marijuana: drug of abuse or therapeutic...

Handout for the Neuroscience Education Institute (NEI) online activity:

Marijuana: Drug of Abuse or Therapeutic Option?

Learning Objectives

• Explain how cannabinoids affect the body and the brain

• Educate patients about:– Evidence of efficacy for mental health and other

conditions– Potential risks of cannabis use

Timeline

1992: Endogenous cannabinoid anandamide discovered

1995: Endogenous

cannabinoid 2-AG discovered

~2000 BC: Chinese

emperors recommend marijuana as

medicine

1851: Marijuana listed as a

medication in US Pharmacopeia

1943: Marijuana removed from

listing as a medication in US Pharmacopeia

1961: United Nations Single Convention on Narcotic Drugs:

marijuana said to be dangerous with no medical value

1970: Marijuana is labeled Schedule I

by the US Substance Abuse Act; this restricts

both personal use and access for

research purposes

2015: Elimination of US Public Health Service oversight

for obtaining marijuana for

research purposes

1963: Cannabidiol

isolated

1964: THC isolated

1989? 90?: Discovery of binding site for THC—

CB1 receptor

Aug 11 2016: DEA declines to

reschedule marijuana

THE INTERSECTION OF THE HEALTHCARE AND CANNABIS INDUSTRIES

What is Cannabis?

500 chemicals100 cannabinoidsBest understood: THC and CBD

Scheduling of Controlled Substances

Schedule I Schedule II Schedule III Schedule IV Schedule VMarijuanaHeroinLSDEcstasyMethaqualone (Quaalude)Peyote

CocaineMethamphetamineDexedrineAdderallRitalinVicodinMethadoneHydromorphoneMeperidineOxycodoneFentanyl

Tylenol w/ codeineKetamineAnabolic steroidsTestosterone

TramadolAlprazolamZolpidem

Robitussin ACLyrica

No medicinal value, high potential for

abuse

High potential for abuse

Moderate to low potential

for abuse

Low potential for abuse

Lower potential for

abuse

https://www.dea.gov/druginfo/ds.shtml

Legalization of Cannabis in the US

legal

Public Perception

121516

28 25 25 23 253134 34 36

4446

50

48

58

51

58

0

10

20

30

40

50

60

70

1969 1973 1977 1981 1985 1989 1993 1997 2001 2005 2009 2013

1. http://www.gallup.com/poll/186260/back-legal-marijuana.aspx.2. http://www.samhsa.gov/data/sites/default/files/report_2404/ShortReport-2404.html.

Do you think the use of marijuana should be made legal?1

% Y

es

% who perceive great risk of harm from monthly use2:28.5%

Cannabis is marketed as a therapeutic, medicinal product—but not developed or dispensed by health professionals

Concerns for Healthcare Professionals

Remember when cigarettes, alcohol, and heroin were marketed as therapeutic products to treat specific conditions?

Concerns for Healthcare Professionals

Concerns for Healthcare Professionals: Increasing Potency

DEA-seized materials.ElSohly MA et al. Biol Psychiatry 2016; http://dx.doi.org/10.1016/j.biopsych.2016.01.004.

WHAT DOES CANNABIS DO?

The Endocannabinoid System

The Endocannabinoid System Regulates:

http://www.fundacion-canna.es/en/endocannabinoid-system;Lu et al. Biol Psychiatry 2016;79:516-25.

CB1 in Brain:Cortex

Nucleus accumbensBasal gangliaHypothalamus

CerebellumHippocampus

AmygdalaSpinal cordBrainstem

CB2 in Brain:Glial cellsBrainstem

Emetic reflexIntraocular pressure

Heart rate

GI motility

Immune function

Neurodevelopment Coordination

MemoryCognitionReward

Female reproductive

function

StressAppetite

The Endocannabinoid System:Retrograde Neurotransmission

CB receptor

1. EC precursors in lipid membranes

The Endocannabinoid System:Retrograde Neurotransmission

CB receptor

1. EC precursors in lipid membranes

2. NT binding (or depolarization) triggers enzymatic reaction to form and release EC

3. Released EC binds to presynaptic

CB1 or CB2 receptors

4. Inhibits release of inhibitory and excitatory NTs

The Endocannabinoid System:Receptors and Ligands

central and peripheral neuron terminals immune cells

CB1 CB1

CB2 CB2

2-AG: high-efficacy agonist

anandamide: low-efficacy agonist 2-AG: high-

efficacy agonistanandamide: very low-efficacy agonist

Pre- (and Post-)Natal Neurodevelopment:Role of Endocannabinoid System

Stahl SM. Stahl's Essential Psychopharmacology. 3rd ed. 2008; Zhou Y et al. Int J BiochemCell Biol 2014;47:104-8; Maccarrone M et al. Nat Rev Neurosci 2014;15(12):786-801.

