Miriam Komaromy, MD
Associate Director, ECHO Institute
miriamk1@salud.unm.edu

Cannabis
› Epidemiology
› Effects
› Risks
› Cannabis Use Disorder
› Treatment

Overview of Synthetic Cannabinoids
Pollan, The Botany of Desire, 2002, p 128

By far the most widely cultivated, trafficked
and abused illicit drug in the world.

Half of all drug seizures worldwide are
cannabis seizures, and occur in almost
every country.

About 147 million people, or 2.5% of the
world’s population, consume cannabis
annually, compared with 0.2% consuming
cocaine and 0.2% consuming opiates.
WHO, 2012
Figure 1 Use of cannabis in 2007 The boundaries and names shown and the designations used on this map do not imply
official endorsement or acceptance by the UN. Sources: UN Office on Drugs and Crime (UNODC) annual report
Wayne Hall , Louisa Degenhardt
Adverse health effects of non-medical cannabis use
The Lancet Volume 374, Issue 9698 2009 1383 - 1391
http://dx.doi.org/10.1016/S0140-6736(09)61037-0
Prevalence: In 2009, 28.5 million
Americans >12 used cannabis at least
once in the year prior to being surveyed.
 Initiation

› 59 % of recent cannabis initiates were <18
when they first used.
› Among youths aged 12-17, 5 % had used for
the first time within the past year
SAMHSA NSDUH 2011
WHO, 2008
% of adults reporting ever having used cannabis, by country
Degenhardt L, Chiu W-T, Sampson N, Kessler RC, et al. (2008) Toward a Global View of Alcohol, Tobacco, Cannabis, and
Cocaine Use: Findings from the WHO World Mental Health Surveys. PLoS Med 5(7): e141.
doi:10.1371/journal.pmed.0050141
http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050141
•Cannabinoid
receptors are
among the most
widely distributed
•Lower brainstem
has few; minimal
lethality
•Pre-synaptic
receptor; regulates
activity of GABA
glutamate, and
dopamine systems
Terry, J Nuc Med 2009
Leussink, Th Adv Neur Dis, 2012
Immune system
(thymus)
CB2 receptors
found on immune
cells:
• B lymphocytes
• NK cells
• Monocytes
• T cells
Major effect:
Decreased
inflammation/
immune activation
CB2
Cannabinoid
receptor
T cells
Leussink, Th Adv Neur Dis, 2012
CB1


Subjective
›
›
›
›
›
Euphoria
Relaxation
Altered perception (hallucinogen)
Social lubricant
Anxiety, paranoia
›
›
›
›
›
›
Tachycardia
Conjunctival injection(red eyes)
Increased appetite
Dry mouth
Decreased nausea/vomiting
Hyperemesis syndrome (rare)
Objective
Motives: personal and
social
•Enhancement of positive affects
•Expansion of experimental
awareness
•Social conformity
•Social cohesion
•Reduction of negative affect
(Coping)
Simons, J Counseling Psychol, 1998
Dependence
 Psychosis
 Cognitive impairment
 Drugged driving

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Cannabis is often taken in larger amounts or over a longer period than
was intended
Persistent desire/unsuccessful efforts to cut down on cannabis use
A great deal of time is spent in activities necessary to obtain cannabis,
use cannabis, or recover from its effects
Craving, or a strong desire or urge to use cannabis
Recurrent cannabis use resulting in a failure to fulfill major role
obligations at work, school, or home
Continued cannabis use despite recurrent social or interpersonal
problems caused or exacerbated by the effects of cannabis
Important social, occupational, or recreational activities are given up
or reduced because of cannabis use
Recurrent cannabis use in situations in which it is physically hazardous
Continued cannabis use despite knowledge of having a persistent or
recurrent physical or psychological problem that is likely to have been
caused or exacerbated by cannabis
Tolerance
Withdrawal
SAMHSA NSDUH 2011
Potency of Cannabis has increased
from 2-3% THC up to 8.8% in the past
couple of decades
Mehmedic, J
Forensic Sci, 2010

2011 meta-analysis of non-genetic risk
factors for schizophrenia: cannabis was one
of 3 factors with high quality evidence

At least 9 studies show that cannabis use is
assoc with increased risk of schizophrenia
later in life

