What do we know about cannabis
and synthetic cannabinoids
(“Spice”)?
Miriam Komaromy, MDAssociate Director, ECHO Institute [email protected]
overview
Cannabis› Epidemiology› Effects› Risks› Cannabis Use Disorder› Treatment
Overview of Synthetic Cannabinoids
“Marijuana” (AKA cannabis) “is unique among illegal drugs in its political symbolism, its safety, and its wide use.”
G.J.AnnasProfessor and Chair of the Department of Health Law, Bioethics & Human Rights Boston UniversityEditorial, NEJM, 1995
“Cannabis, the most widely used illicit drug in the world, is increasingly being recognized for both its toxic and its therapeutic properties.”
Madeline Meier, PhD.Duke UniversityProceedings of the National Academy of Science, Sept 2012
Smoking cannabis is thought to have originated with the ancient Scythians in 700 BC.
“According to Herodotus, they would put their heads into small tents designed to trap the fumes from cannabis buds placed on red-hot rocks “until they rise up to dance and betake themselves to singing””
Pollan, The Botany of Desire, 2002, p 128
International epidemiology of Cannabis use
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
US epidemiology of cannabis use
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 2011WHO, 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.0050141http://www.plosmedicine.org/article/info:doi/10.1371/journal.pmed.0050141
Distribution of CB1 receptors in the brain
•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 2009Leussink, Th Adv Neur Dis, 2012
CB2 receptors
Immune system(thymus)
CB2Cannabinoidreceptor
T cells
CB1
CB2 receptors found on immune cells:• B lymphocytes• NK cells• Monocytes• T cells
Major effect: Decreased inflammation/ immune activation
Leussink, Th Adv Neur Dis, 2012
Effects Subjective
› Euphoria› Relaxation› Altered perception (hallucinogen)› Social lubricant› Anxiety, paranoia
Objective› Tachycardia› Conjunctival injection(red eyes)› Increased appetite› Dry mouth› Decreased nausea/vomiting› Hyperemesis syndrome (rare)
•Enhancement of positive affects•Expansion of experimental awareness•Social conformity•Social cohesion•Reduction of negative affect (Coping)
Simons, J Counseling Psychol, 1998
Motives: personal andsocial
Risks of Botanical cannabis
Dependence Psychosis Cognitive impairment Drugged driving
Cannabis Use Disorder: DSM V 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
Drugs for which people >12 receive treatment, 2011
SAMHSA NSDUH 2011
Natural History of Cannabis Use
Changes in botanical cannabis
Potency of Cannabis has increased from 2-3% THC up to 8.8% in the past couple of decades
Mehmedic, J Forensic Sci, 2010
Among people who use cannabis, approx. 9% will develop dependence
-or-
9 out of 10 Cannabis users will not develop dependence
Risks: Psychosis & SchizophreniaWhat lines of evidence suggest an association?
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, 2010Zammit, BMJ, 2002
Cannabis and psychosis
•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
Age at onset of cannabis use and schizophrenia
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, 2011Galvez-Buccollini, Schizophrenia Research, 2012
Risks: Cognitive decline
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, 2008Meier, PNAS 2012
Dunedin cannabis cohort study
dependent at >/= 3 waves
dependent at 2 waves
dependent at 1 wave
used, never regularly
never used
-0.4 -0.35 -0.3 -0.25 -0.2 -0.15 -0.1 -0.05 0 0.05 0.1
change in IQ SD units
Key: drop of .38 IQ SD units = drop of 6 IQ points
Meier, PNAS, 2012
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-use-by-teens-really-cause-a-drop-in-iq/#ixzz28728rZXK
IQ difference only occurs with adolescent onset
IQ difference only significant among former users who started (>weekly) before age 18
Findings persist after excluding various groups: recent cannabis users, regular tobacco users, regular use of drugs or alcohol, & those with schizophrenia
92
98
104
Child IQAdult IQ
Infreq use age
38
frequent use age
38
80
90
100
110
Child IQAdult IQ
p = .03 p = .0002
p = .11p = .73A
dole
scen
t O
nset
Ad
ult
O
nset
Meier, PNAS, 2012
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
Perspective on risks 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, 2012CDC, 2004Calabria, Drug & Alcohol Rev 2010Smyth, Prev Med 2007
Productive years of life lost due to disability from cannabis dependence relative to other substance use disorders
Globally
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.0076635http://www.plosone.org/article/info:doi/10.1371/journal.pone.0076635
Disability Adjusted Life years Lost = DALYs
Cannabis was the only substance studied that caused zero Years of Life Lost
Treatment: Psychosocial 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
What is Contingency Management?