stem cell

immature neurons

neurogenesis

eliminated

eliminated

selection migration differentiation synaptogenesis

involved in neural stem cell survival

involved in proliferation

cue migration

direct axonal growth

promote neurite

outgrowth

position cortical

interneurons

Brain Changes During Adolescent Development

Competitive elimination of synapses(loss of dendritic arborization)

ages 6–19 adulthoodage 5

Prefrontal excitatory synapses

Prefrontal inhibitory synapses

Prefrontal DA innervation

AnandamideCB1 receptors

drop off in adulthood

ECS regulates glutamate, GABA, synaptic pruning, and white matter

development

CB1: increase in striatum, PFC, and hippocampus. Abundant in white matter during neural development. Present in oligodendrocytes.

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Insel TR. Nature 2010;468(7321):187-93; Viveros MP et al. J Psychopharmacol 2012;26(1):164-76;

Lubman DI et al. Pharmacol Ther 2015;148:1-16.

WHAT DOES CANNABIS DO?

Effects on Cognition, Motivation, Psychosis, and the Developing Brain


Emetic reflex

PainIntraocular pressure

Potential Effects of Cannabis

Heart rate

GI motility

Immune function

Neurodevelopment Coordination

Female reproductive

function

StressAppetite


Impaired short-term memory, concentration,

alertness, judgment, time

perception, reaction timeAmotivation

Emetic reflexAnti-emetic?

PainIntraocular pressureTreat glaucoma?

Potential Effects of Cannabis

Heart rate

GI motility

Immune function

Neurodevelopment CoordinationRisk of neuro-development d/o?

TachycardiaCV risk

Female reproductive

function

Impaired fertility?

StressAppetite

Treat IBS?

Treat wasting syndrome?

Treat cancer?Treat autoimmune d/o?

Treat chronic pain?

Impaired coordination

Effects of Chronic, Heavy Cannabis Useon Endocannabinoid System

• Reduced anandamide in cerebrospinal fluid1

– Correlated with persistent psychotic symptoms• Reduced cannabinoid 1 receptor2

• Abnormalities in brain regions high in CB1 receptors (hippocampus, PFC)3

– Associated with higher levels of cannabis use (dose, age of onset, duration)

1. Morgan CJA et al. Br J Psychiatry 2013;202:381-2.2. Rotter A et al. Eur Addict Res 2013;19:13-20.3. Lorenzetti V et al. Biol Psychiatry 2016;79:e17-31.

Does Cannabis UseAffect Cognitive Capacity?

• Short-term: YES• Long-term: mixed data

– Meta-analysis: non-intoxicated users do worse than non-users, BUT

– In studies with at least 1 month abstinence, difference not seen• Neuroimaging data: inconsistent, don't seem to correlate with

neuropsychological test performance• Genetic factors that increase risk of impairment (COMT, AKT1)?• Magnitude and persistence of impairment may depend on:

– Frequency and duration of use– Age of onset of use– Length of abstinence

Volkow ND et al. JAMA Psychiatry 2016;73(3):292-7.Meta-analysis: Schreiner AM et al. Psychopharmacology 2012;20(5):420-9.

Degree Attainment168421

<Monthly Monthly or more

Weekly or more

Daily

Adju

sted

odd

s ra

tio

Does Cannabis Use Reduce Motivation?

Silins E et al. Lancet Psychiatry 2014;1(4):286-93.

High School Completion168421

<Monthly Monthly or more

Weekly or more

Daily

Adju

sted

odd

s ra

tio

Cannabis Use Blunts Nucleus AccumbensResponse to Reward Anticipation

Left: Past marijuana use at age 20 (time 1) and NAcc activation during reward anticipation at age 22 (time 2). Right: Past marijuana use at age 22 (time 2) and NAcc activation during reward

anticipation at age 24 (time 3). Martz ME et al. JAMA Psychiatry 2016; doi:10.1001/jamapsychiatry.2016.1161.