Study of 50K Swedish soldiers followed for 28
years: adolescent cannabis use >50x
associated with 7-fold increased risk of
psychosis
Matheson, Schizophrenia Research, 2011
Bossong, Prog Neurobiology, 2010
Zammit, BMJ, 2002
•Cannabis use associated with 40% increase
in the risk of psychosis
•Dose-response relationship: heavy cannabis
use is associated with 100% increase in risk
Moore, Lancet, 2007

2011 meta-analysis of 83 studies: age of
schizophrenia onset in cannabis users is 2.7 years
younger than in non-users

Retrospective study of schizophrenic cannabis
users & family members found early age of
initiation of cannabis was associated with younger
age of onset of psychosis and first hospitalization

Mean delay from cannabis initiation to psychosis: 7
years
Large, Arch Gen Psych, 2011
Galvez-Buccollini, Schizophrenia Research, 2012

Studies suggest long-term heavy cannabis use is
associated with enduring neuropsychological
impairment

However, studies have been retrospective or
case/control; inconclusive

Recent prospective 20 year study

Neuropsych/IQ testing at ages 13 and 38

Ascertainment of cannabis use/dependence at 18,
21, 26, 32, & 38
Jager, Curr Drug Abuse Rev, 2008
Meier, PNAS 2012
never used
used, never regularly
dependent at 1 wave
dependent at 2 waves
dependent at >/= 3 waves
-0.4
-0.3
-0.2
-0.1
0
change in IQ SD units
Key: drop of .38 IQ SD
units = drop of 6 IQ points
Meier, PNAS, 2012
0.1
Meier notes that for someone
with average intelligence (an
IQ score of 100, the 50th
percentile), an eight-point
decline in IQ would move
that person down to the 29th
percentile. This magnitude of
decline in IQ was seen in the
most persistent adolescent
cannabis users.
http://healthland.time.com/2012/08/28/does-weekly-marijuana-useby-teens-really-cause-a-drop-in-iq/#ixzz28728rZXK

Findings persist after
excluding various
groups: recent
cannabis users,
regular tobacco
users, regular use of
drugs or alcohol, &
those with
schizophrenia
Meier, PNAS, 2012
Adolescent
Onset
IQ difference only
significant among
former users who
started (>weekly)
before age 18
p = .03
p = .0002
Child IQ
Adult IQ
Infreq use frequent
age 38
use age
38
Adult
Onset

105
100
95
90
85
80
110
105
100
95
90
p = .73
p = .11
Child IQ
Adult IQ
Infreq use frequent
age 38 use age
38
Meta-analysis of observational studies investigating the association
between acute cannabis consumption and motor vehicle crashes.
Asbridge M et al. BMJ 2012;344:bmj.e536
©2012 by British Medical Journal Publishing Group

Lifetime risk of dependence:
› Tobacco: 32%
› Alcohol:
15%
› Cannabis: 9%

Risk of mortality:
› Tobacco: long term smoker has 50% chance of dying
prematurely from tobacco related cause, and adult smokers
lose 13-14 yrs of life
› Alcoholism: decreases life expectancy 10-12 yrs
› Cannabis: unclear whether life expectancy is decreased at
all by cannabis use; no known cases of mortality due to
intoxication
Bostwick, Mayo Clin Proc, 2012
CDC, 2004
Calabria, Drug & Alcohol Rev 2010
Smyth, Prev Med 2007
Productive years of life lost due to disability from cannabis dependence
relative to other substance use disorders Globally
Cannabis was the only substance studied that caused zero
Years of Life Lost
Disability
Adjusted Life
years Lost =
DALYs
Degenhardt L, Ferrari AJ, Calabria B, Hall WD, et al. (2013) The Global Epidemiology and Contribution of Cannabis Use and
Dependence to the Global Burden of Disease: Results from the GBD 2010 Study. PLoS ONE 8(10): e76635.
doi:10.1371/journal.pone.0076635
http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076635

Multiple treatment modalities shown to
have some benefit; none clearly superior
to the other:
› Motivational Enhancement Therapy
› CBT
› Several community and family interventions

