Medicinal cannabis use among PLWH in the era of legalization

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1 Medicinal cannabis use among PLWH in the era of legalization June 8, 2017 David Grelotti, MD Assistant Professor University of California, San Diego Center for Medicinal Cannabis Research

2 Outline Overview of medicinal cannabis Studies of medicinal cannabis in HIV Guidance for patients interested in using medicinal cannabis

3 Question 1 What best describes the intended impact of medicinal cannabis on patient health and functioning? A. Negative impact B. No impact C. Positive impact Source:Harwick et al. in preparation

4 Cannabis Different sources of cannabis - Personal, Retail, Illicit, Pharmaceutical Different types of cannabis users - Casual: I will take a hit if it s around - Therapeutic: I use it because it helps with my pain - Intentional: I use girl scout cookies to help me sleep, and CBD oil before a presentation at work Different impact on functioning - No impact (some recreational use) - Positive impact (ideally all medicinal use) - Negative impact (abuse, dependence, etc.) Source:Harwick et al. in preparation

5 Cannabis: not a new medicine

6 Possible therapeutic benefits 1913 Pain relief (analgesia) Neurologic disorders (antispasmodic) Sleep (hypnotic) Today Neuropathic pain Multiple sclerosis / Parkinson disease Sleep Nausea and vomiting Appetite stimulation Psychiatric disorders IBD / Inflammation Epilepsy And counting

7 Medicinal cannabis CA Medical Marijuana Laws Pursuant to the Compassionate Use Act of 1996 (Prop 215) - Legalized medical marijuana - Allowed physicians to recommend marijuana and avoid facing disciplinary action Medical Cannabis Regulation and Safety Act (2015) - Regulates the medical marijuana industry Control, Regulate and Tax Adult Use of Marijuana Act (Prop 64) - Legalized marijuana for adults 21 or older

8 Question 2 True or False: People who use medicinal cannabis do not also enjoy the high. A. True B. False

9 Medicinal cannabis People found it helpful - Including people living with HIV (PLWH) 143/523 persons in urban HIV clinic (27%) More likely to be male (29% vs. 9%) More likely to be disabled (90% vs. 58%) Lived longer with HIV (10 years vs. 7 years)

10 Medicinal cannabis use in PLWH Percent (%) Reason for use (n=143)

11 Medicinal cannabis use in PLWH Much better Lack of appetite Pain in muscles Nausea Anxiety Nerve pain Depression Tingling Better Numbness Weight loss Headaches Tremor Worse Memory loss Speech (slurred) Source: Woolridge, et al. 2005

12 Medicinal cannabis People found it helpful Political shifts toward favoring access - Medicinal cannabis legal in 29 states and DC - Recreational cannabis use legal in 8 states and DC

13 Legalization of marijuana * * * * NCSL.org 2017

14 Medicinal cannabis People found it helpful Political shifts toward favoring access Discovery of the endocannabinoid system

15 Endocannabinoid system Cannabinoids act on human cannabinoid receptors 1 and 2 (CB1 and CB2) In the brain, they slow neurons down when they get excited Elphick & Egertova, Phil T

16 Synaptic activity 1. Cannabinoid interacts with CB1 on presynaptic neuron 2. CB1 activation inhibits adenylyl cyclase and decreases cellular cyclic adenosine monophosphate (camp) 3. Reduces membrane potentials 4. Inhibits neurotransmitter release Guzman, Nature Reviews Cancer 2003

17 Question 3 Which of the following are plantderived cannabinoids? A. Anandamide and 2-arachidonoylglycerol B. 9-delta-tetrahyrdocannabinol and cannabidiol C. Dronabinol and nabilone

18 Endogenous cannabinoids - Anandamide - 2-arachidonoylglycerol Phytocannabinoids (Plantderived) - 9-deltatetrahyrdocannabinol (THC) - Cannabidiol Synthetic cannabinoids - Dronabinol (synthetic THC) - K2, Spice, and approximately 100 others Cannabinoids

