Its High Time to

Talk about

Marijuana in

KidsWilliam T. Zempsky, MD, MPH

Disclosures

I did not inhale

Disclosures

Consultant

Pfizer

GSK

Endo Pharmaceuticals

Physicians Medical

Marijuana Board State

of CT

Its all off label

Grant Funding

DOD

NICHD

NIDDK

NIAMS

Mayday Fund

UCONN

Objectives

Discuss Connecticut medical marijuana

law

Review evidence regarding treatment of

pain and associated conditions with

marijuana

Review the data regarding marijuana use

and the adolescent brain

Debilitating Medical Conditions- over 18 Cancer Glaucoma Positive Status for Human

Immunodeficiency Virus or Acquired Immune Deficiency Syndrome

Parkinson's Disease Multiple Sclerosis Damage to the Nervous Tissue of the

Spinal Cord with Objective Neurological Indication of Intractable Spasticity

Epilepsy Cachexia Wasting Syndrome Crohn's Disease Post-Traumatic Stress Disorder Sickle Cell Disease Post Laminectomy Syndrome with Chronic

Radiculopathy Severe Psoriasis and Psoriatic Arthritis

Amyotrophic Lateral Sclerosis

Ulcerative Colitis

Complex Regional Pain Syndrome

Cerebral Palsy

Cystic Fibrosis

Irreversible Spinal Cord Injury with Objective Neurological Indication of Intractable Spasticity

Terminal Illness Requiring End-Of-Life Care

Uncontrolled Intractable Seizure Disorder

Spasticity or Neuropathic Pain Associated with Fibromyalgia

Severe Rheumatoid Arthritis

Post Herpetic Neuralgia

Hydrocephalus with Intractable Headache

Intractable Headache Syndromes

Neuropathic Facial Pain

Muscular Dystrophy

Osteogenesis Imperfecta

Chronic Neuropathic Pain Associated with Degenerative Spinal Disorders

Chronic pain recommended to be added 9/2019

Under 18

Cerebral Palsy

Cystic Fibrosis

Irreversible Spinal

Cord Injury with

Objective

Neurological

Indication of

Intractable Spasticity

Severe Epilepsy

Terminal Illness Requiring End-Of-Life Care

Uncontrolled Intractable Seizure Disorder

Muscular Dystrophy

OsteogenesisImperfecta

Patient info

$100 registration fee

Can purchase 2.5 ounces per month

Health insurers are not required to provide

coverage

One person is allowed to be certified as

primary caregiver if MD confirms

How to qualify

Step 1: The physician initiates the

registration process by logging into a

secure, online system and certifying their

patient.

Step 2: After the physician electronically

submits a valid certification, their patient

can access the online system to

complete the patient portion of the

application.

Physicians Possess an active CT medical license

Practice within CT.

Possess an active CT controlled substance registration

Possess an active DEA license

Be registered with, and able to access, the CT Prescription Monitoring Program

Register at https://www.biznet.ct.gov/dcp-mmrp

Physicians do not “prescribe” marijuana in the same way other medications are prescribed to patients. Rather, physicians may certify patient

Marijuana by the numbers

Registered patients 30,425 as of 1/13/2019

Registered Physicians 1045

Dispensaries 9- more on the way

Producers 4

1 ounce = $320-$400

Monthly max-2.5 ounces

Dispensary

“Budtenders”

Forms `

Smoked

Vaporized

Sprays

Capsules

Edibles

Topicals

Tinctures

How to use Find your ratio. Cannabis products have varying amounts of CBD and THC.

A high CBD strain or product (with little THC) is not necessarily superior to a strain or product with a more balanced CBD:THC ratio. Find the proper combination for you.

Begin with a low dose – especially if you have little or no experience with cannabis.

Take a few small doses over the course of the day rather than one big dose.

Use the same dose and ratio for several days. Observe the effects and consider if you need to adjust the ratio or amount.

Don’t overdo it. Often with cannabinoid therapeutics, “less is more.” Cannabinoid compounds have biphasic properties. This means that higher doses of CBD may not be as effective as low or moderate doses. Also, too much THC—while not lethal—can increase anxiety and mood disorders.

Consider the condition you’re treating. For anxiety, depression, spasms, and pediatric seizure disorders, you may do better with a moderate dose of a CBD-dominant remedy—look for a CBD:THC ratio of more than 14:1. For cancer or pain, you may need more THC, for instance, a 1:1 ratio.

