beyond the smoke: the new era of cannabis as medicine · volcano vaporizer comparison with smoked...

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

Beyond the Smoke: The New Era of Cannabis as Medicine

Thomas D. Marcotte, PhD Center for Medicinal Cannabis Research (CMCR)

University of California, San Diego


Cannabis Legalization by State

Source: CNNMoney, 1/31/18


Prevalence of Cannabis Use

4.1

9.5

0

2

4

6

8

10

12

14

Use in Past Year

Per

cent

2001-2 2012-13

National Epidemiologic Survey on Alcohol and Related Conditions Use in Past Year (Hasin et al., 2015)

22.2 million (8.3% of the population) Americans > 12 yo used cannabis in the past month (2015 National Survey on Drug Use and Health)

Age 2001-2 2012-13

18-29 10.5% 21.2%

30-34 4.1% 10.1%

45-64 1.6% 5.9%

<65 0.0% 1.3%

Increases across all sex, race/ethnicities, educational levels, income levels, urbanicity, geographic regions


Cannabis Constituents

§  104 different cannabinoids §  Terpenoids, flavonoids, etc. §  Δ-9 THC »  Synthesized within the glandular trichomes in the

flowers, leaves, and bracts of the female plant


Cannabinoid Receptors

Two types of cannabinoid receptors: §  CB1 »  Primarily in the brain, intestine, liver »  Responsible for the psychoactive

effects §  CB2 »  Immune cells »  Reduce inflammation

© CCIC TM 2010

www.ccic.net

Distribution of CB1Receptors

• Green shading indicates distribution of cannabinoidreceptors in the body– CNS– Intestine– liver

CB1 Receptors


Distribution of CB1 Receptors in the Brain Acute Effects

© CCIC TM 2010

www.ccic.net


Endogenous Cannabinoids (Endocannabinoids)

§  Two have been identified »  Anandamide (ananda [“supreme joy” I Sanskrit]) »  2-arachidonylglycerol (2-AG)

§  Feeding, emotion, cognition, pain, reward §  eCBs can be neuroprotective


Potential Medicinal Uses of Cannabis: NIH & IOM Reviews in late 1990s

NIH Workshop on the Medical Utility of Marijuana (1997) and the Institute of Medicine (1999), identified medical conditions warranting further research regarding the possible therapeutic effects of cannabis.

§ Appetite Stimulation § Nausea and Vomiting

§ Analgesia § Neurological and Movement Disorders


California Developments: Center for Medicinal Cannabis Research

§  1996 - Compassionate Use Act §  1999 - Medical Marijuana Research Act §  2000 - CMCR established (California SB 847; Vasconcellos) §  Mission »  Facilitate high quality scientific studies »  Ascertain the safety and efficacy of cannabis and

cannabinoid products


Initial Study Locations

UCSD

UC-Davis

UC-Irvine

UCSF

San Mateo

UCLA


CMCR: Ellis et al. Reduction in HIV Neuropathic Pain 28 patients receiving active (2-8% THC) vs

placebo (0% THC) cigarettes 4x/d for 5 days

Source: Ellis, et al. Neuropsychopharmacology 2009 Feb;34(3):672-80.


CMCR: Wilsey et al. Medium and High Dose THC Demonstrated Equivalent Analgesia

Wilsey B, Marcotte T, Tsodikov A, et al. A randomized, placebo-controlled, crossover trial of cannabis cigarettes in neuropathic pain. J Pain 2008.


Source: Corey-Bloom, et al. (2012) CMAJ 184(10); 1143-1150.

Ashworth spasticity scores before and after active and placebo cannabis administration. Active treatment reduced Ashworth Total Scores by an average of 2.7 points more than placebo (p<0.0001).

Cannabis improves MS spasticity in brief placebo controlled randomized study of 30 patients receiving 0% or 4% THC (1x/d x 3 d)


Challenges in Using Smoked Cannabis as Medicine

§  Safety of combustible material in clinical setting

§  Second hand smoke as an irritant, possibly health hazard

§  Efficiency and tolerability in smoking naïve

§  Availability of cigarettes with standardized dose


Alternative Delivery Systems: Vaporization

•  Volcano •  Cannabis heated to 180°C •  Below the point of combustion

(230°C) •  Releases cannabinoids as vapor into

balloon •  Inhaled via mouthpiece attached to

balloon

STORZ & BICKEL GMBH & CO. KG


Vaporized administration yields plasma THC concentrations comparable to smoking

Plasma THC using vaporizer and smoked cannabis by THC strength (mean and 90% CI).

