SafeMinds Comments to FDA on Cannabis & Autism

Controlled Substance Staff
Center for Drug Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave., Bldg. 51, Rm. 5150
Silver Spring, MD 20993-0002

RE: Docket No. FDA-2018-N-1072 for “International Drug Scheduling; Convention on Psychotropic Substances; Single Convention on Narcotic Drugs; Cannabis Plant and Resin; Extracts and Tinctures of Cannabis; Delta-9-Tetrahydrocannabinol (THC); Stereoisomers of THC; Cannabidiol; Request for Comments.”

Dear Sirs/Madams:

On behalf of our organization, SafeMinds, we are writing to ask the Food and Drug Administration, on behalf of the U.S. Department of Health and Human Services (HHS), to request that the World Health Organization (WHO), through its Expert Committee on Drug Dependence (ECDD), reconsider its control policies on cannabis and products derived from cannabis. We are advocating for the rescheduling of these products from Schedule 1 to Schedule IV substances as defined by WHO, or for the removal of cannabis and products derived from cannabis from the controlled substance schedule completely. We support this policy change due to the potentially high therapeutic benefits which cannabis in its many forms may hold for people with an autism spectrum disorder. Further, rescheduling cannabis will enhance public health, rather than pose a higher risk to it.

SafeMinds (safeminds.org) is a national 501 (c)3 nonprofit focusing on preventing the development of moderate to severe autism and finding effective treatments for autism. We are a parent-led organization with ongoing interactions with caregivers of people with autism and with scientists and clinicians working to address autism. Autism prevalence is growing, including more severe presentations of the disorder.^1,2  While autism is defined as deficits in social communication and restricted interests, nearly all individuals with autism have multiple co-occurring conditions, including problems with sleep, aggression, self-injury, cognitive impairment, seizures, gastrointestinal problems, and hyperactivity.^3–6

Many parents of young and adult children with autism, as well as more independent adults with autism themselves, are trying cannabis to address these myriad symptoms and behaviors. They are reporting meaningful improvements.^7-9 Scientific research suggests reasons why cannabis may be of therapeutic benefit for autism. Converging lines of evidence from animal models of autism and biological studies of affected individuals suggest alterations in the endocannabinoid system, inflammation, and oxidative stress in many cases of autism.^10-17 Phytocannabinoids and their synthetic mimetics may ameliorate these conditions.^18-21 Research is showing effectiveness of cannabis compounds in addressing co-occurring conditions like seizures, sleep disorders, and gastrointestinal problems.^22-25 Studies are also showing that cannabis does not impair cognitive function,²⁶ and in fact can enhance cognitive ability and social function for those who have deficits in these areas.^{23, 27-29} Preliminary observational and case studies are reporting that cannabis can reduce aggression and self-injury, two potentially life-threatening behaviors that have few approved medications.^22,30,31 Existing medications to address these behaviors frequently have significant side effects which may be worse than any associated with therapeutic cannabis use.^32,33

Some parents are finding that whole plant formulations with high CBD but also some THC work best. Their observations suggest that the optimal ratio of CBD to THC depends on the symptom or behavior targeted, and that CBD alone may be less effective depending on the outcome targeted. Their observations may possibly be due to the entourage effect.³⁵⁴³⁵ Thus, it is important that all types of cannabis and cannabinoid substances be reclassified to Schedule IV or are de-classified, so that research and clinical practice can proceed to identify the formulation and presentation that works best for the individual or underlying pathology, which is the goal of personalized and precision medicine.

Parents and adult self-treaters with autism need professional guidance based on evidence and the ability to access the widest variety of cannabis and cannabinoid options. Classifying cannabis and cannabis-derived products as Schedule I has the following negative consequences for persons with autism:

(a) Severely limits research activity in the United States. Researchers are hindered in obtaining Federal/NIH funding and have burdensome, expensive, and restrictive regulations securing cannabis products for studies. Our excellent research institutions are falling behind as the advanced studies are going to other countries.

(b) Prevents qualified U.S. health care professionals from helping their patients with autism integrate cannabis into treatment plans because the Drug Enforcement Administration  (DEA) would suspend their prescribing license.

(c) Prevents parents and adult self-treaters from identifying the formulation which will have the greatest therapeutic benefit and the least side effects for the individual. Finding the right regimen almost always involves iterative adjustments in dosing and formulations. The current Schedule I classification prevents access to the widest variety of options.

The lack of adequate evidence, barriers to health care access, and limitations on treatment access from a Schedule I classification impose greater public health risks than Schedule IV or decontrol options for our community.

We thank the FDA and HHS for considering the interests of the autism community as they prepare a scientific and medical evaluation of cannabis and cannabinoid substances, responsive to the WHO Questionnaire request for these substances, for WHO’s consideration in deciding whether to recommend changes to the international control/decontrol of these substances. In sum, we believe that public health will be served by reclassifying these substances to Schedule IV or removing them from the controlled substances list.

