1. Cannabis: Updates, Neurobiology and Public Health
Garth Terry, MD, PhD
Senior Fellow, Department of Psychiatry and Behavioral Sciences & Department of Radiology  University of Washington School of Medicine
Advanced Fellow, Mental Illness Research, Education, and Clinical Center (MIRECC)  VA Puget Sound
November 9, 2018

2. Disclosures No financial disclosures
The content presented here might not represent those of the VA or University of Washington
Cannabis is not approved for any use by the FDA, and remains a Schedule I listed substance by the DEA
There are currently no FDA approved medications for treatment of cannabis use disorder

3. Objectives
Learn the primary components and function of cannabis and the endocannabinoid system
Describe the biological and behavioral effects of cannabis in cannabis users
Understand the risks associated with cannabis on:
Mental health
Dependence
Withdrawal

5. Cannabinoids typically refer to certain compounds found in the cannabis plant
Cannabichromene
D9-Tetrahydrocannabivarin
D9-Tetrahydrocannabinol (THC)
Cannabidiol (CBD)
Cannabivarin
Cannabigerol
As of 2018, 538 naturally occurring compounds in cannabis sativa, and >100 identified as cannabinoids
Cannabinol is a product of non-enzymatic oxidative breakdown of THC, and therefore can become a marker of prior THC content and age of cannabis product.
Cannabidivarin
D8-Tetrahydrocannabinol
Pacher, et al., Pharmacological Reviews, 2006
Howlett, et al., Pharmacological Reviews, 2002
Bonini et al., Journal of Ethnopharmacology, 2018

6. Synthetic Cannabinoids were developed for research and medical purposes
Agonists
Inverse Agonists
Rimonabant
WIN 55,212-2
CP 55,940
AM281
Pacher, et al., 2006

7. Endogenous Cannabinoids are compounds found in the body and are involved in many regulatory processes
Anandamide
Virodhamine
2-Arachidonoylglycerol
2-Arachidonoyl
glycerol ether
(noladine ether)
N-Arachidonoyl dopamine
Pacher, et al., Pharmacological Reviews, 2006

8. Where do cannabinoids go in the body?
Cannabinoid receptor, subtype 1 (CB1)
Primarily found in brain
Also found in peripheral neurons, adrenal gland, heart, liver, bone marrow, testis, spleen, immune cells
Cannabinoid receptor, subtype 2 (CB2)
Primarily found on immune cells
Also found in spleen, thymus, bone marrow
Transient receptor potential vanilloid 1 channels (TRPV1), 5-HT3, 5-HT1a, GPR55, peroxisome proliferator-activated nuclear receptors, ligand gated ion channels, glycine transporter 1, fatty acid amide hydrolase, disrupted in schizophrenia protein (DISC1), …
Pacher, et al., Pharmacological Reviews, 2006
Howlett, et al., Pharmacological Reviews, 2002
Pertwee, et al., Pharmacological Reviews, 2010

9. Retrograde Neurotransmission to the CB1 Receptor
Ca2+
Ca2+
Ca2+
NAPE-PLD
Ca2+
Ca2+
Cell activation
Anandamide Gi
CB1 AC
FAAH
Arachidonic acid
Ethanolamine
Presynaptic neuron
Post-synaptic neuron
■ = GABA, glutamate, or dopamine

10. Estimation of CB1 receptor expression in human brain

11. Objectives
Learn the primary components and function of cannabis and the endocannabinoid system
Describe the biological and behavioral effects of cannabis in cannabis users
Understand the risks associated with cannabis on:
Mental health
Dependence
Withdrawal

12. Potential Beneficial Effects of:
D9-THC
Anti-emetic (nausea)
Increased appetite
Anti-spasmodic
Analgesic (pain relief)
Anxiolytic (anti-anxiety)
Bronchodilation
Decrease intraocular pressure
Therapeutic dose lower than psychoactive dose
Heightened senses
Cannabidiol (CBD)
Anti-inflammatory
Anti-convulsant
Anti-anxiety
Anti-psychotic
Anti-oxidant
Not intoxicating
Cannabis use is associated with decreased risk of metabolic syndrome and diabetes, however is associated with increased risk of pre-diabetes.

