Medical Marijuana

What’s the Buzz?

THC vs CBD?

Alan Kaplan MD CCFP(EM) FCFP

Pain Consultant

• Faculty: Alan Kaplan MD CCFP(EM) FCFP

• Chair Family Physician Airways Group of Canada

• Past Chair of Special Interest Focused Practice, College

of Family Physicians in Respiratory Medicine

• Chronic Pain Consultant

• Relationships with commercial interests:

– Have given one talk for Cannimed in March 2018

Faculty/Presenter Disclosure

• This program has received no financial support .

• This program has received no in-kind support.

• Potential for conflict(s) of interest:

– A) there are no organizations supporting this program

– B) I have given one talk for Cannimed in March 2018

– C) EVERY DAY, I see patients admitted to hospital with the

untoward effects of THC

Disclosure of Commercial Support

My bias is that smoking is BAD and is the major cause of preventable deaths

I want to help patients manage their pain in a safe way

Mitigating Potential Bias

Objectives

a) Understand the pros and cons of

prescribing medical marijuana

b) Understand the difference between

CBD and THC

c) Understand where to place medical

marijuana in your pain management

strategies

History

History

Evidence from 3rd millenium BC

Shakespeare might have used cannabis

Queen Victoria- menstrual cramps

Criminalized in 1906 (USA-DC)

7

CBD/THC Relationship

Over 80 different cannabinoids in the cannabis plant influences effects Cannabinol, terpenes, terpenoids, flavenoids

Main active ingredients are THC (tetrahydrocannabinol) and CBD (cannabidiol)

Provide different potency and therapeutic effects

React differently with each person’s biochemistry and therefore have different potential for adverse or undesired effects

Health Canada. Information for Health Care Professionals: Cannabis (marihuana, marijuana) and the cannabinoids

[Health Canada, 2013]. at http://www.hc-sc.gc.ca/dhp-mps/marihuana/med/infoprof-eng.php

8

Natural Antagonism

CBD

no (or less) euphoria

anti-anxiety

anti-psychotic

Neuroprotective

Anti-inflammatory

bradycardia

Loss of antagonism may lead to

increased side effects and poor tolerability.

THC

euphoria

anxiety

psychosis

cognitive impairment

tachycardia

Cannabidiol (CBD)

• Non-psychoactive cannabinoid?

• Second most common cannabinoid after THC

• Present in hemp

• Has unusual ability to antagonize CB1 receptors at a low nM

levels in presence of THC, despite having little binding affinity

• Can potentially modulate the effects on THC associated

adverse events, such as memory impairment

10

Russo EB. Taming THC: potential cannabis synergy and phytocannabinoid-terpenoid entourage effects. British Journal of

Pharmacology. 2011;163(7):1344-1364. doi:10.1111/j.1476-5381.2011.01238.x.

CBD for psychosis??

Maybe CBD does not cause as much psychosis?? Treatment strategy???

http://www.drugabuse.gov/publications/research-reports/marijuana/how-does-marijuana-produce-its-

effects

Effects of Drug Use on the

Hippocampus

Drugs of abuse are potent negative regulators of adult

neurogenesis in the hippocampus

Chronic administration of opiates, THC, ethanol or nicotine

decreases hippocampal function, decreasing ability of adult

brain to adapt to new information

Regional Brain Abnormalities Associated

with Long-term heavy Cannabis Use Arch

Gen Psychiatry 2008;65:694-701

15 long term (>10 years) and heavy (>5 joints daily) cannabis using men compared with 16 age matched non using controls by MRIs of brains

Cannabis users had bilaterally reduced hippocampal and amygdala volumes p=.001

Increase in positive symptoms (psychotic) p<.001

Significantly worse performance on measures of verbal learning p<.001

Are Cannabinoids Addicting?