Source: Abrams, et al. 2007. Clin Pharmacol Ther.


Source: Abrams, et al. 2007. Clin Pharmacol Ther.

Expired CO at each time point for each mode of administration and THC strength (mean and 95% CI).

Vaporized administration produces less CO than smoking cannabis


Wilsey B, Marcotte T, Deutsch R, Gouaux B, Sakai S, Donaghe H. Low-dose vaporized cannabis significantly improves neuropathic pain. J Pain 2013

Low and Medium Dose Demonstrated Equivalent Analgesia


Initial CMCR Clinical Studies

SITE DISORDER DESIGN N DOSE (% THC) Result

UCSD Mark Wallace

Healthy Volunteers (Experimentally-Induced Pain)

Crossover RCT 15 0%, 2%, 4%, 8% +

UCSD Mark Wallace

Diabetic Neuropathy Smoked Cannabis

Crossover RCT 17 0%, 2%, 4%, 7% +

UCSD Ronald Ellis

HIV Neuropathy Smoked Cannabis

Crossover RCT 28 0%, 1-8%

+

UCSD J. Corey-Bloom

MS Spasticity Smoked Cannabis

Crossover RCT 30 0%, 4% +

UCSF Donald Abrams

HIV Neuropathy, Smoked Cannabis

Parallel Groups RCT 50 0%, 3.5% +

UCSF Donald Abrams Volcano Vaporizer

Comparison with Smoked

Cigarettes 1.7%, 3.4%, 6.8% +

UCD Barth Wilsey

Neuropathic Pain, Smoked Cigarettes

Crossover RCT 33 0%, 3.5%, 7% +

UCD Barth Wilsey

Neuropathic Pain, Vaporized Cannabis

Crossover RCT 39 0%, 1.29%, 3.53%

(Vaporized) +


New CMCR-Associated Projects

§  “Randomized Controlled Trial of Dronabinol and Vaporized Cannabis in Low Back Pain” (B. Wilsey & T. Marcotte; NIH)

§  “Effect of cannabis and endocannabinoids on HIV Neuropathic Pain” (B. Henry; NIH)

§  “Cannabis Use and the Endocannabinoid System in Bipolar Disorder” (W. Perry & J Young; NIH)

§  “Cannabidiol for the Treatment of Behavioral Abnormalities in Children with Autism Spectrum Disorders” (D. Trauner, Noorda Foundation)

§  “Assessing Cannabis-Related Driving Impairment” (T. Marcotte & B. Wilsey; State of California)


The Health Effects of Cannabis and Cannabinoids National Academies Report (2017)

§  Cannabis and cannabinoid studies since 1999 IOM report

§  Systematic reviews (since 2011) and high-quality primary research

§  Human studies (no basic nonhuman research)


Evidence for Therapeutic Benefits of Cannabis National Academies Report (2017)

§  Substantial/conclusive evidence of cannabinoid efficacy in: »  Chronic pain »  Spasticity of multiple sclerosis »  Control of nausea

§  Moderate evidence of cannabinoid efficacy in: »  Improving sleep in those with chronic medical conditions (e.g.,

chronic pain, fibromyalgia, etc.) §  Limited evidence of cannabinoid efficacy in:

»  Treatment of certain anxiety disorders and PTSD »  Promoting appetite and weight gain

§  No or insufficient evidence of cannabinoid efficacy in: »  Treatment of cancers, irritable bowel syndrome, epilepsy, movement

disorders due to Huntington Disease or Parkinson Disease, schizophrenia


Cannabis May Reduce Opioid Use States With and Without Medicinal Cannabis

Reduced Daily Doses Annually per Physician

Bradford & Bradford, 2016

Reduced Annual Medicare Spending

Lower Opioid Overdose Mortality Rates

Bachhuber et al., 2014; JAMA Internal Med

-200

-100

0 2010 2011 2012 2013

Mill

ion

$


Medicinal Cannabis Challenges Research and Implementation

§  DEA Schedule I designation §  Access to different constituents §  Access to real-world cannabis §  Public safety concerns


DEA Scheduling

§  Schedule I (No currently accepted medical use and high potential for abuse) - Heroin, LSD, Ecstasy

§  Schedule II (High potential for abuse, potentially leading to dependence) - Vicodin, cocaine, methamphetamine, methadone, fentanyl, Adderall

§  Schedule III (Moderate to low potential for physical and psychological dependence) - Tylenol with codeine, ketamine, anabolic steroids, testosterone