19 Cannabidiol - CBD Does not appear to be associated with a high or cognitive impairment, unlike THC Many known and theoretical benefits: - Anti-inflammatory - Analgesia - Anti-nausea - Hypnotic and sedative - Antipsychotic - Anticonvulsive - Neuro-protective - Anxiolytic

20 THC Therapeutic effects Psychoactive effects: high / euphoria Adverse effects: - Cognition - Anxiety - Psychosis - Balance

21 Cannabis and T-cells No impact on CD4 or CD8 count No impact on viral load Source: Abrams, et al & 2003

22 Cannabis and ART In vitro evidence of inhibition of CYP3A and SYP2C Statistically significant reductions in indinavir (but not nelfinavir) concentrations in vivo suggests induction of P-450 enzymes Kosel et al. 2002

23 THC helps PLWH gain weight Daily marijuana or dronabinol over 8 days. Bioelectrical impedance analysis (BIA) is a measure of muscle mass. Source: Haney, et al. Psychopharmacology 2005

24 Cannabis helps PLWH sleep Dronabinol (5 and 10 mg) and marijuana (2.0% and 3.9%) administered 4 times daily for 4 days, but only 1 drug was active per day Source: Haney et al. JAIDS 2007

25 University of California Center for Medicinal Cannabis Research (CMCR) Igor Grant, M.D., Director J. Hampton Atkinson, MD & Tom Marcotte, PhD, Co-Directors Barth Wilsey, MD, Ron Ellis, MD, PhD, Mark Wallace, MD, Robert Fitzgerald, PhD, David Grelotti, MD, Investigators; Ben Gouaux and Jennifer Marquie Beck, Senior Staff Established in

26 Cannabis improves HIV neuropathy Smoking Wash-out Smoking Placebo controlled double blind randomized crossover trial of 1 8% THC and placebo MJ cigarettes administered 4x/day for 5 days. Source: EllisI et al. Neuropsychopharmacology 2009

Cannabis improves HIV neuropathy 7-day Outpatient Pre-Intervention 2-day Inpatient Lead-In 5-day Inpatient Intervention 7-day Outpatient Post-Intervention Hospital admission First cigarette

27 Cannabis improves HIV neuropathy 7-day Outpatient Pre-Intervention 2-day Inpatient Lead-In 5-day Inpatient Intervention 7-day Outpatient Post-Intervention Hospital admission First cigarette Last cigarette Placebo controlled double blind randomized trial of 4% THC containing vs 0%THC MJ cigarettes administered 3x/day for 5 days. Source: Abrams, D. I. et al. Neurology 2007;68:

28 Common Analgesics for Neuropathic Pain Number Needed to Treat Tricyclics 2.2 Cannabis 3.6 Gabapentin 3.7 Lamotrigine 5.4 SSRIs *Number Needed to Treat to to achieve a 30% reduction in pain.

29 Completed CMCR Studies SITE DISORDER DESIGN N DOSE (% THC) Result UCSD Mark Wallace Healthy Volunteers (Experimentally-Induced Pain) Crossover RCT 15 0%, 2%, 4%, 8% + UCSF Donald Abrams HIV Neuropathy, Experimental Pain Parallel Groups RCT 50 0%, 3.5% + UCSD Ronald Ellis HIV Neuropathy Crossover RCT 28 0%, 1-8% + UCD Barth Wilsey Neuropathic Pain, Experimental Pain Crossover RCT 33 0%, 3.5%, 7% + UCD Barth Wilsey Neuropathic Pain Crossover RCT 39 0%, 1.29%, 3.53% (Vaporized) + UCSD Jody Corey- Bloom MS Spasticity Crossover RCT 30 0%, 4% + UCSD Mark Wallace Diabetic Neuropathy Crossover RCT 16 0%, 2%, 4%, 7% +

30 Summary of CMCR Studies Cannabis helps neuropathic pain from many different conditions just as much as other therapies The side effects were generally mild: - Feeling high - Fatigue / sedation - Increased heart rate - Dizziness - Cough / throat irritation Temporary impact on memory, sense of time, planning and executing tasks just as much as benzodiazepines, and antispasm, antiepileptic drugs

