1. 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

2. 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 2

3. 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) 3 Source: http://www.drugabuse.gov/publications/drugfacts/marijuana

4. 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. 4

5. 5 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). Interesting finding Ponto et al., Journal of Clinical Pharmacology 2004, 44 (7), 751-66.

6. Tolerance Repeated administration of cannabinoids Down-regulation of CBRs Desensitization of receptor mediated G-protein activation 6 Chronic users CB1 receptor down- regulation Less sensitive to impairing effect of THC

7. UI Investigation of THC Effects on Cognition 7 Study #1 Single occasionPlacebo 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)

8. 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 8

9. “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. 9

10. Optimized parameters (HDC) Cl /F(L/h)255.5 Vc/F (L)127.6 k12 (1/h)6.34 k21 (1/h)0.19 10 Optimizing PK Parameters Using THC Profiles for Chronic Users Using PKPlus Module of GastroPlus® (44.5 mg Dose) Rsq = 0.96

11. Summary of PK analysis The optimized PK parameters can also be used to describe the results obtained from individual smoking sessions. 11

12. OBJECTIVE Rate pressure product (RPP) - marker of myocardial oxygen consumption 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.). 12