Both heroin and cannabinoids increase dopamine levels

in the nucleus accumbens

This effect is blocked by naloxone

When chronic THC use is stopped, the secretion of

“stress” chemicals in the brain is similar to withdrawal

from alcohol, cocaine or opioids

Therefore THC behaves similar to other addicting drug

Gianluigi, et al. Science 1997; 276:2048-2050

Rodriguez de Fonseca, et al. Science 1997; 276: 2050-52

Le Bec et al. Encephale 2009; 35(4): 377-85

00

5050

100100

150150

200200

00 6060 120120 180180

Time (min)Time (min)

% o

f B

as

al D

A O

utp

ut

% o

f B

as

al D

A O

utp

ut

NAc shellNAc shell

EmptyEmpty

BoxBox FeedingFeeding

Source: Di Chiara et al.Source: Di Chiara et al.

FOODFOOD

100100

150150

200200

DA

Co

nc

en

tra

tio

n (

% B

as

eli

ne

)D

A C

on

ce

ntr

ati

on

(%

Ba

se

lin

e)

MountsMountsIntromissionsIntromissionsEjaculationsEjaculations

1515

00

55

1010

Co

pu

latio

n F

req

uen

cy

Co

pu

latio

n F

req

uen

cy

Sample

Number

Sample

Number

11 22 33 44 55 66 77 88 99 1010 1111 1212 1313 1414 1515 1616 1717

ScrScrScrScr

BasBasFemale 1 PresentFemale 1 Present

ScrScrFemale 2 PresentFemale 2 Present

ScrScr

Source: Fiorino and PhillipsSource: Fiorino and Phillips

SEXSEX

Natural Rewards Elevate Dopamine LevelsNatural Rewards Elevate Dopamine Levels

00

100100

200200

300300

400400

500500

600600

700700

800800

900900

10001000

11001100

00 11 22 33 44 5 hr5 hr

Time After AmphetamineTime After Amphetamine

% o

f B

as

al R

ele

as

e%

of

Bas

al R

ele

as

e

DADADOPACDOPACHVAHVA

AccumbensAccumbens AMPHETAMINEAMPHETAMINE

00

100100

150150

200200

250250

00 11 22 3 hr3 hr

Time After NicotineTime After Nicotine

% o

f B

as

al R

ele

as

e%

of

Bas

al R

ele

as

e

AccumbensAccumbensCaudateCaudate

NICOTINENICOTINE

Source: Di Chiara and ImperatoSource: Di Chiara and Imperato

Effects of Drugs on Dopamine LevelsEffects of Drugs on Dopamine Levels

THC/Marijuana

00

100100

150150

200200

250250

00 11 22 33 44 5hr5hrTime After MorphineTime After Morphine

% o

f B

as

al R

ele

as

e%

of

Bas

al R

ele

as

e

AccumbensAccumbens

0.50.51.01.02.52.51010

Dose (mg/kg)Dose (mg/kg)

MORPHINEMORPHINE

Cannabis Dependency

Percentage of people who

have ever used drug

Percentage of users

who became dependent

Tobacco

Alcohol

Cocaine

Heroin

46%

2%

16%

Marijuana(Cannabinoids)

Tranquilizers (and other

prescription drugs)

13%

92%

76% 32%

15%

9%

9%

17%

23%

Adverse Effects: Short-term anxiety, panic attacks

distorted perception, hallucinations

Cannabis use is associated with psychosis especially when started in the teenage years

This increased risk may be as much as 2 – 4 fold

increased heart rate and blood pressure

decreased memory & learning

difficulty thinking & problem solving

decreased coordination

visuomotor skills deficit

*Actual impairment persists past perceived impairment*

*Effects primarily associated with THC*

What about Driving?

