Effect of Acute Marijuana on Cardiovascular Function
and Central Nervous System in occasional
and chronic marijuana users
Rakesh Awasthi
College of Pharmacy
Division of Pharmaceutics and
Translational Therapetics
Research Team
• Dr. Daniel O'Leary
Professor of Psychiatry, UIHC
• Dr. Laura Ponto
Associate Professor in Nuclear Medicine / PET, UIHC
• Dr Maureen D. Donovan
Professor and Chair, Pharmaceutics and Translational
Therapeutics, University of Iowa
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Health Impact of “Legalized” Marijuana
 Impairs judgement and motor
coordination
 Most prevalent illicit drug
detected in fatally injured drivers.
 Relationship between chronic use
and ongoing mental illness
(schizophrenia)
Source: http://www.drugabuse.gov/publications/drugfacts/marijuana
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Frequency of smoking
• Occasional Users: smoked marijuana fewer than 10
times per month
• Chronic Users: reported smoking 7 or more times
weekly for at least the past 2 years.
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Interesting finding
• Chronic users reported significantly lower
“highness” ratings, lower heart rates and smaller
HR changes, resulting in reduced RPP and RPP
changes.
• Changes in systolic and diastolic blood pressure
were not significantly different between the
groups (i.e., “chronic use” was nonsignificant).
Ponto et al., Journal of Clinical Pharmacology 2004, 44 (7), 751-66.
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Tolerance
• Repeated administration of
cannabinoids
• Down-regulation of CBRs
• Desensitization of receptor
mediated G-protein activation
Chronic users
CB1 receptor
downregulation
Less sensitive
to impairing
effect of THC
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UI Investigation of THC Effects
on Cognition
Study #1
Single occasion
Placebo and active drug
Study #2
Two different days
Two different doses of active drug
#1 Placebo & active drug (Dose A)
#2 Active drug (Dose B)
Occasional users: Low (13.2 mg) and medium dose (23.5 mg)
Chronic users: Medium (24.9 mg) and high dose (44.9 mg)
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Data Acquired
 PK Results
 Blood plasma levels of THC and THC-COOH were determined immediately
post-smoking (for both placebo and active joint) and at 3 times, at the
interval of 15-20 min, within the following 60 min. (4 blood
samples/subject/dose)
 Additional information:
 Number of puffs, duration of each smoking session, and refined dose for
each subject.
 PD Measurements (pre-smoking and after each smoking activity)





Heart rate
Blood pressure
Rate pressure product (calculated) - RPP
Subjective effects (highness) – self-reported (scale 1 to 10)
Cerebrovascular function – rCBF
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“Dosing” THC via Marijuana Smoking
 Patients were instructed to smoke entire (2.5 in) cigarette
using a control inhalation/breath hold/exhalation sequence.
 Cigarettes containing THC was smoked for a specific period of
time (6-8 min).
 The number of puffs were recorded and each was treated as
an individual bolus input.
 Example A cigarette with 44.5 mg (high dose) of THC was
smoked in 11 puffs within 7 min of starting time. Then, 11
bolus doses (4.045 mg each) at intervals of 0.0106 h, were
used as the THC input.
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Optimizing PK Parameters Using THC Profiles for Chronic Users
Using PKPlus Module of GastroPlus® (44.5 mg Dose)
Optimized parameters (HDC)
Rsq = 0.96
Cl /F(L/h)
255.5
Vc/F (L)
127.6
k12 (1/h)
6.34
k21 (1/h)
0.19
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Summary of PK analysis
The optimized PK parameters can also be used to
describe the results obtained from
individual smoking sessions.
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OBJECTIVE
• Rate pressure product (RPP) - marker of myocardial oxygen
consumption
RPP  Heart Rate  Systolic blood pressure
• To compare the difference in RPP between the two groups
(i.e. occasional and chronic users), while taking into account
the effect of potential covariates (age, gender, weight,
highness etc.).
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