TPR PODCAST EPISODE 5 “Don’t Harsh My Mellow, Dude”

Written by Theresa Kim, MD

Outline

1)    Introduction

2)    Pharmacology and Pharmacokinetics

3)    Review of “Adverse health effects on marijuana use†(NEJM)

4)    Review of “Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado†(Drugs & Alcohol Dependence)

5)    Review of “Medical Marijuana and Driving: A Review†(Journal of Medical Toxicology)

6)    Take Home Points

Introduction

• 
  
• This episode was inspired by Maureen Dowd’s column “Don’t Harsh Our Mellow, Dude” in the New York Times
  
• In the article Ms. Dowd experiments with a marijuana edible candy bar while traveling in Colorado
  
• She consumes a much larger amount than recommended for novices
  
• What followed:
  

o   “…Then I felt a scary shudder go through my body and brain. I barely made it from the desk to the bed, where I lay curled up in a hallucinatory state for the next eight hours. I was thirsty but couldn’t move to get water. Or even turn off the lights. I was panting and paranoid, sure that when the room-service waiter knocked and I didn’t answer, he’d call the police and have me arrested for being unable to handle my candy.”

Pharmacology and Pharmacokinetics of Cannabinoids

• 
  
• Marijuana contains many compounds including ∆9-tetrahydrocannabinol (THC) and cannabidiol
  

o   ∆9-THC: primarily responsible for the psychotropic effect seen with marijuana use

o   Cannabidiol: no psychotropic properties but thought to have medically useful effects such as sedation, anti-epileptic, anti-emetic, anti-inflammatory, and antagonism of the psychotropic aspects of THC

• 
  
• While many users are familiar with smoking marijuana they may not be aware that the pharmacokinetics of inhalation vs. consumption are distinctly different
  

o   Inhalation

• 
  
• Onset of psychotropic effects within seconds-minutes
  
• Peak blood level of THC within minutes
  
• Maximal effect within a half hour
  
• Duration of action 2-3 hours
  
• Titration is relatively easy given the fast onset and time to peak
  

o   Consumption/Ingestion of edibles

• 
  
• Absorption from the GI tract is slower and more irregular than inhalation
  
• The Cytochrome P450 (CYP) system in the liver metabolizes THC > 11-hydroxy-THC (11-OH-THC) > 11-nor-9-carboxy-THC (TCH-COOH)
  
  • 
    
  • 11-hydroxy-THC is an active metabolite that has psychotropic effects and is possibly even more powerful THC itself
    
  • 11-nor-9-carboxy-THC is an inactive metabolite, and is the main metabolite detected on a urine drug screen
    
  
  
  
• Onset of psychotropic effects is within 30-90 minutes
  
• Maximal effect within 2-3 hours
  
• Duration of action 4-12 hours
  
• Titration is more difficult given the delayed onset and time to maximal effect
  

Review of “Adverse health effects on marijuana use†(NEJM)

• 
  
• This article examines the possible relationship between marijuana and its effects on:
  

o   “Cannabis addiction†and the “cannabis withdrawal syndromeâ€

o   Impairment of brain development especially in adolescence or younger individuals

o   Possible role as a gateway drug

o   Increased risk of mental illness such as anxiety, depression, and schizophrenia

o   Impairment of school performance and lifetime achievement

o   Increased risk of motor vehicle accidents

o   Risk of cancer, and increased incidence of bronchitis

• 
  
• Critique of the article:
  

o   The article states that “The popular notion seems to be that marijuana is a harmless pleasure, access to which should not be regulated or considered illegal.â€

• 
  
• This is actually a “straw man†argument. Few medical professionals or legislators hold this extreme position
  

o   The paper argues, without presenting evidence, that legalizing cannabis will increase use

o   With regards to the relationship to marijuana and addiction, the authors quote talking points from various research articles

• 
  
• The authors do not critically analyze the studies they rely on
  
• Many of the studies the authors cite are large surveys with methods that either dubious or not clear
  

o   The authors reference a cannabinoid withdrawal syndrome which has not yet been clearly established in the literature

o   There is potential bias given that the authors are from the National institute on Drug Abuse

o   Table 2 which is titled “Level of confidence in the evidence for adverse effects of marijuana and on health and well-being†contradicts several parts of the article text itself

• 
  
• Example: In the Table, schizophrenia, depression and anxiety are listed as effects of marijuana with a “medium†overall level of confidence. This is not consistent with the text which states: “It is inherently difficult to establish causality in these types of studies because factors other than marijuana use may be directly associated with the risk of mental illness…This makes it difficult to confidently attribute the increased risk of mental illness to marijuana use.â€
  
• It is also completely unclear how the authors came up with their rating system for “overall level of confidenceâ€
  

o   Agree with table I which illustrates the increasing potency of THC in marijuana

• 
  
• In 1995 4% THC in marijuana vs. in 2012 12%
  

o   Agree with the notion that marijuana use by adolescents has potentially adverse effects on brain development

