New Clinical Information Regarding the Treatment of Individuals for Cocaine and Methamphetamine Dependence Richard A. Rawson, Ph.D Professor Semel Institute for Neuroscience and Human Behavior David Geffen School of Medicine University of California at Los Angeles www.uclaisap.org rrawson@mednet.ucla.edu Supported by: National Institute on Drug Abuse (NIDA) Pacific Southwest Technology Transfer Center (SAMHSA) International Network of Treatment and Rehabilitation Resource Centres (UNODC)

Stimulants COCAINE CRACK METHAMPHETAMINE

Stimulants Description: A group of synthetic and plant-derived drugs that increase alertness and arousal by stimulating the central nervous system. Medical Uses: Short-term treatment of obesity, narcolepsy, and hyperactivity in children Method of Use: Intravenous, intranasal, oral, smoking

Types of Stimulant Drugs Cocaine Products Cocaine Powder (Generally sniffed, injected, smoked on foil) “Crack” (smoked) Major areas of use: South America; USA (predominantly major urban centers, disproportionately impacts African American community); Increasing in Europe.

Types of Stimulant Drugs Amphetamine Type Stimulants (ATS) Amphetamine “Speed” Dexamphetamine “Ice” Methylphenidate “Crank” Methamphetamine “Yaba” “Shabu”

Methamphetamine vs. Cocaine Cocaine half-life: 1-2 hours Methamphetamine half-life: 8-12 hours Cocaine paranoia: 4 -8 hours following drug cessation Methamphetamine paranoia: 7-14 days Methamphetamine psychosis - May require medication/hospitalization and may not be reversible Neurotoxicity: Appears to be more profound with amphetamine-like substances

Scope of the Methamphetamine Problem Worldwide According to surveys and estimates by WHO and UNODC, methamphetamine is the most widely used illicit drug in the world except for cannabis. World wide it is estimated there are over 26 million regular users of amphetamine/methamphetamine, as compared to approximately 16 million heroin users and 14 million cocaine users

Acute Stimulant Effects Psychological Increased energy Increased clarity Increased competence Feelings of sexuality Increased sociability Improved mood Powerful rush of euphoria - freebase and intravenous only

Acute Stimulant Effects Physical Increased heart rate Increased pupil size Increased body temperature Increased respiration Constriction of small blood vessels Decreased appetite Decreased need for sleep Numbness of nasal mucosa - intranasal only

Chronic Stimulant Effects Physical Weight loss/anorexia Sleep deprivation Respiratory system disease Cardiovascular disease Headaches Severe Dental disease Needle marks and abscesses - intravenous only Seizures

Long-term effects of stimulants Strokes, seizures, and headaches Irritability, restlessness Depression, anxiety, irritability, anger Memory loss, confusion, attention problems Insomnia Paranoia, auditory hallucinations, panic reactions Suicidal ideation Sinus infection Loss of sense of smell, nosebleeds, chronic runny nose, hoarseness Dry mouth, burned lips Worn teeth (due to grinding during intoxication) Problems swallowing Chest pain, cough, respiratory failure Disturbances in heart rhythm and heart attack Gastrointestinal complications (abdominal pain and nausea) Loss of libido Malnourishment, weight loss, anorexia Weakness, fatigue Tremors Sweating Oily skin, complexion

Cocaine Hydrochloride Crystalline white powder Snorted in “lines” of 10-35 mg each Adulterated w cheap local anesthetics, stimulants, and inert white powders Yields moderate to high blood levels Gradual onset of effects at 15-20 min with peak at 30-60 min

Cocaine Hydrochloride: Intravenous Administration Soluble in water Peak blood levels achieved instantaneously Rapid onset, brief duration, intense “crash” Rapid develop. of compulsive use pattern “Speedball” when mixed with heroin to cushion the “crash”

Cocaine Freebase “Crack” Extracted from cocaine HCL using ether, ammonia, or sodium bicarbonate Extraction does not remove impurities Pharmacodynamics almost identical to intravenous use Avoids many medical hazards of I.V. use

Cocaine: Mechanism of CNS Action Stimulates dopamine secretion in dopaminergic pathways in brain Prevents dopamine reuptake at synapse Acute effect- dopamine flooding Chronic effect- dopamine depletion Dopamine agonists/replacements have not proved therapeutically useful in addicts

Cocaine: Acute Effects Euphoric mood Increased energy, alertness Increased sexuality Paranoia Increased heart rate, blood pressure

Cocaine: Chronic Effects Lethargy, fatigue Reduced attention span Sexual dysfunction Depression, irritability, anhedonia Paranoid psychosis

