Effects of Drugs on Dopamine Release. Methamphetamine: Current Knowledge about Effects and Treatments

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1 % of Basal Release % of Basal Release % Basal Release % of Basal Release Methamphetamine: Current Knowledge about Effects and Treatments Richard A. Rawson, Ph.D, Research Professor Center for Behavior and Health University of Vermont Professor Emeritus Semel Institute for Neuroscience and Human Behavior David Geffen School of Medicine University of California at Los Angeles rrawson@mednet.ucla.edu A major reason people take drugs is that they like what they do to their brains Effects of Drugs on Dopamine Release 15 Accumbens METHAMPHETAMINE 4 Accumbens COCAINE 1 3 DA DOPAC HVA hr Time After Methamphetamine Time After Cocaine 25 NICOTINE 25 Accumbens ETHANOL Accumbens Caudate 2 15 Dose (g/kg ip) hr Time After Nicotine hr Time After Ethanol Source: Shoblock and Sullivan; Di Chiara and Imperato 1

2 Decreased dopamine transporter binding in METH users resembles that in Parkinson s Disease patients Control Methamphetamine PD Source: McCann U.D.. et al.,journal of Neuroscience, 18, pp , October 15, In other words Their Brains have been Re-Wired by Drug Use Prolonged Drug Use Changes The Brain In Fundamental and Long-Lasting Ways 2

3 How much does the brain heal? Partial Recovery of Brain Dopamine Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence 3 Normal Control METH Abuser (1 month detox) METH Abuser (24 months detox) ml/gm Source: Volkow, ND et al., Journal of Neuroscience 21, , 21. Medical Consequences of Methamphetamine Use 3

4 Cardiovascular effects Heart rate and blood pressure elevation (Newton et al., 25) Autopsy studies: elevated heart weight, microvascular disease, accelerated CAD (Karch, 22) Peripheral catecholamine excess: cardiotoxic Vasospasm, myocyte hypertrophy, fibrous tissue formation Rapid progression of multivessel CAD in young MA abusers relative to controls (Karch, 1999) Arrhythmias Microvascular pathology, fibrous tissue, and pre-existing structural lesions are predisposing factors QTc prolongation (Haning and Goebert, 27) Sudden death reported Prevalence and nature of cardiovascular disease in methamphetamine-related death: A national study Drug and Alcohol Dependence, Oct 217, 179, Darke S, Duflou, J, Kaye, S. Background Methamphetamine dependence is a major public health problem. This study examined the nature, and extent, of cardiovascular disease amongst cases of methamphetamine-related death in Australia, Methods Analysis of 894 cases of methamphetamine-related death with full autopsy reports retrieved from the National Coronial Information System. Prevalence and nature of cardiovascular disease in methamphetamine-related death: A national study Results The mean age was 37.9 yrs (range yrs) and 78.5% were male. A quarter (26.3%) of cases had enlarged hearts and left ventricular hypertrophy was diagnosed in 18.9%. Severe coronary artery disease was present in 19.%, the left coronary artery being the vessel most frequently stenosed (16.6%). Replacement fibrosis (evidence of earlier ischaemic events) in the heart muscle was observed in 19.8% of cases, and cardiomyopathy was diagnosed in 5.5%. Histological evidence of hypertension was observed in 32.7% of cases. With the exception of cardiomyopathy, equally common amongst both sexes, cardiovascular disease was more common amongst males, and those aged >35yrs. Clinically significant levels of cardiovascular disease were also attributed to : cardiomegaly (19.3%), left ventricular hypertrophy (14.6%), severe coronary artery disease (9.4%), replacement fibrosis (14.4%), cardiomyopathy (3.3%). 4

