Transcript Why to study ‘Cannabinoids’

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)
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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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