Sincerely,

Sallie Bernard
Board President, SafeMinds

Lisa Wiederlight
Executive Director, SafeMinds

References

1. Nevison CD. A comparison of temporal trends in United States autism prevalence to trends in suspected environmental factors. Environ Health. 2014 Sep 5;13:73. doi: 10.1186/1476-069X-13-73.
2. Autism Society of San Francisco Bay Area. Autism Rising. A Report on the Increasing Autism Rates in California. April 2015.
3. N. Soke, · M. J. Maenner, · D. Christensen,· M. Kurzius‐Spencer, · L. A. Schieve. Prevalence of Co-occurring Medical and Behavioral Conditions/ Symptoms Among 4- and 8-Year-Old Children with Autism Spectrum Disorder in Selected Areas of the United States in 2010. Journal of Autism and Developmental Disorders
4. Frye and Rossignol. Identification and Treatment of Pathophysiological Comorbidities of Autism Spectrum Disorder to Achieve Optimal Outcomes. Clinical Medicine Insights: Pediatrics 2016:10 43–56 doi: 10.4137/CMPed.s38337.
5. Stephen M Kanne, Micah Mazurek, Micah Mazurek. Aggression in Children and Adolescents with ASD: Prevalence and Risk Factors. October 2010Journal of Autism and Developmental Disorders 41(7):926-37. DOI10.1007/s10803-010-1118-4=
6. Maunoo Lee, Jayasree Krishnamurthy, Apry Susi, Carolyn Sullivan, Gregory H. Gorman, Elizabeth Hisle-Gorman, Christine R. Erdie-Lalena, Cade M. Nylund. Association of Autism Spectrum Disorders and Inflammatory Bowel Disease. Journal of Autism and Developmental Disorders. May 2018, Volume 48, Issue 5, pp 1523–1529
7. WPA4A – Whole Plant Access for Autism. Testimonials.
8. Michael Williams. Medical marijuana used to treat autism-related disorders. 10:56 PM, Feb 5, 2018. https://www.wptv.com/news/health/autism-and-medical-marijuana-1
9. Autism Parent Magazine. Benefits of Medical Marijuana and Autism to Be Studied. January 26, 2018.
10. Bhismadev Chakrabarti, Antonio Persico, Natalia Battista, Mauro Maccarrone. Endocannabinoid Signaling in Autism. NeurotherapeuticsOctober 2015, Volume 12, Issue 4, pp 837–847. https://link.springer.com/article/10.1007/s13311-015-0371-9
11. Debra S. Karhson, Karolina M. Krasinska, Jamie Ahloy Dallaire, Robin A. Libove, Jennifer M. Phillips, Allis S. Chien, Joseph P. Garner, Antonio Y. Hardan and Karen J. Parker. Plasma anandamide concentrations are lower in children with autism spectrum disorder. Molecular Autism 2018, 9:18 | Published on: 12 March 2018.
12. Anna Lisa Brigida, Stephen Schultz, Mariana Cascone, Nicola Antonucci, and Dario Siniscalco. Endocannabinod Signal Dysregulation in Autism Spectrum Disorders: A Correlation Link between Inflammatory State and Neuro-Immune Alterations. Int J Mol Sci. 2017 Jul; 18(7): 1425. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5535916/
13. Alterations in the endocannabinoid system in the rat valproic acid model of autism. Kerr DM1, Downey L, Conboy M, Finn DP, Roche M. Behav Brain Res. 2013 Jul 15;249:124-32.
14. Csaba Földy, Robert C. Malenka, and Thomas C. Südhof. Autism-Associated Neuroligin-3 Mutations Commonly Disrupt Tonic Endocannabinoid Signaling Neuron. 2013 May 8; 78(3): 498–509. doi:10.1016/j.neuron.2013.02.036.
15. Siniscalco D, Sapone A, Giordano C, Cirillo A, de Magistris L, Rossi F, et al. Cannabinoid receptor type 2, but not type 1, is up-regulated in peripheral blood mononuclear cells of children affected by autistic disorders. J Autism Dev Disord. 2013;43:2686–95.
16. Kwang-Mook Jung, Marja Sepers, Christopher M. Henstridge, Olivier Lassalle, Daniela Neuhofer, Henry Martin, Melanie Ginger, Andreas Frick, Nicholas V. DiPatrizio, Ken Mackie, Istvan Katona, Daniele Piomelli & Olivier J. Manzoni. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nature Communications volume 3, Article number: 1080 (2012). doi:10.1038/ncomms2045.
17. M. DOENNI, J.M. GRAY, C.M. SONG, S. PATEL, M.N. HILL, and Q.J. PITTMAN. Deficient Adolescent Social Behavior Following Early-Life Inflammation is Ameliorated by Augmentation of Anandamide Signaling. Brain Behav Immun. 2016 Nov; 58: 237–247. Published online 2016 Jul 21. doi: 10.1016/j.bbi.2016.07.152
