What do we know about cannabis

and synthetic cannabinoids

(“Spice”)?

Miriam Komaromy, MDAssociate Director, ECHO Institute miriamk1@salud.unm.edu

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

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Child IQAdult IQ

Infreq use age

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frequent use age

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Child IQAdult IQ

p = .03 p = .0002

p = .11p = .73A

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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

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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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Respiratory Journal:31;280. Annas, G. 1997. Reefer Madess—the federal response to California’s medical marijuana law. NEJM:

337;435. Asbridge, M, et al. 2011. Acute cannabis consumption and motor vehicle collision risk: systematic

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.

International Review of Psychiatry: 21;113. Brodbeck, J., et al. 2007. Motives for cannabis use as a moderator variable of distress among young

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

Terry G., et al. 2010. Imaging and quantitation of cannabinoid CB1 recpetors in human and monkey brains using F-18 labeled inverse agonist radioligands. J Nuc Med;51:112.

WHO, 2012, accessed 9/23/12 http://www.who.int/substance_abuse/facts/cannabis/en/ Zammit, S., et al. 2002. Self-reported cannabis use as a risk factor for schizophrenia in

Swedish conscripts of 1969: historical cohort study. BMJ;325:1199.

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