History 2000 BC- Assyrians used Cannabis for its

psychoactive and medicinal properties ganzi-gun-nu (“the drug that takes away the

mind”

azzalu, which was apparently a drug for “depression of spirits,”

100 BC China recommended for numerous maladies, “but when

taken in excess it could cause seeing devils”

Europe Brought by Napoleonic era soldiers from mideast

English physicians from India

In the US US Pharmacopeia classified MJ as a legitimate medical

compound in 1851. Effectively criminalized in the US in 1937, against the advice

of the AMA; removed from USP in 1942. “Reefer Madness”. Currently classified as a schedule 1 substance by the FDA:

very difficult to obtain permission to study (NIDA, DEA, FDA). Ronald Reagan’s “war on drugs”. Since 1990, primary focus

has shifted to low-level MJ offenses, constituting 82% of the increase in drug arrests. Most dismissed or adjudicated misdemeanors, costing ~$4 billion per year.

IOM study 1999 – recommends that cannabinoids may have a role in the treatment of pain, movement and memory disorders, but risks are associated with use.

What is Marijuana

Cannabis Sativa, Indica

Delta-9-tetrahydrocannabinol (THC)

Psychoactive ingredient

Cannabinoids

Over 100 different compounds

Cannabidiol (CBD)

What Medical Marijuana THC analogs

Nabilone

Dronabinol

Sativex (1:1 THC:CBDs)

Epidiolex (CBD)

Medical Marijuana

Diverse compounds with different ratios of key ingredients

Consultants in each dispensary to pick correct drug.

Differences Between Medical & Street Marijuana

Pharmaceutical grade

Laboratory tested

Label and active ingredients

Unadulterated

Variety of dosage forms

Differences between medical

marijuana and other

medications

No FDA approval

Multiple active constituents

Wide range of products

Limited data for many approved

indications

Limited data on dosing

Limited data on drug-drug interactions

Endocannabinoid system

(ECS) Physiological role in

broad range of neurological and immunological functions

Endocannabinoids, the brain’s own cannabis-like substances anandamide (AEA) 2-arachidonoylglycerol

(2-AG)

May be responsible for the runner’s high!

CB1

Mostly Located in peripheral and central

nervous system

Distal ends of primary afferents

Dorsal horn of the spinal cord

Cortical regions associated with pain

processing

CB2

Mostly in immune system

Also found in CNS and PNS

Decrease release of proinflammatory mediators

THC

THC is a partial agonist,

THC activates the system in a prolonged

non-physiological manner..

Activation of CB1 & CB2 acts indirectly on

multiple other neurotransmitters, including

ACh, DA and glutamate, while indirectly

affecting NMDA, opioid and 5HT

receptors.

CBD CBD has 100-fold less affinity than THC for CB1

receptors if at all

Likely acts on different targets

Evidence from preclinical studies that CBD has anti-nocioceptive properties

Induces analgesia in a neuropathic pain model, predominantly through TRPV1 activation, reduces anxiety through 5-HT1A receptor activation

May act as a positive allosteric modulator of opioid receptors

Medical marijuana and pain

12-15 % of adults in chronic pain clinics

use marijuana for pain

Population based studies of patients with

fibromyalgia, arthritis, spinal cord injury

and MS all describe use of marijuana

90% of use of medical marijuana in

Europe and US for pain

Does Marijuana work for pain?

Does is work?

Analgesic properties CB1 agonists in a

wide array of animal models

Imaging studies demonstrate effects of

marijuana in the pain matrix

Pharma interest in CB1 and 2 agonists for

pain

Clinical Trials

Chronic Pain- 6 trials 325 patients

Neuropathic Pain-6 trials 396 patients

MS (including pain)-12 trials 1600 patients

Systematic Review

22 of 29 RCTs demonstrated modest

analgesic effect

J Neuroimmune Pharmacol DOI 10.1007/s11481-

0159600-6

Metanalysis

79 trials (6492 particpants)

Compared with placebo cannabinoids were associated with a greater average number of patients showing

reduction of pain greater average reduction in numerical rating scale

pain assessment greater number of patients showing N/V response reduction in spasticty

MODERATE QUALITY EVIDENCE to support the use of CANNABINOIDS in the treatment of CHRONIC PAIN

JAMA 2015, 313:2456-2473

Inflammatory Bowel Disease Double-blind, placebo-controlled study of THC-

rich cannabis inhalation in 21 patients with CD Complete remission (CDAI score <150) was

achieved by 5 of 11 subjects in the cannabis group (45%) and 1 of 10 in the placebo group (10%; p = 0.43).