Contingency management enhances
outcomes of all of the counseling
approaches
Replaces the rewarding effects of drug
use with other tangible rewards
 Rewards can be small or can be tickets
in a lottery
 Effective in improving treatment of
substance use disorders, especially with
adolescents
 Rewards should be immediate, frequent,
and graded, based on level of success

Stitzer, 2006, Ann Rev Clin Psychol
Kadden, 2007, Addict Behav

N-acetylcysteine (NAC) shown in RCT to
double likelihood of negative urine test
(in combo with contingency
management and brief counseling)
› Safe, well-tolerated, over the counter

Gabapentin 1200 mg /d also decreased
amount of cannabis used and improved
executive function and symptoms
› Safe, well-tolerated, generic
From: A Double-Blind Randomized Controlled Trial of N-Acetylcysteine in Cannabis-Dependent Adolescents
Am J Psychiatry. 2012;169(8):805-812. doi:10.1176/appi.ajp.2012.12010055
N=116
Figure Legend:
Proportion of Negative Urine Cannabinoid Tests Over Time Among Cannabis-Dependent Adolescents in a Randomized Controlled
Trial of N-Acetylcysteine (NAC)a
a In this intent-to-treat analysis, all randomized participants (N=116) were included, and urine cannabinoid tests were assumed to be
positive for all missed visits. With adjustment for years of cannabis use, baseline urine cannabinoid test results, and major
depressive disorder, odds ratio=2.4, 95% CI=1.1–5.2; χ2=4.72, p=0.029.
Date of download:
7/24/2014
Copyright © American Psychiatric Association.
All rights reserved.
A proof-of-concept
randomized
controlled study of
gabapentin: effects
on cannabis use,
withdrawal and
executive function
deficits in cannabisdependent adults
Mason BJ et al, 2012
Neuropsychopharmacology
N=50
Bupropion
 Atomoxetine
 Divalproex
 Cannabinoid receptor agonists and
antagonists

Danovitch I. Psych Clin N Am, 2012
Makes physicians gatekeepers for legal
use of cannabis
 Cannabis is not a medication; it is a plant
containing hundreds of active
compounds of varying strengths
 Inadequate data to approve as a
medication
 Many compounds contained in
cannabis have tremendous therapeutic
potential

Borgelt, 2013 Pharmacotherapy

Extraordinarily widespread use in US

Real risks, but less than risks of tobacco and alcohol

Psychological risks are primarily from adolescent
initiation of regular use

About 9% of cannabis users develop Cannabis Use
Disorder

Several counseling methodologies are effective, and all
are enhanced by contingency management

NAC and gabapentin have recent RCT evidence of
their efficacy

Research on medical use of cannabis is needed, and
regulatory barriers should be removed
Inexpensive
 Widely available, especially over the
web
 No commercial drug tests
 “Safe” alternatives
 Altered chemically to avoid legal
restrictions
 Increasingly popular
 Dangerous effects, poorly understood

Wood, J Pediatr, 2013
7000
6000
5000
4000
Bath Salts
3000
"Spice"
2000
1000
0
2009
2010
2011
1. Monitoring the Future Study, 2012 Overview
http://monitoringthefuture.org//pubs/monographs/mtfoverview2012.pdf
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Synthetic drugs that activate the CB1 receptor
Manufactured in search for cannabinoid
medications
Most common forms made by John W. Huffman at
Clemson University with NIDA funding—JWH-018
THC (hallucinogen in marijuana) activates CB1
partially; most of these drugs activate it fully
JWH-018 is 5x as potent as THC 1
HU-210 is 100x as potent as THC 2
Often adulterated with clenbuterol (beta 2
agonist)
1. Seely, Prog Neuropsychopharm 2012
2. Harris, J Emerg Med 2013
www.jeffwolfsburg.com
www.drugabuse.gov
Synthetic chemicals
are sprayed on herbs
and other plants. The
“Spice” is sold as
“potpourri” or “herbal
incense” and labeled
“not for human
consumption”. It is
ingested like
marijuana, by smoking
or eating it.
Synthetic Cannabinoid Effects
Like Cannabis
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Unlike Cannabis
Perceptual
changes
Hallucinations
Sedation
Memory changes
Anxiety
Dilated pupils
Predisposes to
psychosis, but
much more strongly
Agitation
 Seizures (frequent)
 Vomiting
 Dangerously fast heart
rate
 Chest pain, heart
damage
 Serotonin syndrome
 Fatalities