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
Contingency management and relapse to cannabis
Kadden, 2007, Addict Behav
Medications for treatment of cannabis dependence
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
Date of download: 7/24/2014
Copyright © American Psychiatric Association. All rights reserved.
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
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.
Figure Legend:
N=116
A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adultsMason BJ et al, 2012 Neuropsychopharmacology
N=50
Other medications being studied
Bupropion Atomoxetine Divalproex Cannabinoid receptor agonists and
antagonists
Danovitch I. Psych Clin N Am, 2012
What about Medical Cannabis? 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
Conclusions about cannabis 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
Synthetic Cannabinoids or“Spice”
Why are these drugs a problem?
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
Changing Patterns of UseReports to US Poison Control Centers
2009 2010 20110
1000
2000
3000
4000
5000
6000
7000
Bath Salts"Spice"
Wood, J Pediatr, 2013
In 2011 and 2012 the Monitoring the Future Study 1 found that 11.3 % of 12th graders report use of Synthetic Marijuana in the preceding 12 months.
This means that for 12th graders, this is the most commonly used drug after marijuana.
1. Monitoring the Future Study, 2012 Overviewhttp://monitoringthefuture.org//pubs/monographs/mtf-overview2012.pdf
What are synthetic cannabinoids?
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
What do these drugs look like?
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.
www.jeffwolfsburg.com
www.drugabuse.gov
Dru
g e
ffects
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 20122. Mir, Pediatrics 2011
Like Cannabis
Unlike Cannabis
Synthetic Cannabinoid Effects
Case 1An 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
Case 217 year old boy “running in and out of traffic” after smoking “Humbolt Gold”(synthetic cannabinoid) so parents tried to transport to ER
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.
Patient had jerking movements of arms and legs, and then tried to escape from car by breaking the window with his head
Harris, J Emerg Med 2013
Case 3The 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
Case 4
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 4-point 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
Regulation 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
Management of “Spice” intoxication
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
Are control efforts working?
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Synthetic Marijuana
Synthetic Cathinones
2010 2011 2012 2013
Number of Exposure
Calls
Number of Calls to U.S. Poison Control Centers About Exposure*
to Synthetic Cathinones and Synthetic Marijuana, January 2010- June 2013†
CESAR Fax August 2013
Conclusions
“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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review of observational studies and meta-analysis. BMJ:344;e536. Borgelt, L et al. 2013. The pharmacologic and clinical effects of medical cannabis.
Pharmacotherapy: the Journal of Pharmacology and Drug Therapy:33;195. Bossong, M., Niesink, R. 2010. Adolescent brain maturation, the endogenous cannabinoid system
and the neurobiology of cannabis-induced schizophrenia. Progress is Neurobiology:92;370. Bostwick, J. 2012. Burred boundaries: the therapeutics and politics of medical marijuana. Mayo Clin
Proc: 87;172. Breivogel, C., Sim-Seey L. 2009. Basic neuroaatomy and neuropharmacology of cannabinoids.
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adults. Addictive Behaviors:32;1537. Calabria, B., et al. 2010. Does cannabis use increase the risk of death? Systematic review
of epidemiological evidence on adverse effects of cannabis use. Drug & Alcohol Review;29:318.
Degenhardt L, 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.
DiMarzo, V. 2008. Targeting the endocannabinoid system: to enhance or reduce?” Nat Drug Re Discov:7;438.
Galvez-Buccollini J., et al. Association between age at onset of psychosis and age at onset of cannabis use in non-affective psychosis. Schizophrenia Research;139:157.