Marijuana Use, Age 20 y Residuals Marijuana Use, Age 22 y Residuals

Time 1 to Time 2 Results Time 2 to Time 3 Results

NAc

cAc

tivat

ion,

Age

22

y R

esid

uals

NAc

cAc

tivat

ion,

Age

24

y R

esid

uals

Cannabis Users Show Reduced Striatal DA Synthesis Capacity

Data are from Bloomfield MA et al. Biol Psychiatry 2014;75(6):470-8.Additional studies: Bloomfield MAP et al. Psychopharmacology 2014;231(11):2251-9;

van de Giessen E et al. Mol Psychiatry 2016; doi:10.1038/mp.2016.21.

p=0.016

Does Cannabis UseIncrease Risk of Acute Psychosis?

THC data: D'Souza DC et al. Neuropharmacology 2004;29(8):1558-72.Ketamine and amphetamine data: Krystal et al. Arch Gen Psychiatry 2005;62:985-94.

Salvinorin A data: Ranganathan et al. Biol Psychiatry 2012;72:871-9.Sherif M et al. Biol Psychiatry 2016;79:526-38.

Healthy Human Participants:Transient Induction of Psychosis

Does Cannabis UseIncrease Risk of a Psychotic Disorder?

Lifetime risk of schizophrenia in:

13.7% of US population uses cannabis at least once per year3

cannabis users1,2

1% 2%

1. Gage SH et al. Biol Psychiatry 2016;79:549-56; 2. Volkow N et al. JAMA Psychiatry 2016;73(3):292-7; 3. UNODC. World Drug Report 2011 (United Nations Publication,

Sales No. E.11.XI.10); http://www.unodc.org/documents/data-and-analysis/WDR2011/World_Drug_Report_2011_ebook.pdf.

general population

Are there subgroups at higher risk?

Risk of a Psychotic Disorder in Subgroups of Cannabis Patients

Lifetime risk of schizophrenia in:

cannabis users1

2%

1. Gage SH et al. Biol Psychiatry 2016;79:549-56.2. Volkow N et al. JAMA Psychiatry 2016;73(3):292-7.3. Colizzi M et al. Schizophr Bull 2015;41(5):1171-82.4. Henquet C et al. Neuropsychopharmacol 2006;31(12):2748-57.5. van Winkel R et al. Neuropyschopharmacol 2011;36(12)2529-37.6. Di Forti M et al. Biol Psychiatry 2012;72(10):811-6.

20%

users w/first-degree relative1,2

frequent and/or high-potency users2

6%

DRD2 (Rs1076560 T allele)3

COMT (Val-158 allele)4

AKT1 (Rs2494732 C/C genotype)5-6

Does Cannabis Use Affectthe Course of a Psychotic Disorder?

Schoeler T et al. Lancet Psychiatry 2016;3(3):215-25.

Greater risk of psychosis relapse in continued cannabis user

Greater risk of psychosis relapse in non-user

Does Cannabis UseAffect the Developing Brain?


stem cell

immature neurons

neurogenesis

eliminated

eliminated

selection migration differentiation synaptogenesis

involved in neural stem cell survival

cue migration

direct axonal growth

position cortical

interneuronsECS effectsinvolved in proliferation

Cannabis effects (animal data, acute pre/neonatal exposure)

cortical cell death

promote neurite

outgrowth

altered development of major NT

systems


Competitive elimination of synapses(loss of dendritic arborization)

ages 6–19 adulthoodage 5

Prefrontal excitatory synapses

Prefrontal inhibitory synapses

Prefrontal DA innervation

CB1: increase in striatum, PFC, and hippocampus. Abundant in white matter during neural development. Present in oligodendrocytes.

AnandamideCB1 receptors

drop off in adulthood

Cannabis use: downregulated CB1 receptors in white matter

ECS regulates glutamate, GABA, synaptic pruning, and white matter

development

Cannabis use: disrupted

glutamate NT

Stahl SM. Stahl's Essential Psychopharmacology. 4th ed. 2013; Insel TR. Nature 2010;468(7321):187-93; Viveros MP et al. J Psychopharmacol 2012;26(1):164-76;


Heavy Cannabis Use Prior to Brain Maturation: Animal Studies

• Greater and more persistent cognitive deficits– Learning, working memory, object recognition

• Disruption in social behavior• More depressive-like behaviors

– Reduced consumption of palatable food, passive response to acute stress

• Impaired prepulse inhibition• Increased locomotor activity



Meier MH et al. PNAS 2012;109(40):E2657-64.

