STIMULANTS- PART I

Michael H. Baumann, Ph.D.

Designer Drug Research Unit (DDRU), Intramural Research Program, NIDA, NIH Baltimore, MD 21224 Chronology of Stimulant Misuse

1. 1980s: Cocaine

2. 1990s: Ecstasy

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 1980s: Cocaine Cocaine, a Plant-Based Alkaloid Andean Cocaine is Trafficked Globally

UNODC World Drug Report, 2012

Formulations and Methods of Use

 Cocaine Free Base (i.e., Crack)  Smoking of free base “rock” using pipes

 Cocaine HCl  Intravenous injection of solutions using needle and syringe  Intranasal snorting of powder Pharmacokinetics and Metabolism

 Pharmacokinetics  Smoked drug reaches brain within seconds  Intravenous drug reaches brain within seconds  Intranasal drug reaches brain within minutes

 Metabolism  Ester hydrolysis to benzoylecgonine  Ecgonine methyl ester

Cone, 1995 Rate Hypothesis of Drug Reward

 Smoked and Intravenous Routes  Faster rate of drug entry into the brain  Enhanced subjective and rewarding effects

 Intranasal and Oral Routes  Slower rate of drug entry into the brain  Reduced subjective and rewarding effects Desired Effects

 Enhanced Mood and Euphoria  Increased Attention and Alertness  Decreased Need for Sleep  Appetite Suppression  Sexual Arousal Adverse Effects

 Psychosis  Tachycardia, Arrhythmias, Heart Attack  Hypertension, Stroke  Hyperthermia, Rhabdomyolysis  Multisystem Organ Failure Tolerance- Blunted Effects

 Acute Tachyphylaxis or “First Dose” Effect  Cardiovascular Effects  Euphoria and sexual arousal  But no longer-term tolerance

 Anorexia

13 Sensitization- Enhanced Effects

 Seizures  Psychosis  Paranoid delusions  Visual, auditory and tactile hallucinations  Virtually indistinguishable from schizophrenia  Stereotypical Behaviors

14 Withdrawal Effects

 Anhedonia and Depressed Mood  Increased Appetite  Anergia and Fatigue  Vivid or Unpleasant Dreams  Insomnia or Hypersomnia Molecular Sites of Action

 SLC6 Monoamine Transporters  Dopamine transporter (DAT)  Norepinephrine transporter (NET)  5-HT transporter (SERT)

 Other sites  Sodium channels DATs mediate DA uptake

 DATs are membrane proteins cytoplasm  DATs are responsible for uptake of released dopamine (DA)

 Drugs that disrupt DAT function increase synaptic DA DAT

 Increases in DA are rewarding synapse Cocaine Blocks DAT (Inhibits DA Uptake)

Vesicles Presynaptic DA cell VMAT

D2

DAT Synapse

D2/3-type Postsynaptic cell D1-type Cocaine Increases Synaptic DA in Rats

Saline 600 Saline 6000 Cocaine Cocaine ** 400 3 4000 ** 3 1 ** ** ** 200 * 2000 1

DA (% basal) (% DA * *

Activity (% basal) (% Activity 0 0 -40 0 40 80 120 -40 0 40 80 120 Time (min) Time (min)

Baumann et al., 1994 Cocaine is Self-Administered by Rats

8 0 A c t i v e C o c a i n e I n a c t i v e 6 0

4 0

2 0

0

A 1 A 6 E 1 E 6 D a y

Schindler et al., 2016 Treatment for Cocaine Dependence

 Pharmacotherapy  No FDA-approved medication for cocaine dependence

 Psychologically-Based Therapies  Cognitive Behavioral Therapy  Group and Community Therapies  Twelve Step Programs Dopamine Agonists - FAIL

Amato et al. 2011 1990s: Ecstasy Ecstasy (MDMA), a synthetic club drug MDMA is a ring-substituted amphetamine

Methamphetamine 3,4-Methylenedioxymethamphetamine (MDMA) Formulations and Methods of Use

 Powders, tablets and capsules  Oral ingestion of tablets or capsules most common  Some intranasal and intravenous use

 “Bumping”, or repeated doses over time  “Stacking”, or multiple doses at once  “Binge and crash” cycling Pharmacokinetics And Metabolism

 Pharmacokinetics  Cmax reached within 2 h of oral ingestion  Non-linear drug accumulation at doses > 3 mg/kg

 Metabolism  N-demethylation to form MDA (bioactive)  O-demethylenation to form hydroxylated metabolites

de la Torre et al., 2004 MDMA metabolism is complex

Baumann et al., 2007 Desired Effects

 Combined effects of a stimulant and hallucinogen  Enhanced mood and energy  Heightened or altered sensory perception

 Feelings of empathy and closeness to others  Cardiovascular stimulation Adverse Effects

 Psychosis  Sympathetic stimulation  Palpitations and heart attack  Hypertension  Serotonin Syndrome  Hyperthermia and dehydration  Treat with hydration, cooling, and sedation  Avoid b-blockers, which may worsen and hypertension Withdrawal

 Anhedonia and depressed mood  Lethargy and fatigue for several days  Sleep disturbances  No indication for treatment Molecular Sites of Action

 SLC6 Monoamine Transporters  5-HT transporter (SERT)  Dopamine transporter (DAT)  Norepinephrine transporter (NET)

 Other sites  Vesicular Monoamine Transporter 2 (VMAT2)  5-HT2A receptors SERTs mediate 5-HT uptake

 SERTs are membrane proteins cytoplasm  SERTs are responsible for uptake of released 5-HT

 Drugs that disrupt SERT function increase synaptic 5-HT SERT

 Increases in 5-HT are not synapse rewarding (e.g., SSRIs) MDMA 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 MDMA Increases 5-HT more than DA

4 0 0 1 2 0 0

S a l i n e ) S a l i n e

l

)

l a

a M D M A * s M D M A

s 3 0 0 9 0 0

a

a

b

b

* * *

2 0 0 % 6 0 0 (

% * * *

(

*

T A

1 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., 2008 Neurotoxic Potential

 MDMA acutely increases synaptic 5-HT  SERT-mediated 5-HT release (i.e., reverse transport)

 MDMA chronically decreases tissue 5-HT  Depletion of serotonin stores  Inhibition of 5-HT synthesis

 Neurotoxicity? 1. Cocaine is the prototypical dopaminergic stimulant that acts by blocking DAT

2. MDMA acts as a mild stimulant and hallucinogen due to its SERT-mediated 5-HT release

37