Cocaine: Toxic Reactions Cardiac arrhythmias, fibrillation Hyperthermia- > 106 degrees F Convulsions, loss of consciousness Respiratory & cardiac arrest Abruptio placentae (miscarriage) Fatal reactions rare, but unpredictable

Cocaine “Crash” Rebound dysphoria Agitation, restlessness Intensifies w dosage & chronicity of use Cravings & drug-seeking behavior Abuse of alcohol & other drugs Suicidal ideation, behavior Often followed by prolonged sleep

Cocaine: Clinical Considerations No clearcut physical withdrawal syndrome Pharmacotherapies: See Vocci notes Serious medical consequences are uncommon Psychiatric consequences are extremely common: Depression, anhedonia, labile moods, irritability, paranoia, suicidal ideation Usually remit within several days/weeks of abstinence & without pharmacotherapy Persisting symptoms beyond 6 to 8 weeks may warrant psychiatric evaluation & possible pharmacotherapy

Speed It is methamphetamine powder ranging in color from white, yellow, orange, pink, or brown Color variations are due to differences in chemicals used to produce it and the expertise of the cooker Other names: Shabu, Crystal, Crystal Meth, Crank, Tina, Yaba

Ice High purity methamphetamine crystals or coarse powder ranging from translucent to white, sometimes with a green, blue, or pink tinge

Their Brains have been Re-Wired by Drug Use Because…

Abuser After Protracted Abstinence Partial Recovery of Brain Dopamine Transporters in Methamphetamine (METH) Abuser After Protracted Abstinence 3 ml/gm Normal Control METH Abuser (1 month detox) METH Abuser (24 months detox) Source: Volkow, ND et al., Journal of Neuroscience 21, 9414-9418, 2001.

33 year old man, high on methamphetamine admitted to emergency room complaining of severe headache in Portland Oregon. X-ray revealed 12, 2 inch nails (6 on each side) in his head, administered with aq nail gun. The man at first claimed it was an accident, but he later admitted that it was a suicide attempt. The nails were removed, and the man survived without any serious permanent damage. He was eventually transferred to psychiatric care; he stayed for almost one month under court order but then left against doctors’ orders MSNBC-TV

Brain Serotonin Transporter Density and Aggression in Abstinent Methamphetamine Abusers* * Sekine, Y, Ouchi, Y, Takei, N, et al. Brain Serotonin Transporter Density and Aggression in Abstinent Methamphetamine Abusers. Arch Gen Psychiatry. 2006;63:90-100.

Cardiac Disorders and MA Use Coronary Syndromes Arrhythmia Cardiomyopathy Hypertension Valvular Disease

Neurologic Disorders and MA Use Headache Seizure Cerebrovascular Ischemic stroke Cerebral hemorrhage Cerebral vasculitis Cerebral edema

Respiratory Disorders and MA Use Pulmonary edema Bronchitis Pulmonary hypertension COPD

METH Use Leads to Severe Tooth Decay “METH Mouth” Source: The New York Times, June 11, 2005.

Methamphetamine Psychiatric Consequences Paranoid reactions Permanent memory loss Depressive reactions Hallucinations Psychotic reactions Panic disorders Rapid addiction

MA Psychosis Inpatients from 4 Countries No. of patients having symptoms (%) Psychotic symptom Lifetime Current Persecutory delusion Auditory hallucinations Strange or unusual beliefs Thought reading Visual hallucinations Delusion of reference Thought insertion or made act Negative psychotic symptoms Disorganized speech Disorganized or catatonic behavior 130 (77.4) 122 (72.6) 98 (58.3) 89 (53.0) 64 (38.1) 56 (33.3) 35 (20.8) 75 (44.6) 39 (23.2) 27 (16.1) 38 (22.6) 20 (11.9) 18 (10.7) 36 (21.4) 19 (11.3) 14 (8.3) Srisurapanont et al., 2003

MA Psychosis 69 physically healthy, incarcerated Japanese females with hx MA use 22 (31.8%) no psychosis 47 (68.2%) psychosis 19 resolved (mean=276.2±222.8 days) 8 persistent (mean=17.6±10.5 months) 20 flashbackers (mean=215.4±208.2 days to initial resolution) 11 single flashback 9 Recurrent flashbacks Yui et al., 2001 Polymorphism in DAT Gene associated with MA psychosis in Japanese Ujike et al., 2003

Treatment

Is Treatment for Methamphetamine Effective? A pervasive rumor has surfaced in many geographic areas with elevated MA problems: MA users are virtually untreatable with negligible recovery rates. Rates from 5% to less than 1% have been quoted in newspaper articles and reported in conferences.

