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10.30.19 Didactic STIMULANTS PART II Michael H. Baumann, Ph.D. Designer Drug Research Unit (DDRU), Intramural Research Program, NIDA, NIH Baltimore, MD 21224 Chronology of Stimulant Misuse 1. 2000s: Methamphetamine 2. 2010s: Bath Salts 3. Summary 2 Topics Covered for Each Substance Chemistry Formulations and Methods of Use Pharmacokinetics and Metabolism Desired and Adverse Effects Chronic and Withdrawal Effects Neurobiology Treatments 2000s: Methamphetamine Methamphetamine, a synthetic stimulant 5 Formulations and Methods of Use Methamphetamine (i.e., Ice or Crystal) Smoking using pipes Methamphetamine HCl Intravenous injection of solutions using needle and syringe Intranasal snorting of crystals Pharmacokinetics and Metabolism Pharmacokinetics Smoked and intravenous drugs reach brain within seconds Intranasal drug reaches brain within minutes Much longer half-life than cocaine Metabolism N-demethylation to form amphetamine (bioactive) Hydroxylation to form inactive metabolites Desired Effects Enhanced Mood and Euphoria Increased Attention and Alertness Decreased Need for Sleep Appetite Suppression Sexual Arousal Adverse Effects Psychosis Arrhythmias, Palpitations, Heart Attack Hypertension, Stroke Hyperthermia, Rhabdomyolysis Multisystem Organ Failure 11 www.facesofmeth.us. “METH Mouth” 12 Molecular Sites of Action SLC6 Monoamine Transporters Dopamine transporter (DAT) Norepinephrine transporter (NET) 5-HT transporter (SERT) Other sites Vesicular Monoamine Transporter 2 (VMAT2) Trace amine-associated receptors (TAAR1) METH is a DAT substrate (DA releaser) Vesicles Presynaptic DA cell VMAT D2 synapse DAT D2/D3-type Postsynaptic cell D1-type METH Increases DA more than 5-HT 2 4 0 0 1 2 0 0 ) * l ) S a l i n e S a l i n e l a a * M E T H s M E T H s 1 8 0 0 9 0 0 * a a b b 1 2 0 0 * % 6 0 0 * % ( ( * T * A 6 0 0 * H 3 0 0 - D 5 0 0 - 4 0 0 4 0 8 0 1 2 0 - 4 0 0 4 0 8 0 1 2 0 T i m e ( m i n ) T i m e ( m i n ) Baumann et al., 2002 Cocaine vs Methamphetamine COCAINE METH Inhibits DAT-mediated Inhibits DAT-mediated reuptake of synaptic reuptake of synaptic dopamine dopamine Evokes DAT-mediated release of dopamine 16 Cocaine vs Methamphetamine COCAINE METH Rapidly metabolized Slowly metabolized Effects last 1-2 hours Effects last 10-20 hours Withdrawal lasts 1-2 Withdrawal lasts many days days 17 METH decreases DAT sites in brain 18 Volkow et al., 2001 The Matrix Model Group Psychotherapy Individual Counseling Family Therapy Contingency Management (CM) Crystal Methamphetamine Anonymous Treatment of Co-occurring Disorders 19 Lee & Rawson, 2008 Role of METH in Gay Subculture 1. METH intoxication 2. Decreased inhibitions and judgment 3. Increased sensation seeking and sexual arousal 4. Unsafe sexual practices 5. HIV transmission 20 Levounis & Ruggiero, 2006 METH, Sex, and the Internet The Perfect Storm Sex, both virtual and real, both safe and unsafe, is only a click away Variable Intermittent Reinforcement 21 Internet websites foster risky behaviors 22 2010s: Bath Salts Cathinone, a Plant-Based Alkaloid 24 Khat plant Catha edulis En.Wikipedia.org Cathinone is b-keto amphetamine Bath salts induce serious adverse effects Neurological Confusion, aggression, paranoia, psychosis Cardiovascular Tachycardia, hypertension, stroke, heart attack Autonomic Hyperthermia, rhabdomyolysis, organ failure “Bath Salts” contain synthetic cathinones En.Wikipedia.org MDPV is an analog of pyrovalerone MDPV Blocks DAT (Inhibits DA Uptake) Vesicles Presynaptic DA cell VMAT D2 DAT Synapse D2/3-type Postsynaptic cell D1-type Methylone is b-keto analog of MDMA Methylone is a SERT substrate (5-HT releaser) Vesicles Presynaptic 5-HT cell VMAT 5-HT1B synapse SERT 5-HT1A-type Postsynaptic cell 5-HT2A-type Cathinones have replaced MDMA 1. METH is a powerful stimulant due to its DAT-mediated dopamine release 2. MDPV is a cocaine-like blocker at DAT whereas methylone is an MDMA-like releaser at SERT 34 1. No FDA-approved medications for stimulant dependence, so treatment is psychologically-based 2. No specific antidotes for stimulant intoxication, so treatment is supportive 3. Stimulant-induced deaths are increasing due to fentanyl co-administration: intentional or accidental? 35 .
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