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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
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
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.
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.
MemoryCognitionReward
Emetic reflex
PainIntraocular pressure
Potential Effects of Cannabis
Heart rate
GI motility
Immune function
Neurodevelopment Coordination
Female reproductive
function
StressAppetite
MemoryCognitionReward
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?
Lubman DI et al. Pharmacol Ther 2016;148:1-16.
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
Does Cannabis UseAffect the Developing Brain?
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;
Lubman DI et al. Pharmacol Ther 2015;148:1-16.
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
Lubman DI et al. Pharmacol Ther 2015;148:1-16.
Does Cannabis UseAffect the Developing Brain?
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/
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
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
"…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?
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