31 Cannabis-associated harms Conclusive Moderate Limited Respiratory symptoms and more frequent chronic bronchitis episodes Overdose injuries, including respiratory distress, among pediatric populations Non-seminoma-type testicular germ cell tumors Motor vehicle crashes Lower newborn birth wt Myocardial infarction Development of schizophrenia or other psychoses *Less high school completion Mood, anxious, suicidal ideation, and suicide completion Other substance abuse Ischemic stroke or subarachnoid hemorrhage Pregnancy complications COPD NAS 2017

32 Favorable clinical trials of cannabis Conclusive Moderate Limited Chronic pain Sleep (short-term) HIV/AIDS wasting Nausea Spasticity in multiple sclerosis (patient report) *Severe intractable epilepsy (cannabidiol) Tourette syndrome Spasticity in multiple sclerosis (clinician rating) Anxiety related to public speaking (cannabidiol) PTSD Outcomes after TBI *Schizophrenia (cannabidiol) NAS 2017

33 Rescheduling cannabis Effort to reschedule cannabis from Schedule I to Schedule II failed in DEA/FDA rejected citing: The potential for abuse The need for more research establishing its efficacy The need for dose standardization and a method for drug delivery that avoids smoking Making a recommendation for marijuana may trigger federal action DEA 2016

34 Recommending cannabis Follow state legal guidelines Establish a physician-patient relationship - An ongoing commitment to patient, such as an attending physician - No prescribing to yourself or a family member Conduct a patient examination Establish a specific indication (qualifying condition) Provide a forum for informed, shared decision making Create a treatment agreement Provide ongoing monitoring Assure consultation and referral is available Maintain adequate medical records Avoid conflicts of interest Federation of State Medical Boards 2016

35 Cannabis dosing Depends on the method of use - State recommendations for oral THC dosing WA and CO: No more than 10 mg THC initially OR: No more than 5 mg THC initially Wide variations in CBD dosing Oral doses less than 30 mg are available at dispensaries Oral doses as high as 1200 mg/day have been used in clinical trials - Inhalation ad libitum

36 Pharmacokinetics of cannabis THC blood concentration (μg/l) Smoking, Vaporization, or ingestion Time (Hours) Newmeyer, et al. 2016

37 Cannabis dosing Depends on the source of the cannabis - Retail cannabis products available from growers / dispensaries Variability between units Variability within units Depends on how experienced the user is - Some novice users have anxiety, panic, psychosis, hypotension and other side effects EVIOlabs, Oregon 2017

38 Start with low doses Low doses of THC are equianalgesic Doses may be therapeutic and not produce a high Wilsey et al. 2013

39 Treatment agreement Keep in secure location Consult doctor if start using cannabis recreationally Abstain if pregnant Abstain if heart disease or heart rhythm problem Abstain if serious mental illness Minimize exposure to smoke Do not use in public unless legal Do not drive a car or operate machinery for 3-4 hours after using Use minimal amount of cannabis to achieve relief Consider dronabinol Look out for withdrawal Re-evaluate regularly Avoid combining with narcotics, sedatives, and alcohol Wilsey et al. 2015

40 Summary Cannabis has many known and putative benefits for PLWH Cannabis can t be prescribed in a traditional sense, but providers can provide guidance on its use - Discuss the potential benefits and side effects - Describe the differences between oral use and inhalation - Start low, go slow until you know how it affects you - Use a medicinal cannabis treatment agreement to review key safety concerns

41 Resources The Health Effects of Cannabis and Cannabinoids. National Academies of Sciences, Engineering, and Medicine (Free): - Wilsey, et al. (2015) The Medicinal Cannabis Treatment Agreement: Providing Information to Chronic Pain Patients Through a Written Document. Clin J Pain. The University of California Center for Medicinal Cannabis Research (Free / Link to Research):

42 University of California Center for Medicinal Cannabis Research (CMCR) Thank you!

Medical Marijuana Martin P. Eason MD, JD Associate Chief of Staff for Education Mountain Home VA Medical Center. Disclosure.

Medical Marijuana Martin P. Eason MD, JD Associate Chief of Staff for Education Mountain Home VA Medical Center Controversies in Pain Management Conference Johnson City, TN November 13, 2015 Disclosure