Smoke gets in your tics

Authorea preprint April 25, 2017 DOI: 10.22541/au.149308896.61629534

Many (though not all) of my patients who have tried marijuana have felt that their tics improved after using it. Such self-treatment is not rare (poster P94 here), and other doctors report similar results (see for example poster P6 here). Pharmacological benefits from cannabis products are plausible, since cannabinoid receptors in the brain's basal ganglia are well positioned to affect movement (Kluger et al., 2015).

Of course, in addition to any real benefit from marijuana, there could be expectation effects, or one could simply care less about tics when high. Random allocation clinical trials with blind rating of benefit (RCTs) are essential to demonstrating whether marijuana has any true benefit for tics. Müller-Vahl and colleagues carried out two RCTs about 15 years ago in Tourette syndrome (TS) using THC (tetrahydrocannabinol), the main intoxicating ingredient in cannabis (Müller-Vahl et al., 2002; Müller-Vahl et al., 2003). Both trials showed benefit, but the trials were relatively small. Two to 3 years ago, the Tourette Association of America funded two pilot studies in this field, but results have not yet been reported. One trial, at Yale, was to study the FAAH (fatty acid amide hydrolase) inhibitor PF-04457845 in TS (Ahn et al., 2011), but the trial was placed on clinical hold pending results from a different trial. Investigators at Toronto Western Hospital were funded for a trial in TS of medical cannabis products with varying concentrations of THC and cannabidiol. Cannabidiol is being studied in several brain disorders, including epilepsy, with hopes that it may provide benefit without the psychological side effects of THC.

Not surprisingly, the paucity of data has led to different viewpoints. Müller-Vahl has argued that THC may be appropriate in some TS patients (Müller-Vahl, 2013), whereas an American Academy of Neurology review and a Cochrane-style review in JAMA concluded that the evidence was insufficient to recommend THC for tic disorders (Koppel et al., 2014; Whiting et al., 2015). The clinical utility of cannabinoids in TS was one of two clinical controversies debated at the 2015 First World Congress on Tourette Syndrome and Tic Disorders (Mathews et al., 2016).

In this setting, several recent announcements demonstrate hope for answering whether, for cannabinoids in TS, "where there's smoke, there's fire." At the beginning of 2017, an Israeli company announced enrollment of the first subject in a phase IIa clinical trial of THX-TS01. Notably, this study is enrolling in the USA. THX-TS01 is a combination product, containing both THC and palmitoylethanolamide (PEA), another "endocannabinoid-like" compound. Based on some preclinical studies, the company hopes the combination may prove more effective than either ingredient alone.

In mid-April, 2017, the first patient was enrolled in a Phase 1b study of the monoacylglycerol lipase (MGLL) inhibitor ABX-1431. Inhibition of MGLL in mice increases the concentration of the endogenous cannabinoid receptor ligand 2-arachidonoylglycerol (2AG) in brain, with consequent activation of cannabinoid CB1 receptors (Savinainen 2012).

Müller-Vahl and her colleagues are about to start a much more definitive RCT of cannabinoids in TS. This multicenter study aims to enroll almost 100 subjects in a study of nabiximols, a combination product containing THC and cannabidiol in nearly a 1:1 ratio. This product is available by prescription in some European countries for spasticity in multiple sclerosis.

At this time, there is insufficient evidence of anti-tic efficacy to recommend any of the products discussed above for treatment of tics. This is especially true given medical, practical and legal drawbacks to marijuana smoking (Svrakic et al., 2012) and substantial recent changes in the pharmacology of cannabis and related products available on the street (Cascini et al., 2012; Ford et al., 2017; Monte et al., 2017). On the other hand, there is good reason to expect that some of these products—perhaps cannabidiol or the small molecule modifiers of endocannabinoid metabolism—may prove to be safe and effective, and the appropriate studies are finally underway. An update on this topic likely will look very different in a few years.

Addendum 26 April 2017: A nice review of cannabinoid safety appeared recently in Lancet Psychiatry (Englund et al., 2017).