• 
  
• Of note, no states have legalized marijuana use by adolescents
  

o   Agree with the claim that marijuana use can impair driving skills

o   Agree with the need for further research to clarify the relationship between legislative policy and marijuana use

Review of “Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado†(Drugs & Alcohol Dependence)

• 
  
• This study looked at the rates of registered medical marijuana users pre- and post-legalization of marijuana in Colorado and compared it to rates of positive urine and serum marijuana tests of Colorado drivers involved in a fatal motor vehicle crash
  

o   It found a positive correlation: as the rates of marijuana users went up, the rates of fatal motor vehicle crashes in which drivers tested positive for marijuana went up as well

• 
  
• Critique of the article:
  

o   Urine tests can be positive for days-months after the last use so drivers who tested positive for marijuana were not necessarily under the influence at the time of the crash

o   The article does not stress the interesting point that motor vehicle related fatalities in Colorado declined over the course of the study (figure 4)

• 
  
• ~750 fatalities in 2002 compared with ~500 in 2011
  
• Potential explanations for this:
  
  • 
    
  • Some marijuana users may be staying at home and not driving
    
  • Some marijuana users may be abstaining from concurrent alcohol use while driving
    
  • Safer vehicles and road rules may have contributed to reduced motor vehicle fatalities
    
  
  
  

Review of “Medical Marijuana and Driving: A Review†(Journal of Medical Toxicology)

• 
  
• Comprehensive literature review of marijuana and driving using MEDLINE and Google Scholar from January 1964-May2013
  
• Some key highlights from the article:
  

o   Bioavailability of marijuana:

• 
  
• Inhalation: 10-35%
  
• Ingestion: 5-20%
  

o   Literature on drug testing:

• 
  
• Some investigators have tried to institute a “legal limit†of 2-5 ng/ml THC
  
• Unlike alcohol, marijuana does not have the pharmacokinetics that allows serum THC concentration to easily be used to measure of the degree of intoxication
  
  • 
    
  • When inhaled:
    
  
  
  

o   THC concentration peaks within minutes

o   THC only measurable for the first 2 hours or so

o   Psychomotor effects peak within 30 min and can last 8 hours or more

• 
  
• Thus, although a positive blood THC may indicate recent use, the THC concentration itself doesn’t necessarily correlate with the severity of intoxication
  

• 
  
• Urine drug screen as a measure of acute intoxication is useless as it detects the inactive metabolite which may remain positive up to several months after the initial use
  
• Psychomotor effects taper off around 8 hours but can potentially last > 24 hours
  
  • 
    
  • One study showed that there were significant flight simulator performance detriments noted 24 hours after use. (These results could not be reproduced in a repeat study.)
    
  • More data is needed before a clear time cutoff is given for how many hours after use of marijuana it is safe to drive
    
  
  
  

o   Route of administration (inhalation vs. ingestion) of marijuana has an important effect on onset and duration of impairment

o   Literature on impairment not completely clear

o   Marijuana compared to ethanol

• 
  
• Marijuana users tend to drive slower, have greater following distances, and overestimate degree of impairment, whereas ethanol users tend do the opposite
  

• 
  
• Critique
  

o   Overall excellent article with extensive amount of literature analysis

o   More research needed correlating THC and other marijuana metabolites with level of impairment

Take Home Points

• 
  
• Overall increased amounts of THC in marijuana today compared with the past
  
• Pharmacokinetics of inhalation vs. consumption of marijuana are distinctly different
  
• When ingesting edible marijuana products, the onset of effects is delayed and the duration of action is much longer than when marijuana is smoked
  
• Medical providers need to be educated on the adverse effects of marijuana, and should caution patients regarding coingestion of marijuana with other drugs and substances such as alcohol
  

Past Quizzler

Q: This person held the Guinness world record for the longest coma

A: Elaine Esposito. After an appendectomy in Chicago in 1941, she remained in a coma for 37 years!

Congratulations Nadia Awad!

Honorary mention: Sean Ragone

Current Quizzler

Posted at the end of the podcast

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Comments

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Bibliography

Dowd, M. (2014, June 3). Don’t harsh our mellow, dude. The New York Times.

Grotenhermen, F. (2003). Pharmacokinetics and pharmacodynamics of cannabinoids. Clinical Pharmacokinetics. 42(4), 327-360.

Healy, J. (2014, May 31). After 5 months of sales, Colorado sees the downside of a legal high. The New York Times.

Neavyn, M.J., Blohn, E., Babu, K.M., Bird, S.B. (2014, March 20). Medical marijuana and driving: a review. The Journal of Medical Toxicology.

Salomonsen-Sautel, S., Min, S-J, Sakai, J.T., Thurstone, C., Hopfer, C. (2014, April). Trends in fatal motor vehicle crashes before and after marijuana commercialization in Colorado. Drug and Alcohol Dependence. 140, 137-144.

KIRO. (2013, February 13). Stoned drivers test skills. CNN.

Volkow, N.D., Baler, R.D., Compton, W.M., Weiss, S.R.B. (2014, June 5). Adverse health effects of marijuana use. The New England Journal of Medicine. 370(23), 2219-2227.