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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 2 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 3 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 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. 5 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 6 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) 7 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 “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 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 10 Summary of PK analysis The optimized PK parameters can also be used to describe the results obtained from individual smoking sessions. 11 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.). 12