medicinal cannabis use among plwh in the era of...

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

Center for Medicinal Cannabis Research | University of California, San Diego

Outline

• Overview of medicinal cannabis

• Studies of medicinal cannabis in HIV

• Guidance for patients interested in using medicinal cannabis


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


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


Cannabis: not a new medicine


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…


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


Question 2

• True or False: People who use medicinal cannabis do not also enjoy the “high.” A. True B. False


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)


Medicinal cannabis use in PLWH

020406080

100Reason for use (n=143)

Per

cent

(%)


Medicinal cannabis use in PLWH

Much better • Lack of appetite • Pain in muscles • Nausea • Anxiety • Nerve pain • Depression • Tingling

Worse • Memory loss • Speech (slurred)

Source: Woolridge, et al. 2005

Better • Numbness • Weight loss • Headaches • Tremor


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


Legalization of marijuana

NCSL.org 2017

* *

*

*


Medicinal cannabis

• People found it helpful

• Political shifts toward favoring access

• Discovery of the endocannabinoid system


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 R S B 2001


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


Question 3

• Which of the following are plant-derived cannabinoids? A. Anandamide and 2-arachidonoylglycerol B. 9-delta-tetrahyrdocannabinol and

cannabidiol C. Dronabinol and nabilone


Cannabinoids • Endogenous cannabinoids

- Anandamide - 2-arachidonoylglycerol

• Phytocannabinoids (Plant-

derived) - 9-delta-

tetrahyrdocannabinol (THC) - Cannabidiol

• Synthetic cannabinoids

- Dronabinol (synthetic THC) - K2, Spice, and

approximately 100 others


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


THC

• Therapeutic effects • Psychoactive effects:

“high” / euphoria • Adverse effects:

- Cognition - Anxiety - Psychosis - Balance


Cannabis and T-cells • No impact on

CD4 or CD8 count

• No impact on viral load

Source: Abrams, et al. 2002 & 2003


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


THC helps PLWH gain weight

Source: Haney, et al. Psychopharmacology 2005

Daily marijuana or dronabinol over 8 days. Bioelectrical impedance analysis (BIA) is a measure of muscle mass.


Cannabis helps PLWH sleep

Source: Haney et al. JAIDS 2007

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


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 2000 www.cmcr.ucsd.edu


Cannabis improves HIV neuropathy

Source: EllisI et al. Neuropsychopharmacology 2009

Placebo controlled double blind randomized crossover trial of 1 – 8% THC and placebo MJ cigarettes administered 4x/day for 5 days.

Smoking “Wash-out” Smoking


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;68:515-521

7-day Outpatient Pre-Intervention

5-day Inpatient Intervention

7-day Outpatient Post-Intervention

Hospital admission First cigarette Last cigarette

2-day Inpatient Lead-In

Cannabis improves HIV neuropathy


*Number Needed to Treat to to achieve a 30% reduction in pain.

Common Analgesics for Neuropathic Pain

6.7

5.4

3.7

3.6

2.2

0 2 4 6 8

SSRIs

Lamotrigine

Gabapentin

Cannabis

Tricyclics

Number Needed to Treat


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% +


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


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

Mood, anxious, suicidal ideation, and suicide completion

Ischemic stroke or subarachnoid hemorrhage

*Less high school completion

Other substance abuse Pregnancy complications COPD

NAS 2017


Favorable clinical trials of cannabis

Conclusive Moderate Limited Chronic pain Sleep (short-term) HIV/AIDS wasting Nausea Tourette syndrome Spasticity in multiple sclerosis (patient report)

Spasticity in multiple sclerosis (clinician rating)

*Severe intractable epilepsy (cannabidiol)

Anxiety related to public speaking (cannabidiol) PTSD Outcomes after TBI *Schizophrenia (cannabidiol)

NAS 2017


Rescheduling cannabis

• Effort to reschedule cannabis from Schedule I to Schedule II failed in 2017 - 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


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


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”


Pharmacokinetics of cannabis

Newmeyer, et al. 2016

Time (Hours) THC

blo

od c

once

ntra

tion

(μg/

L) Smoking, Vaporization, or ingestion


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


Start with low doses

Wilsey et al. 2013

• Low doses of THC are equianalgesic • Doses may be therapeutic and not produce a high


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


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


Resources

• The Health Effects of Cannabis and Cannabinoids. National Academies of Sciences, Engineering, and Medicine (Free): - https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-

cannabinoids-the-current-state

• 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): - http://www.cmcr.ucsd.edu - [email protected]

https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state

https://www.nap.edu/catalog/24625/the-health-effects-of-cannabis-and-cannabinoids-the-current-state


University of California Center for Medicinal Cannabis

Research (CMCR)

Thank you! www.cmcr.ucsd.edu

[email protected]

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