Gaoni Y, Mechoulam R. 1964. Isolation, structure and partial synthesis of an active constituent of hashish. J Am Chem Soc:1646.
References Cannabis, cont. Green, B. 2003. Being stoned: A review of self-reported cannabis effects. Drug and Alcohol
Review: 22;453. Greineisen, W., Turner, H. 2010. Immunoactive effects of cannabinoids: considerations for the
therapeutic use of cannabinoid receptor agonists ad antagonists. International Immunnopharmacology:10;547.
Hyman, S., et al. 2009. Stress-related factors in cannabis use and misuse: implications for prevention and treatment. J Subst Abuse Treatment:36;400.
Jager, G., Ramsey, N. 2008. Long-term consequences of adolescent cannabis exposure on the development of cognition, brain structure, and function: an overview of animal and human research. Curr Drug Abuse Rev: Jun;1:114.
Kadden RM et al. 2007. Abstinence rates following behavioral treatments for marijuana dependence. Addict Behav:32;1220.
Large, M., et al. 2011. Cannabis use and earlier onset of psychosis; a systematic meta-analysis. Arch Gen Psychiatry; 68:555.
Leussink, V., et al. 2012. Symptomatic therapy in multiple sclerosis: the role of cannabinoids in treating spasticity. Therapeutic Advances in Neurological Disorders:5;255.
Lynskey, M. 2012. An Australian twin study of cannabis and other illicit drug use and misuse, and other psychopathology. Twin Res Hum Genet: 15;631.
Mason BJ et al, 2012. A proof-of-concept randomized controlled study of gabapentin: effects on cannabis use, withdrawal and executive function deficits in cannabis-dependent adults. Neuropsychopharmacology: 37;1689.
Mechoulam R, Parker L. 2012. The endocannabinoid system and the brain. Annu Review Psychol; 64;6.
Mechoulam R, Braun P, Gaoni Y. 1967. A stereospecific synthesis of (−)-1 and (−)-6-tetrahydrocannabinols. J Am Chem Soc 89:4552.
Mehmedic, Z. et al. 2010. Potency trends of Δ9-THC and other cannabinoids in confiscated cannabis preparations from 1993 to 2008. J Forensic Sci 55:1209.
References Cannabis, cont. Meier, M., et al. 2012. Persistent Cannabis users show neuropsychological decline from
childhood to midlife. PNAS, August 27 epub. Moore, T., et al. 2007. Cannabis use and risk of psychotic or affective mental outcomes: a
systematic review. Lancet:370;319. Pollan, M. 2002. The botany of desire, a plant’s eye view of the world. New York: Random
House. Reilly, D. 1998. Long-term cannabis use: Characteristics of users in an Australian rural area.
Addiction: 93; 837. Simons, J., et al. 1998. Validating a 5-factor marijuana motives measure: relations with use,
problems, and alcohol motives. J Counseling Psychology;45:265. Smyth, B. 2007. Year of potential life lost among heroin addicts 33 years after treatment.
Preventive Medicine:44;369. Stitzer M and Petry N. 2006. Contingency management for treatment of substance abuse.
Ann Rev Clin Psychol:2;411. Substance Abuse and Mental Health Administration, National Survey on Drug Use and
Health, 2011. Accessed 9/23/12 http://www.samhsa.gov/data/NSDUH/2k10NSDUH/2k10Results.htm#8.1
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References, Synthetic Cannabinoids
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.
3. Harris C, Synthetic cannabinoid intoxication: a case series and review. J Emerg Med 2013;44:360.
4. Mir A, Myocardial infarction associated with use of the synthetic cannabinoid K2. Pediatrics 2011;128:e1622.
5. Seely K Spice drugs are more than harmless herbal bleds: a review of the pharmacology and toxicology of synthetic cannabis. Prog NeuroPharm 2012
6. Vardakou I Spice drugs as a new trend: mode of action identificaiton, and legislation. Toxicology Letters 2010:197;157.
7. Wood KE, Exposure to bath salts and sythetic tetrahydrocannabinol from 2009 to 2012 in the United States. J Pediatr 2013