5 Methamphetamine use and heart failure: Prevalence, risk factors, and predictors The American Journal of Emergency Medicine, January 218 John R.RichardsMDBrian N.HarmsMDAmandaKellySamuel D.TurnipseedMD Objectives To compare methamphetamine users who develop heart failure to those who do not and determine predictors. Methods Patients presenting over a two-year period testing positive for methamphetamine on their toxicology screen were included. Demographics, vital signs, echocardiography and labs were compared between patients with normal versus abnormal B-type natriuretic peptide (BNP). Methamphetamine use and heart failure: Prevalence, risk factors, and predictors Conclusion Methamphetamine-positive patients have a significantly higher prevalence of heart failure than the general emergency department population who are methamphetamine-negative or not tested. The methamphetamine-positive subgroup who develop heart failure tend to be male, older, White, former smokers, and have higher creatinine, heart and respiratory rates. This subgroup also has greater biventricular dysfunction, dimensions, and higher pulmonary arterial pressures. Pulmonary Effects Dyspnea common in ED settings (Albertson et al., 1999) Inhalation injuries from toxic fumes during MA manufacture (Santos et al., 25) Pulmonary edema (Nestor et al., 1989; Karch, 1999) Idiopathic pulmonary HTN (Chin et al., 23) Birefringent crystals in pulmonary vasculature (Karch, 1999) Mechanisms: catecholamine-mediated vasoconstriction and endothelial injury, direct toxicity, MJ/tobacco use 5

6 Dental effects Rampant caries and tooth fracture most common (Shaner, 22; 26) Periodontal disease Mechanisms: Poor oral hygiene Xerostomia (dry mouth) Alpha 2 receptor stimulation inhibits saliva Dehydration from appetite suppression and increased psychomotor activity Soft drink consumption Bruxism Acidic content of MA (controversial) Corrosive contaminants of MA (smoking) Dermatological Effects Pruritis from vasoconstriction Cutaneous ulcers and excoriations from skin picking (formication, meth bugs ) Abscesses ( skin popping confers greatest risk) Cellulitis Burn injuries Psychiatric Illness Among Methamphetamine Users 6

7 Psychiatric Diagnoses and Outcomes Of those who participated in the Methamphetamine Treatment project, 48% met criteria for a current or past psychiatric disorder. Mood disorders, anxiety disorders, and antisocial personality disorders were the most common diagnoses. MA use Those with an Axis I disorder reported greater frequency of MA use during follow-up (M=15.5 months, SD=.8) compared to those without a diagnosis (M=12.8 months, SD=.8), t(523)= -2., p=.3.. MA use frequency during FU increased as a function of the number of psychiatric diagnoses (β=.68, SE=.29, p=.2). Results: Psychotic Disorders 12.9% of the sample was diagnosed with a psychotic disorder (current or past). Those with psychotic illness were more likely to have been hospitalized within the year prior to FU than those without a diagnosis (OR=2.4, 95% C.I., ) and reported more episodes (β=.33, SE=.11, p<.1). Those with psychotic illness evidenced declining functional outcomes on the ASI (medical, employment, legal) and worsening psychological impairment on the BSI from baseline to FU. No difference in MA use frequency among those with and without psychotic disorders during FU (M= versus months); no difference in tx adherence. Risk Factors for Depression and Suicide Attempts in Methamphetamine Dependent Adults Glasner-Edwards, S., Mooney, L.J., Marinelli-Casey, P., Hillhouse, M., Ang, A., Rawson, R.A. (28). Identifying methamphetamine users at risk for major depressive disorder: findings from the Methamphetamine Treatment Project at 3-year follow-up. American Journal on Addictions, 17: Glasner-Edwards, S., Mooney, L.J., Marinelli-Casey, P., Hillhouse, M., Ang, A., Rawson, R.A. (28). Risk factors for suicide attempts in methamphetamine dependent patients. American Journal on Addictions, 17(1):

8 Risk Factors for Major Depressive Disorder Candidate risk factors included Female gender Route of MA administration Alcohol dependence History of suicide attempts or serious depression Clinically significant depressive sx s at baseline (BDI > 2) Family hx psychiatric problems Lifetime hx physical or sexual abuse Key findings: Depression severity at treatment entry (BDI>2) and lifetime history of suicide attempts were reliable predictors of a depression diagnosis 3 years after treatment. Predictors of SA 28.7% (n=151) of MA dependent patients at follow-up had attempted suicide in their lifetime After controlling for age, marital status, education and lifetime MA use, five risk factors for lifetime SA included: BDI>2 (OR=1.8, 95% C.I., ) Female gender (OR=2., C.I., ) IV use (OR=2.2, C.I., ) Psychiatric admission hx (OR=1.7, C.I., ) Serious depression hx (OR=3.1, C.I., ) Dose-Related Psychotic Symptoms in Chronic Methamphetamine Users McKetin, et al. (213). Dose-Related Psychotic Symptoms in Chronic Methamphetamine Users. JAMA Psychiatry. 213;7(3),