Addendum 03 May 2017: Abi-Jaoude and colleagues published today a retrospective case series of cannabis in 19 adults with TS who were using cannabis in various forms (smoked, inhaled vapor, ingested) (Abi-Jaoude et al., 2017). Nearly all of their 19 adult patients were rated as having substantially lower tic burden when using compared to when not using. Many patients reported side effects, but overall they were relatively mild.

Addendum 23 Aug 2017: A case report describes a previously treatment-resistant man with TS who responded well to nabiximols (Kanaan et al., 2017).

Addendum 05 Dec 2017:

  1. The draft TS treatment guidelines from AAN discuss cannabinoids.
  2. (Levine et al., 2017) review the strong evidence associating "early, frequent, and heavy adolescent cannabis exposure and poor cognitive and psychiatric outcomes in adulthood," with the appropriate caveat that most of this evidence does not allow a conclusion as to whether the cannabis use caused the poor outcomes.

Addendum 27 Sep 2018: The US FDA approved Epidiolex® (CBD) for certain seizure syndromes in June, 2018, and today the DEA rescheduled it as a Schedule V controlled substance (the least restrictive). This will greatly facilitate clinical use and clinical trials of CBD in the U.S.

Addendum 18 Jan 2018:
A review of the National Academy report summarizes: "The evidence supporting improvement in ... Tourette syndrome ... and a variety of neurodegenerative disorders was described as limited, insufficient or absent" (Abrams, 2018).

Addendum 16 Jul 2018:
Abide Therapeutics reports promising early results from a Phase 1 study of ABX-1431 in TS at the AAN meeting a couple of months ago (Abide Therapeutics, 2018).

Addendum 12 Nov 2018:
Phone interviews of Israeli patients treated with (open-label) medical cannabis revealed that many reported benefits, but about a quarter of patients who had taken it for a year or more had discontinued it for several reasons, including side effects (Thaler et al., in press).

Addendum 31 Jan 2019:
European clinicians report a single boy whose parents treated him with vaporized cannabis and oral THC, who reported marked if incomplete improvement. This report is interesting, but the authors go too far in concluding that "from this single case study, it is suggested that cannabis-based medicines ... are effective and safe in the treatment of severe tics in minors with TS" (Szejko et al., 2019). They go on to warn that even they view "cannabis-based medicine in children ... as a last-line treatment, when well-established treatments have failed to improve tics."

Addendum 28 Mar 2019:
Clinical trial in Australia

References

  1. Elia Abi-Jaoude, Lei Chen, Patrina Cheung, Tracy Bhikram, Paul Sandor. Preliminary evidence on cannabis effectiveness and tolerability for adults with Tourette syndrome. The Journal of Neuropsychiatry and Clinical Neurosciences 391–400 (2017). Link

  2. Abide Therapeutics. ABX-1431 Study Data Featured in AAN Emerging Science Session Data Blitz. (2018). Link

  3. DI Abrams. The therapeutic effects of Cannabis and cannabinoids: An update from the National Academies of Sciences, Engineering and Medicine report. Eur J Intern Med 49, 7–11 (2018). Link

  4. K Ahn, SE Smith, MB Liimatta, D Beidler, N Sadagopan, DT Dudley, T Young, P Wren, Y Zhang, S Swaney, Becelaere K Van, JL Blankman, DK Nomura, SN Bhattachar, C Stiff, TK Nomanbhoy, E Weerapana, DS Johnson, BF Cravatt. Mechanistic and pharmacological characterization of PF-04457845: a highly potent and selective fatty acid amide hydrolase inhibitor that reduces inflammatory and noninflammatory pain.. J Pharmacol Exp Ther 338, 114-24 (2011).

  5. F Cascini, C Aiello, Tanna G Di. Increasing delta-9-tetrahydrocannabinol (Δ-9-THC) content in herbal cannabis over time: systematic review and meta-analysis.. Curr Drug Abuse Rev 5, 32-40 (2012).