18. Corbus Pharmacetucials. Lenabasum Mechanism of Action.
19. Paloczi J, Varga ZV, Hasko G, Pacher P. Neuroprotection in Oxidative Stress-Related Neurodegenerative Diseases: Role of Endocannabinoid System Modulation. Antioxid Redox Signal. 2017 Jul 18. doi: 10.1089/ars.2017.7144
20. Kerr DM, Gilmartin A, Roche M. Pharmacological inhibition of fatty acid amide hydrolase attenuates social behavioural deficits in male rats prenatally exposed to valproic acid. Pharmacol Res. 2016;113:228–35.
21. Siniscalco D, Bradstreet JJ, Cirillo A, Antonucci N. The in vitro GcMAF effects on endocannabinoid system transcriptionomics, receptor formation, and cell activity of autism-derived macrophages. Journal of Neuroinflammation. 2014;11:78. doi:10.1186/1742-2094-11-78.
22. Adi Aran, Hanoch Cassuto, Asael Lubotzky. Cannabidiol Based Medical Cannabis in Children with Autism- a Retrospective Feasibility Study (P3.318). Neurology Apr 2018, 90 (15 Supplement) P3.318 http://n.neurology.org/content/90/15_Supplement/P3.318
23. Kuester, G. et al. Oral cannabis extracts as a promising treatment for the core symptoms of autism spectrum disorder: Preliminary experience in Chilean patients. Journal of the Neurological Sciences, Volume 381 , 932 – 933.
24. Elizabeth A Thiele, Eric D Marsh, Jacqueline A French, et al. Cannabidiol in patients with seizures associated with Lennox-Gastaut syndrome (GWPCARE4): a randomised, double-blind, placebo-controlled phase 3 trial. The Lancet. Volume 391, No. 10125, p1085–1096, 17 March 2018
25. Roger G. Pertwee. Targeting the endocannabinoid system with cannabinoid receptor agonists: pharmacological strategies and therapeutic possibilities. Review. Phil. Trans. R. Soc. B (2012) 367, 3353–3363 doi:10.1098/rstb.2011.0381
26. Cobb Scott, Samantha T. Slomiak, Jason D. Jones, et al. Association of Cannabis With Cognitive Functioning in Adolescents and Young Adults. A Systematic Review and Meta-analysis. JAMA Psychiatry. Published online April 18, 2018. doi:10.1001/jamapsychiatry.2018.0335.
27. Ashleigh L Osborne, Nadia Solowij, Ilijana Babic, Xu-Feng Huang & Katrina Weston-Green. Improved Social Interaction, Recognition and Working Memory with Cannabidiol Treatment in a Prenatal Infection (poly I:C) Rat Model. Neuropsychopharmacology volume 42, pages 1447–1457 (2017).
28. Wei D, Dinh D, Lee D, Li D, Anguren A, Moreno-Sanz G, et al. Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment. Cannabis Cannabinoid Res [Internet]. 2016 [cited 2016 Mar 18];1:81–89.
29. D S Karhson, A Y Hardan, and K J Parker. Endocannabinoid signaling in social functioning: an RDoC perspective. Transl Psychiatry. 2016 Sep; 6(9): e905. Published online 2016 Sep 27. doi: 1038/tp.2016.169.
30. Kurz R, Blaas K. Use of dronabinol (delta-9-THC) in autism: A prospective single-case- study with an early infantile autistic child. Cannabinoids. 2010;5(4):4–6
31. Kruger T, Christophersen E. An open label study of the use of dronabinol (Marinol) in the management of treatment-resistant self-injurious behavior in 10 retarded adolescent patients. J Dev Behav Pediatr. 2006;27(5):433
32. Sinead Brophy. Antipsychotics used to manage autism and intellectual disability behaviour can have serious side effects – new study. April 4, 2018 4.45am EDT.
33. Sinead Brophy, Jonathan Kennedy, Fabiola Fernandez-Gutierrez, Ann John, Robert Potter, Christine Linehan and Michael Kerr. Characteristics of Children Prescribed Antipsychotics: Analysis of Routinely Collected Data. JOURNAL OF CHILD AND ADOLESCENT PSYCHOPHARMACOLOGY Volume 28, Number 3, 2018. Pp. 180–191. DOI: 10.1089/cap.2017.0003
34. Ethan B Russo. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. Br J Pharmacol. 2011 Aug; 163(7): 1344–1364. doi: 1111/j.1476-5381.2011.01238.x
35. Turner SE, Williams CM, Iversen, Whalley BJ. Molecular Pharmacology of Phytocannabinoids. Prog Chem Org Nat Prod. 2017;103:61-101. doi: 10.1007/978-3-319-45541-9_3.