9 Predicted Probability of Psychotic Symptoms, % Predicted probability of psychotic symptoms by level of MA, alcohol, and cannabis use McKetin, et al. (213). Dose-Related Psychotic Symptoms in Chronic Methamphetamine Users. JAMA Psychiatry. 213;7(3), Dose-Related Psychotic Symptoms in Chronic MA Users The likelihood of experiencing psychotic symptoms is 5 times higher during periods of methamphetamine use than during periods of no use. Evidence of a strong dose-response effect was found between number of days of MA use and psychotic symptoms. McKetin, et al. (213). Dose-Related Psychotic Symptoms in Chronic Methamphetamine Users. JAMA Psychiatry. 213;7(3), Clinical Challenges with Methamphetamine Dependent Individuals Limited Understanding of Addiction Cognitive Impairment Anhedonia Sexual Reactivity and Meth Craving Elevated Potential for Violence Persisting Flashbacks of Meth Paranoia Sleep Disorders Poor Retention in Outpatient Treatment Elevated Rates of Psychiatric Co-morbidity 9

10 Special treatment consideration should be made for the following groups of individuals: Female MA users (higher rates of depression; very high rates of previous and present sexual and physical abuse; responsibilities for children). Injection MA users (very high rates of psychiatric symptoms; severe withdrawal syndromes; high rates of hepatitis). MA users who take MA daily or in very high doses. Homeless, chronically mentally ill and/or individuals with high levels of psychiatric symptoms at admission. Individuals under the age of 21. Gay men (at very high risk for HIV and hepatitis). Methamphetamine Cognitive and Memory Effects Frequency of Impairment by Neuropsychological Domain 6 6 Controls MA Users % Impaired Attention/ Psychomotor Speed Learning and Memory Working Memory Fluency Inhibition Executive Systems Function 1

11 Percent Responding "Yes" Defining Domains: Executive Systems Functioning Frontal lobe functioning deficits. Deficits on executive tasks assoc. w/: Poor judgment. Lack of insight. Poor strategy formation. Impulsivity. Reduced capacity to determine consequences of actions. Methamphetamine and Sex My sexual drive is increased by the use of opiates alcohol cocaine meth Primary Drug of Abuse male female (Rawson et al., 22) 11

12 Percent Responding "Yes" My sexual pleasure is enhanced by the use of opiates alcohol cocaine meth Primary Drug of Abuse male female (Rawson et al., 22) Sexual Issues and Relapse Sexual compulsivity Concern over sexual abstinence Concern over sexual disinterest Loss of intensity of sexual enjoyment Shame/guilt about sexual behavior Sexual arousal producing craving Sexual behavior and intimacy Methamphetamine Route of Administration 12

13 % of MA-free UA (3 wks) BSI Psychiatric Symptoms by Route IN SM IDU Positive Symptom Total (PST) BL PST TX-End PST 6-Mo PST 12-Mo PST P<.5 MA-Free Samples by Route IN SM IDU.2.1 P<.5 Impact of Methamphetamine Treatment on HIV Risk Behavior Rawson, R., Gonzales, R., Pearce, V., Ang, A., Marinelli-Casey, P., & MTP Corporate Authors. Methamphetamine dependence and HIV risk behavior. Journal of Substance Abuse Treatment. In Press. 13

14 MTP: Treatment Impact on Risky Behavior Longer treatment retention is significantly associated with less risky behavior (based on sex risk score) among MA users (B=-.43, p<.1). Treatment completion is significantly related to less risky sexual behavior among MA users (B=-.565, p<.1). Significant reduction in injection behavior for completers than non-completers (p<.5). Study Implications MA treatment is associated with substantial reductions in HIV risk behaviors. Retention and treatment completion play a critical role in preventing the escalation of HIV risk behaviors. Methamphetamine and Violence 14