1 Diagnosis

2 Diagnoses

3+ Diagnoses

n=17

Cannabis-dependent before age 18Not cannabis-dependent before age 18

n=57n=12 n=21

n=23 n=14

Cha

nge

in F

ull-S

cale

IQ (i

n SD

Uni

ts)

From

Age

13

to A

ge 3

8

Answers Needed

• Adolescent Brain Cognitive Development Study– Funded by NIH– Prospectively following children for 10 years

beginning at ages 9–10– Began recruiting September 2016– http://abcdstudy.org/

HOW MIGHT CANNABIDIOL ATTENUATE THE NEGATIVE EFFECTS OF CANNABIS?

Cannabidiolvs.

psychoactiveanxiogenic

NOT psychoactiveanxiolytic

anticonvulsantunder investigation by

NIDA and NIH for therapeutic uses

isomer of THC

Greydanus DE et al. Disease Month 2015;61:118-75;Iseger TA, Bossong MG. Schizophr Res 2015;162:153-61.

vs. CannabidiolTHC

THC vs. Cannabidiol:Different Binding Properties

CB1 CB1

central and peripheral neuron terminals immune cells

CB2 CB2

THC: partial agonist

THC: partial agonist (low affinity?)

CBD: does not bind CB receptors;may interact with 5HT receptors

Psychosis symptoms

Higher risk of hallucinations and delusions

Lower risk of hallucinations and delusions

Possible antipsychotic effects

Psychotic disorder Earlier age of onset Later age of onset

Cognition Higher risk of acute memory impairment

Lower risk of acute memory impairment

Anxiety AnxiogenicIncreased amygdalar activity

AnxiolyticReduced amygdalaractivity

THC vs. CBD:Psychiatric Effects

Cannabis w/Low CBD Content

Cannabis w/High CBD Content

CBD alone

Iseger TA, Bossong MG. Schizophr Res 2016;162:153-61.

Shifting Ratio of THC: Cannabidiol

DEA-seized materials.ElSohly MA et al. Biol Psychiatry 2016; http://dx.doi.org/10.1016/j.biopsych.2016.01.004.

Cannabis

CB1 CB1

THC: partial agonistCBD

CB1 CB1

Synthetics: full agonist

Cameron K et al. Psychopharmacology 2013;227(3):493-9; Loeffler G et al. Milit Med 2012;177(9):1041-8.

800X greater affinity for CB1

No CBD

“The Synthetics”vs.vs. “The Synthetics”Cannabis

CANNABIS AND CANNABINOIDS AS THERAPEUTIC TOOLSThe State of the Evidence

Approved

Active ingredient

Formulation Approval(s) Schedule

Dronabinol Synthetic THC

Oral capsuleor solution

Chemo-induced nausea and vomiting (US)

Appetite boost in AIDS wasting syndrome (US)

III

Nabilone Synthetic THC analog

Oral capsule Chemo-induced nausea and vomiting (US)

II (due to its potency)

Nabiximols Purified ~1:1 THC and CBD

Spray Spasticity caused by MS (UK, Canada, Europe, Australia, New Zealand, Israel)

Pain in MS and in cancer (Canada, Israel)

N/A

Cannabinoids for Medical Use:Meta-analysis

MODERATE-QUALITY EVIDENCE

POSITIVE EFFECTNO EFFECT

Spasticity in MS4 trials/2280 participants

(nabiximols, nabilone, dronabinol, THC/CBD

capsule)Chronic neuropathic or

cancer pain28 trials/2454 participants

(smoked THC, nabiximols)

LOW-QUALITY EVIDENCE VERY LOW-QUALITY EVIDENCE

Nausea/vomiting from chemo28 trials/1772 participants(nabiximols, dronabinol)

Weight gain in HIV4 trials/255 participants

(dronabinol)Tourette syndrome

2 trials/36 participants(THC capsule)

Sleep2 trials/54 participants

(nabilone)Psychosis

2 trials/71 participants(cannabidiol)

Anxiety (public speaking)

1 trial/24 participants(cannabidiol)Depression

No direct study; documented as a result in

5 studies(nabiximols)

Whiting PF et al. JAMA 2015;313(24):2456-73.RCTs from 1975–2014.

