Stimulants Brian J. Piper, Ph.D.
Nov 01, 2014
StimulantsBrian J. Piper, Ph.D.
Goals
• Examples– Methamphetamine– Cocaine– Khat
• Pharmacodynamics• Pharmacokinetics• Epidemiology• Overdose
Amphetamines
__
Amphetamine Methamphetamine
History of Amphetamine
• 1887: first synthesized by L. Edeleano• 1932: SKF introduces Benzedrine• 1970s: peak use in the U.S.
She may be tired for either of two reasons:
*because she is physically overworked. If thisis the case, you prescribe rest because rest is the only cure for this kind of physical tiredness
*because she is mentally “done in”. Many of your patients---particularly housewives---are crushed under a load of dull, routine duties that leave them in a state of mental andemotional fatigue. For these patients, you mayFind “Dexedrine” an ideal prescription.
“Dexedrine” will give them a feeling of energyand well being, renewing their interest in lifeand living.
Amphetamine Sensitization
• Rats given 2.0 mg/kg of d-amphetamine once per day for 10 days
• Measure amount of drug-induced rotational behavior each day
Pharmacodynamics
• Mechanisms– VMAT reversal– DAT reversal– DAT reuptake inhibition
Microdialysis for Dopamine (DA)
1.2
AMPH
1.0
0.8
0.6
0.4
0.2
080 160 240
Time (min)
700
600
500
400
300
200
100
0–40 0 40 80 120 160 200
0.75 mg/infusion0.50 mg/infusion0.25 mg/infusion0.00 mg/infusion
Time (min)
Increasein DA
History of Methamphetamine• 1893: Synthesized by Nagai Nagayoshi in Japan• 1940s- : Popular with military• 1960s- : used for short-term treatment of obesity, narcolepsy,
and, later, ADHD• 1983- : federal and states laws attempt to reduce use by
decreasing availability of ephedrine and pseudoephedrine• 2000s- : several aggressive advertising campaigns are aimed
at reducing demand
History of Methamphetamine• 1893: Synthesized by Nagai Nagayoshi in Japan• 1940s- : Popular with military• 1960s- : used for short-term treatment of obesity, narcolepsy,
and, later, ADHD• 1983- : federal and states laws attempt to reduce use by
decreasing availability of ephedrine and pseudoephedrine• 2000s- : several aggressive advertising campaigns are aimed
at reducing demand (Faces of Methamphetamine)
Montana Meth Project• Businessman Thomas
Siebel supported graphic advertising in 2005
• Goal was to reach each teenager 3+ times/week (TV, radio, print).
To View Ads: http://www.methproject.org/ads/tv/tracy.htmlhttp://www.montanameth.org/View_Ads/index.php
True of False: “the MMP results in Montana have been more significant than any other drug
prevention program in history”?
Youth Risk Behavior Survey
• High School students were asked about lifetime methamphetamine use before and after the Montana Methamphetamine Project.
Anderson (2010) J Health Econ
True or False: “the MMP results in Montana have been more significant than any other drug
prevention program in history”?
Youth Risk Behavior Survey
• High School students were asked about lifetime methamphetamine use before and after the Montana Methamphetamine Project.
Anderson (2010) J Health Econ
Other Faces of Methamphetamine
Robert Downey, Jr.Andre Agassi
Stacy Ann Ferguson “Fergie” Ted Arthur Haggard
Other Faces of Methamphetamine
Methamphetamine Epidemiology (MtF)
Past year use of crystal.
Year Year
% Reporting “fairly easy” or “very easy”to get.
Meth & Young-Adults
Meth & Spatial Memory In Rodents• Rodent research has found that early developmental
Methamphetamine treatments cause persistent impairments in spatial memory.