13. Potential Harmful Effects of Cannabis
Anxiogenic
Short term memory impairment
Cognitive impairment
Impaired judgment
Impaired senses
Impaired motor skills
Motor vehicle accidents
Paranoia
Increased risk for psychosis
Talkativeness/ hyperactivity
Increased heart rate
Dry mouth
Dry, red eyes
Symptoms of chronic bronchitis
Stroke
Myocardial infarction
Cancer
Low birth weight
Altered brain development (particularly in adolescents)
Addiction/Dependence
Withdrawal symptoms
Cancer: moderate evidence of no association between lung or head & neck cancers and cannabis smoking; there are some reports of increased risk of bladder cancer and cannabis smoking; there is limited evidence of statistical association between non-seminoma-type testicular germ cell tumors and cannabis smoking. Most other cancers have insufficient evidence to support or refute an association with cannabis use.

14. Cognitive impairment
is greatest in persistent heavy cannabis users who started during adolescence, and is dose dependent
Adolescent vulnerability. Shown is change in full-scale IQ (in SD units) from childhood to adulthood among study members with 1, 2, or 3+ diagnoses of cannabis dependence as a function of age of onset of cannabis dependence. Individuals with adolescent-onset cannabis dependence (black bars) experienced greater IQ decline than individuals with adult-onset cannabis dependence (gray bars). IQ decline of approximately −0.55 SD units among individuals with adolescent-onset cannabis dependence in the 3+ group represents a decline of 8 IQ points. Error bars = SEs.
Represents decline of 8 IQ points
Meier, et al,
PNAS, 2012

15. Objectives
Learn the primary components and function of cannabis and the endocannabinoid system
Describe the biological and behavioral effects of cannabis in cannabis users
Understand the risks associated with cannabis on:
Mental health
Dependence
Withdrawal

16. Psychiatric Illness can be potentially worsened with cannabis use
Psychosis and schizophrenia
Paranoia, hallucinations more likely to reoccur if experienced with early use
Increased risk of schizophrenia in adolescents
Increased risk for those with first degree relative with psychotic disorder
Heavier marijuana use, greater drug potency, and exposure at a younger age can all negatively affect the disease trajectory (e.g., by advancing the time of a first psychotic episode by 2 to 6 years)
Depression
Anxiety
May lower anxiety in some individuals, but at higher doses, appears to cause anxiety in most individuals
Post Traumatic Stress Disorder (PTSD)
ASSOCIATION, not causality, has been established
Depression is a risk factor for the development of problem cannabis use.
Bipolar disorder, anxiety disorders, ADHD, and personality disorders (with exception of oppositional behaviors in youth) are not risk factors for problem cannabis use.
Marijuana use also worsens the course of illness in patients with schizophrenia and can produce a brief psychotic reaction in some users that fades as the drug wears off. The amount of drug used, the age at first use, and genetic vulnerability can all influence this relationship. One example is a study  that found an increased risk of psychosis among adults who had used marijuana in adolescence and who also carried a specific variant of the gene for catechol-O-methyltransferase (COMT), an enzyme that degrades neurotransmitters such as dopamine and norepinephrine.
Notes courtesy of Jodi Gilman

17. Cannabis use in PTSD
Positive reinforcement: improves sleep, nightmares, night sweats, pain, and may enable avoidance
Negative reinforcement: cannabis withdrawal symptoms overlap with PTSD symptoms
Cannabis use (and cessation) has been associated with more severe PTSD symptoms
Less reduction of PTSD symptoms during treatment
Interference with fear extinction
Currently, quality evidence for cannabis as beneficial for PTSD treatment remains lacking
Since cannabis use and PTSD symptoms has been shown as association, its presently unclear if cannabis is used by those with more severe PTSD, or if cannabis is ineffective in reducing (or perhaps worsens over the long term) PTSD symptoms.
An association has been made between cannabis use and increased incidence in violence of individuals with PTSD who use cannabis.
Boden et al., Am J Addict 2013
Wilkinson et al., J Clin Psychiatry 2016