Cannabinoids for Medical Use:American Academy of Neurology Review

"A" (strong) "B" (moderate) "C" (weak)Spasticity (MS)

OCEPain (MS)

OCE

Spasticity (MS)THC, nabiximols

Pain (MS)THC, nabiximols

Urinary dysfunction (MS)

nabiximolsUrinary dysfunction

(MS)OCE, THC

Tremor (MS)OCE, THC

Levodopa-induced dyskinesia

OCE

Tremor (MS)nabiximols

POSITIVE EFFECTNO EFFECT

Koppel BS et al. Neurology 2014;82:1556-63.RCTs from 1948–2013.

OCE: oral cannabis extract (THC or THC/CBD)

"U" (insufficient)Spasticity (MS)

smoked cannabisPain (MS)

smoked cannabisHuntington's

diseasenabilone, CBD

capsuleTourette

syndromeTHC

Cervical dystoniadronabinolEpilepsy

CBD

ECS-Based Medicines No Longer Under Investigation

• Peripherally restricted CB1 agonists– Studied in pain; failed due to metabolic and cardiovascular effects

• Synthetic CB1 agonists– Damaged kidneys in young children; serious cardiovascular adverse

effects• Global CB1 antagonists

– Efficacy in diabetes and obesity, but failed due to CNS side effects– Negative study for smoking cessation

• Fatty acid amide hydrolase (FAAH) inhibitors– Promote cardiovascular inflammation, metabolic side effects– Phase I study of French formulation in healthy volunteers halted due to

death and serious brain injury• US FDA: "BIA 10-2474 exhibits a unique toxicity that does not extend to

other drugs in the class"

Under Investigation: Cannabidiol

Dravet syndrome (GW Pharma; epidiolex*)

Lennox-Gastaut syndrome (GW Pharma; epidiolex*)

tuberous sclerosis (GW Pharma; epidiolex)

Preclinical Phase I Phase II Phase III

*Orphan drug designation

glioma (GW Pharma; GWP42003*)

severe pediatric epilepsies (INSYS)

schizophrenia (GW Pharma; GWP42003)

neonatal hypoxic-ischemic encephalopathy (GW Pharma; GWP42003*)

Under Investigation: Other

cancer pain (GW Pharma; nabiximols spray)

MS spasticity (GW Pharma; nabiximols spray)

epilepsy (GW Pharma; cannabidivarin)

Preclinical Phase I Phase II Phase III

type 2 diabetes (GW Pharma; delta-9-tetrahydrocannabivarin)

*Orphan drug designation

Why Is Medical MarijuanaNot a Viable Prescription Option?

Drug approval standards• Consistent, pure, well-defined

chemical formulation• Consistent, well-defined

pharmacokinetic profile• Safety data in healthy

population and in specific medical disorder (double-blind, placebo-controlled RCT)

• Efficacy data in specific medical disorder (double-blind, placebo-controlled RCT)

• Warnings regarding all potential side effects

Medical marijuana status• Unprocessed plant containing

500 chemicals with 100+ cannabinoids

• Compounds may vary from plant to plant

• Residual impurities (pesticides, fungal contaminants)

• Dosing is not well regulated

Cannabis Is Like a Box of Chocolates…

Benbadis SR et al. Expert Rev Neurother 2014;14(12):1453-65.

"…future medicinal useswill most likely lie in drugs

based on cannabinoid chemicals or extracts with defined concentrations

that can be reliably produced."

—Nora Volkow

Questions for Future Research

• What factors contribute to negative effects and risks of cannabis exposure?– Age at initiation?– Quantity used?– Frequency of use?– Potency?– Duration of use?

• What are the long-term consequences of heavy cannabis use prior to brain maturation?

WHAT'S A HEALTHCARE PROFESSIONAL TO DO?