Acevedo SF, de Esch IJ, Raber J (2007) Neuropsychopharmacology 32:665-672
Exclusion Criteria:* born before 35 weeks gestational age* epilepsy * Tourette’s syndrome * cerebral palsy* congenital abnormalities * severe brain trauma* Fetal Alcohol Syndrome* uncorrected visual impairments
Flyers Posted at:* OHSU* Coffee shops, Book stores* Grocery stores* Drug Tx programs•Needle exchange programs•Crystal Meth Anonymous
Meth/Polysubstance Use
Unexposed (N=35) Exposed (N=31)
Trimesters of Methamphetamine 0 (0) 2.5 (0.3)***
Income while pregnant : <15,000Income currently : >35,000
17.1%51.4%
76.2*60.0%
Maternal Age at Birth (years) 26.9 (1.1) 29.8 (1.5)
Nicotine 17.1% 76.2***
Alcohol 11.4% 71.4%***
Marijuana 11.4% 58.8%*
Biological father involved 85.7% 44.8%***
Number of other childrenIn home
2.7 (0.3) 1.3 (0.3)**
Piper et al. (2011) Pharm Biochem Behav
Reduced Academic Performance in Exposed Children
Unexposed (N=35) Exposed (N=31)
Birth Weight (g) 3,279 (114) 3,367 (194)
Females 42.9% 53.3%
Ethnicity (% non-Caucasian) 25.7% 20.0%
Age at testing (7-9) 8.4 (0.2) 8.1 (0.2)
Below Grade Level (%) 3.0% 25.9%*
Below Reading Level (%) 20.6% 38.5%
.Piper et al. (2011) Pharm Biochem Behav
Memory IslandVisible (x 4)
Hidden (x 4)
Rizk-Jackson et al. (2006) Behav Brain Res 2006;173(2):181-90, Piper et al. Behav Brain Res.
Memory Island
Memory Island Performance is Reduced by Exposure
Increased Rates of ADHD
.
Behavioral Rating Inventory of Executive Function (BRIEF)
• Please rate whether the following behaviors are never, sometimes, or often a problem (1-3 points):– Emotional Control (EC) : overreacts to small problems– Inhibit (INH): interrupts others– Shift (SHI): becomes upset with new situations– Working Memory (WM): when given three things to do, remembers only the first or last– Initiate (INI): has trouble coming up with ideas for what to do in play time– Plan/Organize (PO): gets caught up in details and misses the big picture– Organization of Materials (OM): cannot find things in room– Monitor (MON): does not check work for mistakes
– Behavioral Regulation Index + Metacognition Index = Global Executive Composite (Mean= 50.0, SD = 10)
Gioia GA, Isquith PK, Guy SC, et al. (2000). Behavioral Rating Inventory of Executive Function: Professional Manual. Psychological Assessment Resources: Lutz.
*** p < .0005, ** p < .005, * p < .05 .
“Clinically Significant” Behavioral Problems in Exposed Children
Piper et al. (in review) Psychopharmacology.
Selectivity of Domains AlteredUnexposed Exposed
IQ (WASI) 104.5 (3.7) 95.1 (3.5)#
Vocabulary 51.0 (2.2) 46.3 (1.7) #
Matrix Reasoning 53.8 (1.9) 48.4 (2.2) #
Block Design 52.7 (2.2) 50.0 (1.8)
Spatial Span (Forward) 5.7 (0.3) 5.3 (0.3)
Spatial Span (Backward) 4.9 (0.4) 4.5 (0.4)
Family Pictures (Immediate) 57.0 (5.3) 46.5 (5.1)
Family Pictures (Delayed) 52.6 (5.7) 43.4 (5.1)
#p < .10
Piper et al. (2011) Pharm Biochem Behav
Blood levels of “Ice”
Blood level (ng/ml)
Hours
Spiders• Web building was
examined the day before and after stimulant administration.
Before After
Vehicle
0.04 uL/mgMethamphetamine
0.10 uL/mgCaffeine
Hesselberg & Vollrath (2004) Physiology & Behavior, 82, 519-529.
Araneus diadematus
History of Cocaine
• 1850s: Cocaine isolated from Erythroxylon coca• 1880s: Sigmund Freud evolves from strong cocaine proponent
(therapy for heroin addiction, antidepressant) to become more cautious & stops using (migraines) in 1896
• 1904: Cocaine is removed as an ingredient from Coca Cola
1856-1939
History of Cocaine
• 1984: Crack emerges in LA, NY, & Miami• 1985: Sentencing laws, 500 g cocaine or 5 g crack = 5 years, 100:1!• 2010: Fair Sentencing Act (Kucinich & Paul): 18:1
Keith Haring, 1958-1990
http://www.youtube.com/watch?v=ytJpZguSy2U
Pharmacodynamics
• Reuptake inhibition of– DAT– NET– SERT
Short video of Cocaine and Neurotransmission: http://www.utexas.edu/research/asrec/cocaine.mov
Is cocaine addictive?• Cocaine withdrawal:
– does not produce physical symptoms
– does produce psychological symptoms:
• exhaustion• depressed mood• anhedonia• anxiety• craving
Other Neurotransmitters?