Some evidence that marijuana use is associated with an

increased risk of motor vehicle accidents

It is illegal to drive in Ontario after smoking marijuana

No data exists regarding what is a safe dose of medical

marijuana to drive

This also may vary depending upon the strain

Effects of smoked marijuana last about 3 – 4 hours so

prudent not to drive for at least 4 hours after smoking

marijuana

POT CHECK!

immunosuppression

inhalation: increased risk cancer of head, neck, lungs, respiratory tract

increased risk testicular cancer

occlusion brain arteries, increased stroke

oculomotor control deficit

hyperemesis syndrome

testosterone suppression and possible impotence.

can increase prolactin in women leading to potential problems with ovulation and fertility

Adverse Effects: Long-term“associated with”

Adverse Effects: Long-term, cont.“associated with”

Neurological changes

sustained decreased IQ

adolescents: change in neuroanatomy?

altered memory, esp verbal

decreased cerebral blood flow

decreased neural efficiency

increased DA neurotransmission, psychosis, anxiety

disorder(s), schizophrenia

+ genetics mental illnessyounger age +

extent of use

Cannabinoid Hyperemesis Syndrome

chronic heavy users can develop severe nausea, emesis

and abdominal pain which resolves once stopping

marijuana

National Post September 1, 2017

Smoking is BAD!

No other medication uses smoke as a delivery system

Cannabis combustion produces hundreds of chemicals that are potentially toxic and carcinogenic

Worsens lung function and increases cancer risk

One joint = 8 cigarettes

Smoking, vaporizing cause rapid rise and decline in serum THC levels

Even 1-2 inhalations can cause cognitive impairment

This is unacceptable for a long-term medication

Rapid rise and fall sets up ideal addiction risk, as per Cigarette smokers

www.cfpc.ca/Dried_Cannabis_Prelim_Guidance

Cannabis and death rates Study from 1999-2010 compared 13 states with medical

cannabis laws vs. no medical cannabis laws

States with medical cannabis laws had a 24.8% lower mean

annual opioid overdose mortality rate (95% CI, -37.5% to -

9.5%; P = .003) compared with states without medical

cannabis laws1

In 2013 there were 0 deaths from marijuana2

Have to consume 1/3 your bodyweight -to 15,000 pounds of

cannabis all at once to reach the LD3

1.http://www.ncbi.nlm.nih.gov/pubmed/25154332

2. http://www.drugwarfacts.org/cms/Causes_of_Death#sthash.XRaCjZG6.dpbs

3. http://druglibrary.org/schaffer/library/mj_overdose.htm

32

Prescription Cannabinoids

Pharmaceutical agents containing synthetic

cannabinoids are available in Canada

nabilone (Cesamet®) THC only (1mg $1.55)

CBD/THC 1:1 (Sativex®)(12.25/day)

These are not medical cannabis, and are

dispensed through pharmacies

http://www.cmcia.ca/insurance-and-provincial-drug-benefit-program-

coverage/

Nabilone

Synthetic THC

Available in Canada for a number of years

Useful for sleep, pain and nausea

Should be trialed first before medical marijuana

HOWEVER, many patients cannot tolerate because of

sedation

Starting dose is usually 0.5 – 1.0 mg at night

Health Canada

“Dried marijuana is not an approved drug or medicine

in Canada. The Government of Canada does not endorse

the use of marijuana, but the courts have required

reasonable access to a legal source of marijuana when

authorized by a physician.”

Health Canada Government of Canada. Medical Use of Marijuana - Drugs and Health Products - Health Canada.

http://www.hc-sc.gc.ca/dhp-mps/marihuana/index-eng.php.

Published June 13, 2005. Accessed December 13, 2014.

Legalization of Cannabis in

Canada

In April 2017, the government of Canada introduced the Cannabis Act to legalize and regulate recreational cannabis in Canada. The act is designed to decriminalize many aspects of cannabis use and distribution whilst reducing the legal burden of minor cannabis possession charges.

The goal is to have this enacted into Canadian law by no later than July 2018.12

The act states that the current medical cannabis program in Canada will remain unchanged. At this point, it is impossible to determine what impact these changes will have on the medical cannabis patient.

Positives could include lower cannabis cost as suppliers have a larger market for cannabis products and there can be easier access to cannabis through a wider number of retail settings.

Issues include taxation of cannabis purchased through non-medical routes and a focus of LP’s on the recreational market which could limit strains and products used by some medical users.

