantly changed serum levels of clobazam, rufinamide, topiramate, zonisamide, and eslicarbazepine were seen in the study by Gaston et al (2017) on interactions between cannabidiol (Epidiolex®) and commonly used antiepileptic drugs. Abnormal liver function test results were noted in participants taking concomitant valproate. This study emphasizes the importance of monitoring serum AED levels and LFTs during treatment with supraphysiological doses of CBD (e.g. 1000mg/kg).

 

  • Caution with blood thinners like Warfarin, Heparin, Clopidogrel (Plavix)
  • Additionally, pharmacodynamic interactions should be expected between cannabis and drugs with sympathomimetic activity (tachycardia, hypertension), central nervous system depressants (drowsiness, ataxia), and drugs with anticholinergic effects (tachycardia, drowsiness).

 

Many of these drug interactions can be mitigated in complex patients with polypharmacy by slowly titrating cannabis.

Approved treatments for this medical condition

Currently available pharmacological treatments include:

  • serotonin reuptake inhibitors
  • serotonin–norepinephrine reuptake inhibitors
  • benzodiazepines
  • monoamine oxidase inhibitors
  • tricyclic antidepressant drugs, and
  • partial 5-hydroxytryptamine (5HT)1A receptor agonists.

 

These medications are associated with limited response rates and residual symptoms, and adverse effects may also limit tolerability and adherence (Otto et al., 2001; Ballenger et al., 2004; Krystal et al., 2011; Shin et al., 2014).

Why is medicinal cannabis appropriate for use?

Medicinal cannabis will only be trailed after an approved therapeutic goods have been trailed and failed due to ineffective response or undesirable effects.

 

Currently available pharmacological treatments for anxiety including serotonin reuptake inhibitors, serotonin–norepinephrine reuptake inhibitors, benzodiazepines, monoamine oxidase inhibitors, tricyclic antidepressant drugs, and partial 5-hydroxytryptamine (5HT)1A receptor agonists are associated with limited response rates and residual symptoms, and adverse effects may also limit tolerability and adherence (Otto et al., 2001; Ballenger et al., 2004; Krystal et al., 2011; Shin et al., 2014).

References

  • Ballenger JC. Remission rates in patients with anxiety disorders treated with paroxetine. J Clin Psychiatry 2004;65:1696-1707.
  • Blessing, E. M., Steenkamp, M. M., Manzanares, J., & Marmar, C. R. (2015). Cannabidiol as a potential treatment for anxiety disorders. Neurotherapeutics12(4), 825-836.
  • Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimaraes FS. Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond Ser B Biol Sci 2012;367:3364-3378.
  • Gaston TE, Bebin EM, Cutter GR, Liu Y, Szaflarski JP; UAB CBD Program. Interactions between cannabidiol and commonly used antiepileptic drugs. Epilepsia. 2017 Sep;58(9):1586-1592. doi: 10.1111/epi.13852. Epub 2017 Aug 6. PMID: 28782097.
  • Gustavsson A, Svensson M, Jacobi F, et al. Cost of disorders of the brain in Europe2010.Eur Neuropsychopharmacol 2011;21:718-779
  • https://www.tga.gov.au/medicinal-cannabis-guidance-documents
  • Izzo AA, Borrelli F, Capasso R, Di Marzo V, Mechoulam Nonpsychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol Sci 2009;30:515-527.
  • Khan A, Leventhal RM, Khan S, Brown WA. Suicide risk in patients with anxiety disorders: a meta-analysis of the FDA database. J Affect Disord 2002;68:183-190.
  • Kroenke K, Spitzer RL, Williams JB, Monahan PO, Lowe B. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med 2007;146:317-325.
  • Krystal JH, Rosenheck RA, Cramer JA, et al. Adjunctive risperidone treatment for antidepressant-resistant symptoms of chronic military service-related PTSD: a randomized trial. JAMA 2011;306:493-502.
  • Olatunji BO, Cisler JM, Tolin DF. Quality of life in the anxiety disorders: a meta-analytic review. Clin Psychol Rev 2007;27:572-581.
  • Otto MW, Tuby KS, Gould RA, McLean RY, Pollack MH. An effect-size analysis of the relative efficacy and tolerability of serotonin selective reuptake inhibitors for panic disorder. Am J Psychiatry 2001;158:1989-1992.
  • Shin HJ, Greenbaum MA, Jain S, Rosen CS. Associations of psychotherapy dose and SSRI or SNRI refills with mental health outcomes among veterans with PTSD. Psychiatr Serv 2014;65: 1244-1248.
  • Wang PS, Lane M, Olfson M, Pincus HA, Wells KB, Kessler RC. Twelve-month use of mental health services in the United States: results from the National Comorbidity Survey Replication. Arch Gen Psychiatry 2005;62:629-640.
  • Whiting PF, Wolff RF, Deshpande S, Di Nisio M, Duffy S, Hernandez AV, et al. Cannabinoids for medical use: a systematic review and meta-analysis. JAMA 2015;313(24):2456-73. Errata in: JAMA 2016;315(14):1522, JAMA 2015;314(21):2308, JAMA 2015;314(5):520, JAMA 2015;314(8):837.