Immunostraining for DAT (A) or tyrsoineHydroxylase (B) in wild-type (+/+), hetero-Zygotous or DAT knock-out (-/-) mice.
Sora et al. (2001). PNAS, 95, 7699-7704.
Other Neurotransmitters?
Rocha et al. (1998) Nature Neuroscience, 1, 132-137.
Other Neurotransmitters (5-HT/NE)?
• Autoradiography using [123I]RTI55 & also with a SERT inhibitor (Alaproclate)
Rocha et al. (1998) Nature Neuroscience, 1, 132-137.
Conditioned Place Preference
• CPP to cocaine is present in DAT or SERT knock-outs
• Double knock-outs do not show CPP
Sora et al. (2001). PNAS, 98, 5300-5305.
DAWN ER Visits
Rank Me: Stimulants, MJ, Heroin, Cocaine
DAWN ER Visits
Comparison
Cocaine Methamphetamine
Schedule II (surgery) II (ADHD)
Base form “crack” “crystal”
Half-life (hours) 1 11
Metabolite Benzoylecgonine (BE) amphetamine
Mechanism(s) DA, NE, 5-HT uptake inhibition DA, NE, 5-HT uptake inhibition + release
Julien (2009) Primer of drug action.
Methylphenidate
• Treatment for ADD/ADHD• Blocks dopamine reuptake, increases norepinephrine• Pills crushed and snorted
Methylphenidate
C
O
OCH
N
CH3
MtF: “Amphetamines” =Adderall & Ritalin
Juvenile Methylphenidate alters CPP to cocaine
Rats received methylphenidate (2 mg/kg) or saline as juveniles (PD 20-35) followed by cocaine in adulthood (PD 60). Juvenile methylphenidate altered the conditioned place preference (A) and locomotor (B) responses to cocaine.
Anderson et al. (2001) Nature Neuroscience, 5,13-14.
Cathinone
– active agent in Khat (or qat)– chewed– synthetic version (meth-
cathinone)
CH NH2C
CH3
O
Cathinone
PET images from control subjects, Parkinson’s patients, and abstinent methamphetamine and methcathinone users (average period of abstinence, 3 years). WIN-35,429 binding to the dopamine transporter.
Neurotoxicity?
McCann et al. (1998). J Neurosci 18, 8417-8422.
Sympathomimetic Summary
• Pharmacokinetics• Pharmacodynamics: DA, NE, 5-HT• Epidemiology
Nora Volkow “Mechanisms Underlying Use and Abuse of Stimulant Drugs”http://videocast.nih.gov/summary.asp?Live=1997
DA : dopamine, MAO: Monoamine oxidase
Methylphenidate = Ritalin
Top row: radioactive cocaine labelingBottom row: radioactive methylphenidate labeling
Basal Ganglia: brain area important for movement
Time course for cocaine (2, 4, 8, 10, 20, 30, & 40) orMethylphenidate (2, 4, 8, 10, 20, 30, 40, 60, 90) minutes
High is shown in green
DA: dopamine; MAO A: monoamine oxidase, type A
Outliers: extreme scores statistically
Raclopride: drug that binds to D2 receptors
Top: DAT Occupancy by dose (mg/kg)Bottom: self-rated high by dose (mg/kg)
DA: dopamine receptor, autoreceptor: presynaptic
po: per os or by mouth (oral administration)
DA: dopamine, DAT: dopamine transporter, MP: methylphenidate
Microdialysis for DA (dopamine) following stress, methylphenidate, or stress + methylphenidate
Effects of MP on Perception of the Task andCorrelations with MP-induced DA changes
Effects of Methylphenidate (MP) when given with a Mathematical or a Neutral Task on [11C]raclopride binding, coditions: Placebo + Neutral task; MP + neutral task, Placebo +Mathematical Task, Methylphenidate + Mathematical task
Gr: tyros (cheese)amino acid
Treatment for
Parkinson’s
disease
Neurotransmitter important for movement, reinforcement
Neurotransmitter important for cognition
6.2