DEA Schedule I II III

Cannabis (plant) THC (plant-based) ✔

CBD (plant-based) ✔

Nabilone (Cesamet) THC (synthetic) ✔

Dronabinol (pills; Marinol) THC (synthetic) ✔

Dronabinol (liquid; Syndros) THC (synthetic) ✔


Current Regulatory Pathway

Revisions

RAPC FDA

NIDA

Revised Approved Proposals

DEA HQ

DEA Local

Inspection

Approval Order Product

Begin Studies

Scientific Approval

State of California Review Revisions Revisions

FDAReview

DEA Review

IND

In the United States, cannabis for research purposes is available only through the NIDA Drug Supply Program


Challenges Access to Product with Cannabinoids of Interest

NIDA has limited ability to provide cannabis with the cannabinoid ratios that are of scientific interest (e.g., THC levels representative of current markets; high CBD/low THC)

14

12

10

8

6

4

2

0 1995 2014

ElSohly et al, 2016


Cannabidiol - CBD

§  Natural component of the Cannabis plant §  Devoid of typical psychological effects of THC §  Evidence for:

»  Anti-inflammatory »  Analgesia »  Anti-nausea »  Hypnotic and sedative »  Antipsychotic »  Anticonvulsive »  Neuroprotective »  Anxiolytic

§  Antagonism of the Δ9-THC when both contents are administered concomitantly?


Devinsky et al., 2017 (NEJM)

Cannabidiol (CBD) Significantly Reduces Convulsive Seizure Frequency in Lennox-Gastaut Syndrome (LGS)

14.9 14.1 12.4

5.9

0 2 4 6 8

10 12 14 16

Baseline Treatment Num

ber o

f sei

zure

s (m

onth

ly)

Placebo CBD

•  120 children/young adults •  20 mg/kg CBD •  14-week treatment period •  % with > 50% reduction in

frequency (CBD – 43%; Placebo - 27%

•  AEs (diarrhea, vomiting, fatigue, etc.


Cannabidiol Reduced Anxiety in Simulated Public Speaking in Social Phobia Patients

-5 0 5

10 15 20 25 30 35 40

B P A S F1 F2 Phases

Anxiety

CBD 600mg

PLAC

HEALTH

-2 -1 0 1 2 3 4 5 6 7 8

B P A S F1 F2

∆ fr

om p

rete

st s

core

Phases

Negative Self-statement

CBD

PLAC

HEALTH

Bergamaschi et al., 2011

B (basal); P (pretest), A (anticipation), S (speech performance), F1 (post-speech measures 1), F2 (post-speech measures 2)


CBD improves positive and negative symptoms of schizophrenia: (42 cases randomized to receive 800 mg/d cannabidiol or amisulpride)

Leweke FM, Transl Psychiatry. 2012 Mar 20;2:e94.


Compared to atypical antipsychotic amisulpride, cannabidiol does not worsen extrapyramidal symptoms, and is not associated with

weight gain or elevated prolactin

Leweke FM, Transl Psychiatry. 2012 Mar 20;2:e94.


Challenges Examining Administration Methods

•  Non-flower products are in wide use (edibles, drinks, wax, oils, concentrates)

•  Edibles: THC-infused food (baked goods [cookies, brownies], chocolates, gummies) •  Pass through the liver (first-pass metabolism) •  THC transformed to 11-hydroxy-THC (readily crosses the blood-brain

barrier; more potent than THC) •  Hour to 1.5 hours to feel full effect


Plasma THC Levels – Smoked vs. Oral

Mean plasma concentrations of Δ9-tetrahydrocannabinol (THC), 11-hydroxy-THC (11-OH-THC) and 11-nor-9-carboxy-THC (THC-COOH) following administration smoked cannabis vs. oral dronabinol.

Source: Grotenhermen, et al. 2003. Clin Pharmacokinet 2003; 42 (4): 327-360.

Inhaled cannabis ~34mg THC 15mg oral THC (dronabinol)


Challenges Inability to Legally Access Real-World Cannabis

Unable to even analyze (e.g., true THC levels, contaminants) what is currently in use in the community, since by receiving any of the above is in violation of Federal law


Challenges Obtaining Varieties of Cannabis

§  In 2016, the DEA announced plans to increase the number of entities permitted to grow (manufacture) cannabis

§  To date, no applications (rumored to be 25+) have been approved


Cannabis and driving

§  Cognition: Reduced learning, attention, processing speed, psychomotor abilities

§  Controlled on-road/simulator studies »  Delayed reactions (brake latency) »  Poor lane tracking (standard deviation of lateral position) »  Reduced judgment of speed and distances »  Dose dependent

§  Epidemiology »  Modest increased crash risk (~ two-fold) »  State experience unclear


Impact of Legalization in Colorado •  Marijuana-related traffic deaths (marijuana “mentioned”; includes other substances) increased

48% (2013-15) compared to 2010-2012; All traffic deaths only increased 11%.