Meth. Treatment Statistics During the 2002-2003 fiscal year: 35,947 individuals were admitted to treatment in California under the Substance Abuse and Crime Prevention Act funding. Of this group, 53% reported MA as their primary drug problem

Statistics Analysis of: Drop out rates Retention in treatment rates Re-incarceration rates Other measures of outcome All these measures indicate that MA users respond in an equivalent manner as individuals admitted for other drug abuse problems. Analysis of data from 3 other large data sets and 3 clinical trials data sets suggest treatment response (using psychosocial treatments) of MA and cocaine users is indistinguishable.

Additional Information on Population

Mean Days of Primary Drug Use in Last 30 Days

Why the “MA Treatment Does Not Work” Perceptions? Many of the geographic regions impacted by MA do not have extensive treatment systems for severe drug dependence. Medical and psychiatric aspects of MA dependence exceeds program capabilities. High rate of use by women, their treatment needs and the needs of their children can be daunting. Although some traditional elements may be appropriate, many staff report feeling unprepared to address many of the clinical challenges presented by these patients

Bupropion: An Efficacious Pharmacotherapy? Newton et al., (2005): Bupropion reduces craving and reinforcing effects of meth Elkashef (recently completed): Bupropion reduces meth use in an outpatient trial, with particularly strong effect with less severe users.

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).

Contingency Management A technique employing the systematic delivery of positive reinforcement for desired behaviors. In the treatment of methamphetamine dependence, vouchers or prizes can be “earned” for submission of methamphetamine-free urine samples.

Contingency Management for treatment of methamphetamine dependence Design: RTC Method: 113 patients diagnosed with methamphetamine abuse or dependence were randomly assigned to receive either treatment as usual (TAU) or TAU plus contingency management. Results indicate that both groups were retained in treatment for equivalent times but those in the combined group accrued more abstinence and were abstinent for a longer period of time. These results suggest that contingency management has promise as a component in methamphetamine use disorder treatment strategies. Contingency Management for the Treatment of Methamphetamine Use Disorders. Roll, JM et al, Archives of General Psychiatry, (In Press)

Cognitive Behavioral Therapy and Contingency Management for Stimulant Dependence Design Randomized clinical trial. Participants Stimulant-dependent individuals (n = 171). Intervention CM, CBT, or combined CM and CBT, 16-week treatment conditions. CM condition participants received vouchers for stimulant-free urine samples. CBT condition participants attended three 90-minute group sessions each week. CM procedures produced better retention and lower rates of stimulant use during the study period. Results Self-reported stimulant use was reduced from baseline levels at all follow-up points for all groups and urinalysis data did not differ between groups at follow-up. While CM produced robust evidence of efficacy during treatment application, CBT produced comparable longer-term outcomes. There was no evidence of an additive effect when the two treatments were combined. The response of cocaine and methamphetamine users appeared comparable. Conclusions: This study suggests that CM is an efficacious treatment for reducing stimulant use and is superior during treatment to a CBT approach. CM is useful in engaging substance abusers, retaining them in treatment, and helping them achieve abstinence from stimulant use. CBT also reduces drug use from baseline levels and produces comparable outcomes on all measures at follow-up. Rawson, RA et al. Addiction, Jan 2006

Contingency Management: A Meta-analysis A recent meta-analysis reports that CM results in a successful treatment episode 61% of the time while other treatments with which it has been compared result in a successful treatment episode 39% of the time (Prendergast, Podus, Finney, Greenwell & Roll, submitted)

Matrix Model in Treatment of Methamphetamine Depenence Design: The study was conducted as an eight-site randomized clinical trial. Method: 978 treatment-seeking, MA-dependent persons were randomly assigned to receive either TAU at each site, or a manualized 16-week treatment (Matrix Model) for their MA dependence. Results: Analyses of study data indicate that in the overall sample, and in the majority of sites, those who were assigned to Matrix treatment attended more clinical sessions, stayed in treatment longer, provided more MA-free urine samples during the treatment period, and had longer periods of MA abstinence than those assigned to receive TAU. Measures of drug use and functioning collected at treatment discharge and 6 months post-admission indicate significant improvement by participants in all sites and conditions when compared to baseline levels, but the superiority of the Matrix approach did not persist at these two time points. Conclusions: Study results demonstrate a significant initial step in documenting the efficacy of the Matrix approach. Although the superiority of the Matrix approach over TAU was not maintained at the posttreatment time points, the in-treatment benefit is an important demonstration of empirical support for this psychosocial treatment approach. Rawson, R et al Addiction vol 99, 2004