1. Seely, Prog Neuropsychopharm 2012
2. Mir, Pediatrics 2011
An 18 year old boy became agitated and sweaty at a party and got
in a fight. He was brought to the ER and was found to be aggressive
and uncooperative.
Initial heart rate was 131, pupils were enlarged, and he was
sweating and appeared anxious. Urine tox screen was negative.
He continued to be aggressive and agitated and was given
Lorazepam 2 mg IV and 50 mg diphenhydramine. He reported that
he had smoked “Spice” at the party.
His behavior normalized over the next several hours, and he was
discharged.
Cohen, Pediatrics, 2012
17 year old boy “running in and out of traffic” after smoking
“Humbolt Gold”(synthetic cannabinoid) so parents tried to
transport to ER
Patient had jerking movements of arms and legs, and then
tried to escape from car by breaking the window with his head
Transported to ER by paramedics. Heart rate 134, laughing
inappropriately, not responding to questions. Urine drug screen
negative.
After 2 hours of observation behavior and blood pressure
normalized, and patient was discharged home with his
father.
Harris, J Emerg Med 2013
The mother of a 19 year old man heard him scream and found him
apparently hallucinating, fighting with imagined assailants. He had
returned home 20 minutes earlier after smoking “K2” with a friend. He
had recently lost his job due to heavy marijuana use.
He appeared to have a seizure, began foaming at the mouth,
fell to the ground where he appeared blue and unresponsive.
When paramedics arrived he suddenly became combative and
required 4-point restraints. Pulse was initially 220, and was 180 when
he arrived at the ER.
His pulse and behavior normalized, and he was released after 2 days.
Harris, J Emerg Med 2013
20 year old soldier who had just returned from Iraq was brought to
the ER because of altered mental status. He had recently been
punished for use of synthetic cannabinoids. He was placed in 4point restraints to control combativeness and was given Lorazepam
2 mg IV.
He was admitted to the psychiatric hospital because he continued to
be verbally unresponsive. He appeared to be delirious. On day 2 he
became agitated, his heart rate increased to 160 and he required
sedation.
On the 4th hospital day the patient became incontinent. On the 7th
day he began hearing voices and became increasingly
disorganized. He believed that his conversations with his
psychiatrist were being played on the hospital television.
He was discharged on day 10 but continued to require assistance with
ADLs. He died 3 months later when he lost control of his car and was
not wearing a seat belt.
Berry-Caban, Substance Abuse, 2013
5 of these drugs placed on Schedule 1 in
2011
 3 more added in 2013
 Manufacturers make slight modifications
to avoid legal penalties
 Still widely available over the internet
 Broad legislation could have unintended
consequences; cannabinoids are very
promising as therapeutic agents

Seely, Prog Neuropsychopharm 2012
Little is known about optimal management
 Usually involves benzodiazepines to treat
agitation
 Psychosis often needs treatment, but use of
antipsychotics carries risk of lowering seizure
threshold or causing serotonin syndrome
 No data on treatment of
abuse/dependence

Number of Calls to U.S. Poison Control Centers About Exposure*
to Synthetic Cathinones and Synthetic Marijuana, January 2010June 2013†
800
700
Synthetic
Marijuana
Number of 600
Exposure 500
Calls
400
300
200
Synthetic
Cathinones
100
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
Jul
Aug
Sep
Oct
Nov
Dec
Jan
Feb
Mar
Apr
May
Jun
0
2010
2011
2012
2013
CESAR Fax August 2013
“Spice” continues to grow in popularity
 Much more dangerous than the natural
cannabis they are designed to mimic
 Particularly appealing for monitored
individuals
 Difficult to detect, regulate, control
 Little known about treatment
 Education and Prevention are mainstays
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1. Berry-Caban C Synthetic cannabinoid overdose in a 20-year-old
male US soldier. Substance Abuse 2013;34:70.
2. Cohen J, Clinical presentation of intoxication due to sythetic
canabinoids. Pediatrics 2012;129:e1064.
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review. J Emerg Med 2013;44:360.
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cannabinoid K2. Pediatrics 2011;128:e1622.
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cannabis. Prog NeuroPharm 2012
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