RMHIDTA, 2015

20

25

30

35

40

45

06 07 08 09 10 11 12 13 14 15

Fata

litie

s (th

ousa

nds)

National Fatalities (NHTSA, 2016)

0

1000

2000

3000

4000

5000

2009 2010 2011 2012 2013 2014

Cannabinoid Screening (Colorado)


Complex Pharmacodynamics of THC

.

Counter-clockwise Hysteresis (M. Huestis)

Poor correlation of being “high” and blood THC concentrations

THC is detectable days after smoking (in chronic users; ~30 people)

Day % detect

Median Max

Admit 90% 1.4ng 6.3ng

1 68% 1.8 2.9

2 80% 1.2 2.2

3 79% 1.3 2.6

4 79% 1.1 2.3

5 77% 1.0 1.9

6 72% 1.0 2.2

7 79% 0.9 2.0

Bergamaschi et al., 2013


Magnitude of the THC Effect Relative: SDLP (“swerving”)

0 0.5 1 1.5 2

Alprazolam (1h)[4]

ETOH (BAC = .08)[3]

Hypnotics (zolpidem; next am)[2]

Antidepressants (mirtazapine 2 days)[1]

Low-Dose Cannabis (3h postdose)

[1] Sasada et al. (2013) Human psychopharmacology; Wingen M, et al. (2005) J Clin Psychiatry; [2] Bocca et al. (2011) Psychopharmacology (Berl); [3] Mets et al. (2011) Human psychopharmacology; [4] Verster et al. (2002) Neuropsychopharmacology


Magnitude of the THC Effect : SDLP (“swerving”)

0 0.5 1 1.5 2

Alprazolam (1h)[4]

ETOH (BAC = .08)[3]

Hypnotics (zolpidem; next am)[2]

Antidepressants (mirtazapine 2 days)[1]

Low-Dose Cannabis (3h postdose)

[1] Sasada et al. (2013) Human psychopharmacology; Wingen M, et al. (2005) J Clin Psychiatry; [2] Bocca et al. (2011) Psychopharmacology (Berl); [3] Mets et al. (2011) Human psychopharmacology; [4] Verster et al. (2002) Neuropsychopharmacology


Assessing Cannabis-related Driving Impairment California Assembly Bill 266

§  Parallel design, 180 healthy participants

§  Smoke »  0% THC (n = 60) »  5.9% THC (n = 60) »  13.4% THC (n = 60)

§  Assess throughout the day »  Driving Simulations »  Standardized Field Sobriety Test/DRE assessment »  Blood, Saliva, Breath (THC, other cannabinoids/metabolites) »  Tablet-based (iPad) cognitive/motor performance


Medicinal Cannabis: Future Directions §  Impact of specific cannabinoids (THC, CBD, others), other constituents

(e.g., terpenoids), on medical outcomes

§  Effectiveness and adverse effects associate with various delivery systems (e.g., inhaled, oral, transdermal); ability to provide controlled dosing

§  Role of synthetic cannabinoids and novel modulators of the endocannabinoid system

§  Synergistic or sparing effects (opioids, benzodiazepines, alcohol)

§  Need for larger scale, longer-term clinical trials assessing benefits, and possible toxicities, including in diverse/vulnerable populations (e.g., older age, co-occurring conditions)

§  Government-sponsored research: no immediate incentive for pharma. Studies should also focus on broader social harm (abuse risk, public safety)


University of California Center for Medicinal Cannabis Research

Igor Grant, MD, Director

Co-Directors J. Hampton Atkinson, MD & Thomas D. Marcotte, PhD

Investigators Barth Wilsey, MD; Mark Wallace, MD; Ron Ellis, MD, PhD; David Grelotti, MD;

Robert Fitzgerald, PhD; Brook Henry, PhD; William Perry, PhD; Doris Trauner, MD; Jared Young, PhD Senior Staff

Jennifer Marquie-Beck, MPH, Ben Gouaux, Debra Cookson, MPH www.cmcr.ucsd.edu


Beyond the Smoke: The New Era of Cannabis as Medicine

Thomas D. Marcotte, PhD Center for Medicinal Cannabis Research (CMCR)

University of California, San Diego

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