15 Primary Substance Reported by California Inmates (N=22,93) Marijuana 6 Alcohol Heroin Other Cocaine Methamph Methamphetamine Use, Self-Reported Violent Crime, and Recidivism Among Offenders in California Who Abuse Substances Cartier J, Farabee D, Prendergast M. Methamphetamine Use, Self-Reported Violent Crime, and Recidivism Among Offenders in California Who Abuse Substances. Journal of Interpersonal Violence. 26;21: Participants Methods 88 low- to medium-level inmates Clear history of substance abuse Within 12 months of release Half the sample entering an in-prison substance abuse (SA) program and the other half from a neighboring prison that offered no formal SA treatment Matched by age, ethnicity, sex offender status, and commitment offense 15

16 Results Those who used MA (81.6%) were significantly more likely than those who did not use MA (53.9%) to have been returned to custody for any reason or to report committing any violent acts in the 3 days prior to follow-up (23.6% vs. 6.8%, respectively) MSM, Methamphetamine and Sexual Risks In the United States, methamphetamine is commonly used by gay and bisexual men (and other men who have sex with men) in conjunction with sex (Semple et al., 21; Halkitis et al., 28; Shoptaw, 26; Reback et al., 213) There are strong connections between methamphetamine use, sexual risk behaviors, and HIV prevalence rates among MSM (Plankey et al., 27; Shoptaw & Reback, 26; Colfax et al., 25; Reback, 1997; Molitor et al., 1998; Mattison et al., 21; Mansergh et al., 21; Reback et al., 24) Changes in sexual behaviors Changes in decision-making processes Methamphetamine is highly integrated into gay male socio-sexual contexts (Colfax et al., 21; Mansergh et al., 21; Reback, 1997) MSM, Methamphetamine and HIV Antiretroviral Therapy (ART) HIV-positive methamphetamine users receiving HIV treatment have lower rates of complete viral suppression than former methamphetamine users receiving same treatment (Ellis et al., 23) HIV positive methamphetamine users have greater rates of medical non-compliance to HIV treatment compared to their non-methamphetamaine using counterparts (Reback & Larkins, 23) Methamphetamine-using TB patients have greater rates of TB non-adherence compared to their non-methamphetamineusing counterparts (Gelmanova et al., 27) 16

17 Treatments for Methamphetamine Dependence Intensive Outpatient Psychosocial and Behavioral Therapies Cognitive Behavioral Therapy Contingency Management Combined CBT + CM Matrix Model mhealth Interventions Can Be Coupled with Other Therapies to Optimize Treatment Outcomes Medications: Bupropion Elkashef AM, Rawson RA, Anderson AL, et al. Bupropion for the treatment of methamphetamine dependence. Neuropsychopharmacology. 28;33(5): Heinzerling KG, Swanson AN, Hall TM, Yi Y, Wu Y, Shoptaw SJ. Randomized, placebo-controlled trial of bupropion in methamphetamine-dependent participants with less than daily methamphetamine use. Addiction. 214;19(11): Anderson AL, Li SH, Markova D, et al. Bupropion for the treatment of methamphetamine dependence in non-daily users: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 215;15:

18 Impact of an exercise intervention on methamphetamine use outcomes postresidential treatment care Drug and Alcohol Dependence, 215, 156, Richard A. Rawson 1, Joy Chudzynski 1, Larissa Mooney 1, Rachel Gonzales 1, Alfonso Ang 1, Daniel Dickerson 1, Jose Penate 1, Bilal A. Salem 1, Brett Dolezal 2, Christopher B. Cooper 2 Method We examined the efficacy of an 8-week exercise intervention on posttreatment methamphetamine (MA) use outcomes among MA-dependent individuals following residential treatment. One hundred thirty-five individuals newly enrolled in residential treatment were randomly assigned to a structured exercise intervention or a health education control group. Approximately 1 week after study completion, participants were discharged to the community. Interview data and urine samples were collected at 1- and 3-months post-residential care. Impact of an exercise intervention on methamphetamine use outcomes postresidential treatment care Results A significant interaction for self-reported MA use and MA urinanalysis results (OR =.17, P =.3) by condition and MA severity was found. Lighter users in the exercise group used MA significantly fewer days at 1- and 3-months post-discharge (.7 & 1.8 days, respectively) than light users in the education group (3.8 & 7.3 days, respectively). This relationship was not present in the comparison of the two heavy-user subgroups. Results support the value of exercise as a useful component of treatment for MA-dependent individuals who use lower levels of MA. Thank you rrawson@mednet.ucla.edu 18