A clinical response (a decrease in the CDAI score >100) was observed in 10 of 11 subjects in the cannabis group (90%; from 330 ± 105 to 152 ± 109) and 4 of 10 in the placebo group (40%; from 373 ±94 to 306 ± 143; p = 0.028).

Three patients in the cannabis group were weaned from steroid dependency.

Am J Gastroenterol 2015

110:208-2014

Challenges to research of

medical marijuana

No standard formulation

No standard delivery

No standard patient type

Restricted access to clinical grade material

Schedule 1 classification by FDA Substances in this schedule have no currently

accepted medical use in the United States, a lack of accepted safety for use under medical supervision, and a high potential for abuse.

Medical benefits contrary to anti-drug and anti-smoking campaigns

Safety of Medical Marijuana-

Metaanalysis

More AE’s in active drug group

More withdrawals in active drug group

No difference in incidence of AE based on type of cannabinoid

Common Short-term AE’s included

Asthenia, balance problems, confusion, dizziness, disorientation, diarrhea, euphoria, drowsiness, drymouth, fatigue, hallucination, nausea, somnolence and vomiting.

COMPASS Study 430 adults with chronic pain

50% treated with THC for 1 year Most of treated patients were cannabis experienced Smoking was most common administration method

More dropouts in THC group

No difference in SAE

Increase risk of AE’s THC group

More resp events in THC group

Neurocognitive function improved in both groups- no difference between groups

Pain reduction > in THC group

QOL improved in both groups but more in THC group

J Pain. 2015 Sep 16. pii: S1526-5900(15)00837-8. doi:

10.1016/j.jpain.2015.07.014. [Epub ahead of print]

A few more words about CBD

It is a drug

No standardization

Can contain toxins

Likely contains THC in some amount

Tox screens cant differentiate

Animal studies promising

Probably helpful for anxiety- not clear

what else

Marijuana and the teenage

brain

Within chronic

pain clinics

prevalence of

marijuana use

is12-15%

Maturation of ECS Endocannabinoid (ECS) system involved in brain

development and maturational processes

Evolves during adolescence

Axon elongation, neurogenesis, glial formation, synaptic pruning

THC activates ECS in prolonged nonphysiologicalmanner

Adolescent rat exposure results in long term alterations in ECS and neurotransmitter systems

Epidemiologic studies raise concerns about long-term cognitive impact and risk of psychosis

Impact of Marijuana Known Cannabis abuse, dependence and withdrawal

syndromes. Most commonly treated dependence do after alcohol and tobacco Lifetime risk of dependence 9% (lower than other substances) One in 6 if initiated in adolescence

Acute use- cognitive effects may last 1-several days with subtle effects up to a month later

Chronic use in adolescence associated with 8 point decline in IQ at age 38

More likely to leave school with early onset

Chronic use associated with decreased brain volume in memory centers

Impaired axonal connectivity worsened by earlier onset

Lifetime use -41% increased risk of psychosis, worse in heavy users

13% of schizophrenia prevented by elimination of all use

Unclear association with depression, anxiety

Drug Test Analysis 2014;6:39-45

In contrast

a meta-analysis of the effect of cannabis use on

global neurocognitive performance showed no

significant effect after 25 days of abstinence,

concluding that any negative effects of

cannabis on neurocognitive performance are

attributable to

either cannabis residue in the body

or withdrawal symptoms,

not to irreversible brain damage

Schreiner AM, Dunn ME: Residual effects of cannabis use on neurocognitive

performance after prolonged abstinence: a meta-analysis.

Exp Clin Psychopharmacol 2012:20:420–429.

Pain and the brain

Pain and the brain

Adolescents with chronic pain miss a significant amount of school, experience a decline in grades, and perceive pain to interfere with their school success

Present medications for the treatment of pain impact cognitive functioning and dont work that well

Long-term cognitive impact of adolescent chronic pain unknown

Other impacts of medical

marijuana

Increase in pediatric ingestions in medical

marijuana states

Call rates increase by 30%

Diversion

Common among adolescents in substance

treatment-50% in a colorado study

“sharing” of mj between parents and youth

We are not going back

Understand the risks and benefits

Ask the right questions

Make a personal decision

First do no harm