Assessment for Medical Marijuana

Complete history and physical

Addiction assessment including an ORT

Collateral information

Urine drug testing at time of assessment

Patient agreement

Contraindicated if current

alcohol/drug misuse

Patients who report using medical

marijuana, versus patients with

similar pain conditions: Are more likely to use opioids problematically

Are more likely to use cocaine

Have worse psychosocial function

Marijuana use worsens prognosis in substance users

Aharonovich 2005, Mojarrad 2013

Contraindications/precautions to

medical marijuana

Youth < 25

Current/past hx psychosis

Active substance use disorder

Cardiovascular or respiratory disease

Mood or anxiety disorder

Pregnant/breast feeding

Pregnancy & Lactation

*very lipophilic*

Pregnancy: “Unsafe”

Lower birth weight, shorter gestational period,

abnormal startle response, tremulousness,

smaller head size, premature labor, prolonged

or arrested deliveries

Lactation: “Likely Unsafe”

Poor attention, concentration, and judgment,

problem solving difficulties, ADHD

Cannabis Dependency

Be aware that cannabis dependency does exist

Remember the 4 C’s

Loss of Control

Compulsive Use

Cravings

Use Despite Consequences.

Screening

for risk?

Screening

for risk?

The Process

Pt = patient

HCP = healthcare provider

LP = licensed producer

Pt consults authorized

HCP

HCP provides medical

document

Pt registers with LP

and places order

LP sends medical

cannabis to pt

44

Medical document

Patient and healthcare practitioner information,

Duration of the prescription (maximum of 12 months),

Daily quantity of cannabis in a number of grams, and

May include any specific product recommendations, such as limiting THC concentration or restricting to cannabis oil only (NOTE: the licensed producer may not comply with these specifications).

Dosing High CBD - up to 20: 1THC

High THC - up to 25: 0 CBD

Hybrids – anywhere in between

46

Inhalation (vaporizing? YES) Oral (oils or edibles)

THC Plasma Levels

Absorption • >95% • 10–30% (up to 50%)

Onset of Action • within seconds • 30–90 min (up to 120 min)

Duration of Action • 2–3 (up to 4) hrs • 5–8 (up to 12) hrs

Adapted from Grotenhermen F. J Cannabis Ther 2003;3:3-51.

48

Cannabinoids: Inhalation vs Oral Characteristics

Time during and after smoking (hours)

ng/mL

Time after oral ingestion (hours)

ng/mL

Note: For the purpose of image clarity, the y-axis of the Inhalation graph uses increments of 20 ng/mL and the y-axis of the Oral graph uses

increments of 5 ng/mL.

1.Abrams DI, et al. Clin Pharmacol Ther 2011;90:844-51.

2.Geffrey AL, et al. Epilepsia 2015;56:1246-51.

Drug-Drug Interactions

Pharmacokinetic

There are no clinically significant drug interactions

between cannabis and other medications

Pharmacodynamic

Noted interactions with drugs that cause similar side

effects (e.g., opioids, benzodiazepines, anticholinergic

medications, etc.)

There is potential for additive dizziness, drowsiness and

sedation

49

But!

50

And

What do I do?

Comprehensive pain assessment of pain in the patient

Pain effect, treatments, psychiatric history

Phq9, GAD 7, BPI, UDS, Substance use risk

Never a first line product for me

What do I do?

Cannabis oils, high in CBD for pain

Occasionally add in THC component for sleep at night

only!

Will use vaporizer rarely, in palliative care only, for

more rapid response to pain as the long term harms are

less relevant..

See q 1-3 months

Follow up

Conclusions

Medicinal marijuana has a number of properties that can be useful in pain management. Not all strains are the same!!

Like all treatments there is a risk benefit ratio

Are we with MM now as to opioids 25 y ago??

Proper assessment including addiction screening are essential

Apply the same goals and expectations with marijuana as you would with any other therapeutic agent

Medical marijuana is a reasonable option for some but not all chronic pain patients (especially the higher CBD ratio strains)

DO NO HARM!!

Who wants samples?

Discussion:

56