  6. Amir Englund, Tom P Freeman, Robin M Murray, Philip McGuire. Can we make cannabis safer?. The Lancet Psychiatry Elsevier BV, 2017. Link

  7. BM Ford, S Tai, WE Fantegrossi, PL Prather. Synthetic Pot: Not Your Grandfather’s Marijuana.. Trends Pharmacol Sci 38, 257-276 (2017).

  8. AS Kanaan, E Jakubovski, K Müller-Vahl. Significant tic reduction in an otherwise treatment-resistant patient with Gilles de la Tourette syndrome following treatment with nabiximols. Brain Sci 7, 47 (2017). Link

  9. B Kluger, P Triolo, W Jones, J Jankovic. The therapeutic potential of cannabinoids for movement disorders.. Mov Disord 30, 313-27 (2015).

  10. BS Koppel, JC Brust, T Fife, J Bronstein, S Youssof, G Gronseth, D Gloss. Systematic review: efficacy and safety of medical marijuana in selected neurologic disorders: report of the Guideline Development Subcommittee of the American Academy of Neurology.. Neurology 82, 1556-63 (2014).

  11. A Levine, K Clemenza, M Rynn, J Lieberman. Evidence for the Risks and Consequences of Adolescent Cannabis Exposure. J Am Acad Child Adolesc Psychiatry 56, 214–225 (2017). Link

  12. CA Mathews, JS Stern. The First World Congress on Tourette Syndrome and Tic Disorders: Controversies and Hot Topics in Etiology and Treatment.. Front Neurosci 10, 246 (2016).

  13. AA Monte, DP Calello, RR Gerona, E Hamad, SL Campleman, J Brent, P Wax, RG Carlson. Characteristics and Treatment of Patients with Clinical Illness Due to Synthetic Cannabinoid Inhalation Reported by Medical Toxicologists: A ToxIC Database Study.. J Med Toxicol (2017).

  14. KR Müller-Vahl, U Schneider, A Koblenz, M Jöbges, H Kolbe, T Daldrup, HM Emrich. Treatment of Tourette’s syndrome with Delta 9-tetrahydrocannabinol (THC): a randomized crossover trial.. Pharmacopsychiatry 35, 57-61 (2002).

  15. KR Müller-Vahl, U Schneider, H Prevedel, K Theloe, H Kolbe, T Daldrup, HM Emrich. Delta 9-tetrahydrocannabinol (THC) is effective in the treatment of tics in Tourette syndrome: a 6-week randomized trial.. J Clin Psychiatry 64, 459-65 (2003).

  16. KR Müller-Vahl. Treatment of Tourette syndrome with cannabinoids.. Behav Neurol 27, 119-24 (2013).

  17. JR Savinainen, SM Saario, JT Laitinen. The serine hydrolases MAGL, ABHD6 and ABHD12 as guardians of 2-arachidonoylglycerol signalling through cannabinoid receptors.. Acta Physiol (Oxf) 204, 267-76 (2012).

  18. DM Svrakic, PJ Lustman, A Mallya, TA Lynn, R Finney, NM Svrakic. Legalization, decriminalization & medicinal use of cannabis: a scientific and public health perspective.. Mo Med 109, 90-8 (2012).

  19. Natalia Szejko, Ewgeni Jakubovski, Carolin Fremer, Kirsten R. Müller-Vahl. Vaporized Cannabis Is Effective and Well-Tolerated in an Adolescent with Tourette Syndrome. Medical Cannabis and Cannabinoids 1–4 S. Karger AG, 2019. Link

  20. A Thaler, S Arad, LB Schleider, J Knaani, T Taichman, N Giladi, T Gurevich. Single center experience with medical cannabis in Gilles de la Tourette syndrome. Parkinsonism Relat Disord (in press). Link

  21. PF Whiting, RF Wolff, S Deshpande, Nisio M Di, S Duffy, AV Hernandez, JC Keurentjes, S Lang, K Misso, S Ryder, S Schmidlkofer, M Westwood, J Kleijnen. Cannabinoids for Medical Use: A Systematic Review and Meta-analysis.. JAMA 313, 2456-73 (2015).

[Someone else is editing this]

You are editing this file