American Society of Addiction Medicine (ASAM) Recommendations

• Cannabis-related products should not be distributed unless/until they have FDA approval

• Smoking is not an appropriate drug delivery mechanism• Need for federal regulatory standards for approval and distribution• State should not enact regulatory standards more permissive than federal ones• Clinicians who choose to discuss medical use of cannabis must:

– Adhere to established professional tenets of proper patient care– Have a preexisting and ongoing relationship with the patient– Not recommend cannabis as a disproportionately large portion of practice– Not issue recommendation without adequate information regarding

composition and dose– Have adequate training in identifying substance abuse and addiction

ASAM Medical Marijuana Task Force White Paper. 2012. Learnaboutsam.org/wp-content/uploads/2013/02/American-Society-of-Addiction-Medicine-2011-Medical-

Marijuana-Task-Force-White-Paper.pdf.

College of Family Physicians of Canada (CFPC) Recommendations

• Pain: only for patients with neuropathic pain that has failed to respond to standard treatment (including adequate trial of pharmaceutical cannabinoids)

• Anxiety: not appropriate therapy• Insomnia: not appropriate therapy• Not appropriate for:

– <25 years of age– Personal/family history of psychosis– Current or past cannabis use disorder– Cardiovascular or respiratory disease– Pregnant, planning pregnancy, or breastfeeding

College of Family Physicians of Canada. Authorizing Dried Cannabis for Chronic Pain or Anxiety: Preliminary Guidance from the College of Family Physicians of Canada.

Mississauga, ON: College of Family Physicians of Canada; 2014.

Screening for Cannabis Use Disorder

• NIDA Quick Screen—NIDA-modified ASSIST• NM-ASSIST full• CAGE-AID• Risk factors

– Current mood or anxiety disorder– History of substance use

Cautions About Cannabis Use:Time to Peak Concentration

Inhalation• Fast brain uptake• Higher risk of addiction• Risk of impairment

greatest immediately and within first 2 hours

Oral• Delayed brain uptake• Lower risk of addiction• Risk of impairment

delayed and may be greatest between 2–6 hours after consumption

Summary

• Wide-ranging role of endocannabinoid system suggests potential therapeutic uses of cannabis, but also potential adverse effects, especially during neurodevelopment

• Scant evidence beyond pain in cancer, nausea/vomiting, and spasticity in MS

• Hope for use in severe pediatric epilepsy (Phase III)• Media hype but no actual evidence for use in psychiatric

conditions (PTSD, anxiety, depression)• Variations in potencies, cannabinoid constituents, dosing,

and route of administration make medical marijuana difficult to recommend

• Potential for use in numerous therapeutic indications, but Schedule I status severely limits ability to research

Posttest Question 1

Your patient, a 33-year-old woman whom you have been treating for 3 years for major depressive disorder, discloses to you that 6 weeks ago, she visited a cannabis clinic and was certified for the use of medical marijuana to treat chronic back pain resulting from a car accident and subsequent surgery 2 years ago. As part of your discussion regarding the risk/benefit assessment of cannabis use for chronic pain, you tell her that:1. Randomized controlled trials provide moderate to strong evidence

for efficacy in chronic back pain2. Randomized controlled trials provide moderate to strong evidence

for efficacy in some other types of chronic pain3. Randomized controlled trials provide moderate to strong evidence

for lack of efficacy in chronic pain4. There are not enough data to help determine if there is efficacy for

chronic pain

Posttest Question 2

Your patient, a 26-year-old man whom you have been treating for 3 years for posttraumatic stress disorder (PTSD), discloses to you that 6 weeks ago, he visited a cannabis clinic and was certified for the use of medical marijuana to treat his PTSD symptoms. As part of your discussion regarding the risk/benefit assessment of cannabis use for PTSD, you tell him that:1. Randomized controlled trials provide moderate to strong evidence

for efficacy in multiple symptom domains of PTSD2. Randomized controlled trials provide moderate to strong evidence

for efficacy only in sleep/nightmares associated with PTSD3. Randomized controlled trials provide moderate to strong evidence

for lack of efficacy in PTSD4. There are not enough data to help determine if there is efficacy for

PTSD

Posttest Question 3

Synthetic THC is approved for:1. Nothing2. Chemo-induced nausea3. Appetite boost in AIDS wasting syndrome4. Dravet syndrome (pediatric epilepsy)5. 2 and 36. 2, 3, and 4

marijuana: drug of abuse or therapeutic...

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