Mean Number of Weeks in Treatment

Mean Number of UA’s That Were MA-free During Treatment

Urinalysis Results Results of Ua Tests at Discharge, 6 months and 12 Months post admission** Matrix Group TAU Group D/C: 66% MA-free 65% MA-free 6 Ms: 69% MA-free 67% MA-free 12 Ms: 59% MA-free 55% MA-free **Over 80% follow up rate in both groups at all points

Prenatal Meth. Exposure Preliminary findings on infants exposed prenatally to methamphetamine (MA) and nonexposed infants suggest: Prenatal exposure to MA is associated with an increase in SGA (Small-for-Gestational-Age). Neurobehavioral deficits at birth were identified in NNNS (Neonatal Intensive Care Unit Network Neurobehavioral Scale) neurobehavior, including dose response relationships and acoustical analysis of the infant’s cry (Lester et al., 2005).

Adolescent Meth. Abuse Treatment Admissions Matrix (Boys) (Girls) 2002 16% 63% 2003 25% 67% 2004 22% 69% Phoenix (Boys) (Girls) 2002 25% 43% 2003 23% 51% 2004 27% 53%

My Sexual Pleasure is Enhanced by the use of: (Rawson et al., 2002)

My Sexual Performance is Improved by the use of: (Rawson et al., 2002)

Behavior Symptom Inventory (BSI) Scores at Baseline

Route of Methamphetamine Administration Smoking (SM) was the most common route of MA administration (n=632, 65%), followed by injecting (IDU) (n=228, 23.4%) and intranasal (IN) (n=113, 11.6%).

BSI Psychiatric Symptoms by Route Positive Symptom Total (PST) Results from the BSI show that IDUs were more psychologically impaired across all nine dimensions and three global indices of the BSI before entering treatment and after exiting tx compared to SMs and INs The Brief Symptom Inventory (BSI) is a 53-item self-report symptom inventory used to assess psychological symptoms across nine dimensions and three global indices of distress. The nine symptom dimensions include: somatization, obsessive-compulsive, interpersonal sensitivity, depression, anxiety, hostility, phobic anxiety, paranoid ideation, and psychoticism, and the three global indices include: the Global Severity Index (measuring overall psychological distress level), the Positive Symptom Distress Index (measuring the intensity of symptoms), and the Positive Symptom Total (measuring the number of self-reported symptoms). P<.05

Hepatitis C by Route P<.05 To date, three-year follow-up medical testing data reveal that approximately 28 of the 979 MA users are carriers of the Hepatitis C virus. Results showed that these rates of Hepatitis C significantly differed by route of administration, such that the majority of Hepatitis C cases were diagnosed among injectors (74.1%; n=21, compared to smokers (22.2%; n=6) and intranasal users (3.7%; n=1). P<.05

Methamphetamine Abuse: Treatment as Prevention Richard A Methamphetamine Abuse: Treatment as Prevention Richard A. Rawson, Cathy J. Reback, Steven Shoptaw UCLA Integrated Substance Abuse Programs

Overview Substance abuse concomitant with risky sex for MSM (Stall & Wiley, 1988) Different drugs have differing prevalence of HIV among MSM Drug abuse treatments dramatically reduce methamphetamine use and high-risk sex Reductions are sustained! Policy implications Substances have long been used by members of the gay and bisexual male communities to enhance sexual functioning. Prior to meth, it was cocaine. Poppers continue to be used. These substances are used to cover feelings of shame and homophobia around having sex, to cover fatigue from dealing with HIV infections (whether one is already positive or one is negative, but engaging in risk behaviors periodically so always anxious about becoming positive) and to facilitate a type of extreme sexual behavior that is not available when not medicated (not enough energy to sustain hours to days of continuous sexual behaviors). While substances have been used for a long time, different drugs of abuse have differences in prevalence for HIV among MSM. We provide data on a study that shows reductions in meth use and high risk sex and end with policy implications of this work.

Sex Risks Reduced with Treatment: UARI Past 30 Days

Summary Use of psychostimulants is a significant public health problem in the US. In California (and worldwide), methamphetamine is and has been for some time the most widely used illicit drug other than cannabis. Cocaine and methamphetamine produce man similar acute and chronic effects. Psychosocial treatments currently have greatest empirical support, although research on pharmacotherpies is promising.

Thank you rrawson@mednet. ucla. edu www. uclaisap. org www Thank you rrawson@mednet.ucla.edu www.uclaisap.org www.methamphetamine.org