18. Dependence occurs in some individuals who have difficulty stopping or experience withdrawal
9% lifetime risk among those who try cannabis
1 in 6 (~17%) risk among those who start in adolescence
~50% risk among daily cannabis users
Lifetime risk for dependence of other substances: tobacco 32%, heroin 23%, cocaine 17%, alcohol 15%
Stimulant treatment of attention deficit hyperactivity disorder (ADHD) during adolescence is not  a risk factor for the development of problem cannabis use.
Being male and smoking cigarettes are risk factors for the progression of cannabis use to problem cannabis use.
Initiating cannabis use at an earlier age is a risk factor for the development of problem cannabis use.
No difference between males and females in the recurrence of problem cannabis use.
Hall, Addiction, 2014

19. Cannabis Withdrawal
Cessation of cannabis use that has been heavy and prolonged (i.e., usually daily or almost daily use over a period of at least a few months).
Three (or more) of the following signs and symptoms develop within approximately 1 week after Criterion A:
Irritability, anger, or aggression.
Nervousness or anxiety.
Sleep difficulty (e.g., insomnia, disturbing dreams).
Decreased appetite or weight loss.
Restlessness.
Depressed mood.
At least one of the following physical symptoms causing significant discomfort: abdominal pain, shakiness/tremors, sweating, fever, chills, or headache.
DSM-5

20. Cannabis Withdrawal
Chronic cannabis users, last use ~48 hours prior, average use ~9 joints/day; cohort population decreased over time
Lee et al, Am J Addict, 2014

21. Toxicology Assessment
Urine toxicology:
positive 2-8 days single or light use
Positive 30+ days for heavy, daily use
False positives possible with:
Dronabinol
NSAIDs
Pantoprazole (PPIs)
Hemp seed oil (in very large amounts)
Passive inhalation (yes, it’s possible)
~weekly user
~daily user
~daily user
Ellis et al, Clin Pharmacol Ther, 1985; Anderson, Current Sports Medicine Reports, 2011

22. Pharmacologic Interventions Cannabis Use Disorder
No FDA approved medications
Prior clinical trials either mixed or with limited results
Gabapentin: 1200mg/day for 12 weeks
N-acetylcysteine: 1200mg BID in adolescents
Zolpidem
Several compounds currently in clinical trials
Exercise helpful for initial period of abstinence

23. Cannabis Hyperemesis Syndrome
Chronic cannabis users
Cyclic bouts of nausea & vomiting
Learned hot baths or showers to get relief
Stops with sustained cannabis cessation
Seen in context of ER visit for N/V with negative work-up
Potentially fatal 2o glucose & electrolyte imbalance
May be improved with capsaicin cream
Haloperidol/olanzapine effective in some cases
Typically males with cannabis use, generally daily, >2 years
Diagnostic Criteria:
1 At least one discrete episode in the prior year and two episodes in the past 6 months, occurring at least 1 week apart
2 Presentation after prolonged excessive cannabis use (3–5 times daily for at least 2 years)
3 Relief of vomiting episodes by sustained cessation of cannabis use
The diagnosis is supported by pathologic bathing behavior (prolonged hot baths or showers), age below 50 years, weight loss of more than 5 kg, morning predominance of symptoms and unaffected bowel habits during attacks of nausea and vomiting, morning predominance of symptoms.
Capsaicin cream 0.075% applied TID – q4h in periumbilical region may improve symptoms, due to continued blacking of peripheral TRPV1 receptors, which is dephosphorylated and causes desensitization, leading to vagal afferent communicating with vagal efferents via area postrema, a brain region with high TRPV1 density
Dezieck et al, Cllinical Toxicology, 2017
Lapoint et al, Western Journal of Emergency Medicine, 2018
Moon et al, ACG Case Reports, 2018
Richards et al, Clinical Toxicology, 2018

24. Take Home Summary
Cannabis is a plant that contains chemicals (cannabinoids) that can interact with normal processes in the body.
Cannabinoids have several potential benefits and potential risks.
The risks of cannabis on cognition and psychosis are most profound on adolescents; in adults, cognitive impairment is likely reversible.
It is possible to become dependent on cannabis, and have withdrawal symptoms upon stopping it.
The effects of cannabis may change with the amount and duration it is used, in addition to many other factors.
There is no FDA approved treatments available. Medications may help during withdrawal. Education and psychotherapy may be effective interventions.