Stimulants• Generally work by turning on neurons in

1 of 2 places: – cortex (frontal lobes) - cognitive – subcortical (nucleus accumbens +) - reward

• primarily DA (plus NE, ACh, glu) – fiber pathways from neurons in the striatum

(basal ganglia) release DA into the frontal cortex and nucleus accumbens

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Stimulants

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Caffeine• Other name(s): trimethylxanthine • Class: Phytochemical (methylxanthine) alkaloid – plant-based compound found in coffee, tea, kola,

yerba mate, guarana, guayusa, cocoa & holly – “alkaloid” refers to a broad class of organic

chemicals (i.e., contain carbon) that also contain nitrogen

• Forms: mostly teas, but also pills and powd •plant extracts (tea / coffee), pills (NoDoze),

powder, soaps, sprays

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Caffeine• History: – ~3000 BCE first mention of tea – ~600 BCE cocoa (Mayans) – 760 CE Cha Ching written in China – ~1400-1500s CE coffee in Middle East / northern Africa (dancing goats) – kola nut - used in Africa for ages – 1819 first synthesized (“Kaffebase”) – 1895 first ever "total synthesis” by Hermann

Fischer (1902 Nobel Prize)

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Caffeine• History (cont): –Current clinical usage - primarily to stay awake • also, headache (fx on blood vessels) & asthma (bronchiodialator)

– most widely used psychoactive drug in the world – coffee is: •the most popular drink in the world (after water) •the 2nd largest traded commodity (after oil) •used by 80% of Americans are regular users –daily intake ~200-500 mg »generally not considered to be “abuse”

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Caffeine• Effects: – primarily a CNS stimulant • feel more alert, confident • fast, clear flow of thoughts • wakefulness, reduced fatigue

– ED50 ~100 mg – peripheral effects: • cardiac: increases oxygen supply & output of heart, vascular relaxation • respiratory: bronchial relaxation • diuretic

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Caffeine• Effects (cont): – too much: • ~1500 mg / day, or 6-7 12 oz mugs of coffee – disrupted delicate muscular coordination – agitation – anxiogenesis – rapid breathing – insomnia

• LD50 ~10 g (or ~42 big 12 oz mugs / 4 gal of coffee) – LD50:ED50 ~ 100:1

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Caffeine• Effects (cont): – as little as 100 mg / day may produce

habituation, tolerance & dependence – Withdrawal effects (max in 1-2 days, may last

several days) • headache • drowsiness / mental “fog” / fatigue • bad mood

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Caffeine• Pharmacodynamics: – Primarily acts an adenosine antagonist • adenosine excites GABAergic neurons

– causes release of GABA » inhibits neurons that release DA (also NE, ACh, glu)

– acts as an endogenous “depressant” / sleep regulator

• caffeine blocks adenosine receptors – prevents GABA release

» disinhibits DA neurons, allowing them to fire

– Can also directly block GABAa receptors at higher doses

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Caffeine

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Caffeine

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• Pharmacodynamics: – the randomness of chemistry

DopamineDopamine

DopamineDopamine

Dopamine

GABAX X

• Pharmacodynamics: – During the day (wide awake): • striatal (and other) neurons active and releasing DA

(and other “stimulating” like NTs NE, ACh, glu) • GABAergic fiber pathways terminate on these

neurons, but they are relatively inactive

Caffeine

GABAergic neuron Dopaminergic neuron

• Pharmacodynamics: – End of day (getting sleepy)

• adenosine slowly builds up over the day – binds w/ excitatory adenosine receptors on the GABAergic

neurons that terminate on the “stim” neurons •GABAergic neurons fire, releasing GABA onto

dendrites of DA neurons, inhibiting them

Dopamine

Dopamine

DopamineDopamine

Dopamine

Sleepy (nighttime)

GABAAdenosine X X

Caffeine

GABAergic neuron Dopaminergic neuron

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DopamineDopamine

DopamineDopamine

Dopamine

GABAAdenosine X - Caffeine X

Caffeine• Pharmacodynamics: – With caffeine

• adenosine blocked from activating GABAergic neurons – DA neurons are DISinhibited, allowing them to become

active again » more awake

GABAergic neuron Dopaminergic neuron

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Caffeine• Pharmacodynamics: – caffeine is a “clean” stimulant – DA release disinhibited mostly into the frontal

cortex (cognition / motor) – NOT so much in the nucleus accumbens – it only has mild “reinforcing” properties

Caffeine•Pharmacokinetics: – Routes of administration: • generally oral • also transdermal / sublingual

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Caffeine•Pharmacokinetics: – Absorption: rapid & complete • orally, takes ~30 min to reach significant blood levels – peak blood levels in ~2 hrs

– Distribution: freely & equally distributed throughout body

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Caffeine•Pharmacokinetics: – Metabolism: 90% is metabolized by the liver

(CYP450 enzyme family): • theophylline - psychoactive • paraxanthine - psychoactive • theobromine - not (very ???) psychoactive –some SSRIs inhibit the enzyme sub-family

that metabolizes caffeine – Elimination / Excretion: 10% excreted in urine

unchanged • ½-life is 3-7 hrs – increased in kids, elderly & pregnant

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• Drugs that counteract / synergize: – Alcohol

•4 Locos / vodka & red bull • “caffeinol”, a mixture of caffeine and ethanol,

has been shown to have a potent synergistic neuroprotective effect in rodent stroke models

– Nicotine usage decreases 1/2-life – SSRI usage increases 1/2-life

• Future developments: – potential treatment for neurological

disorders including Alzheimer’s and Parkinson’s diseases, stroke

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Caffeine

• Other name(s): ????? • Class: Phytochemical alkaloid – only liquid alkaloid –primary psychoactive compound in tobacco

(Nicotiana Tobacum) and other “nightshades” • Forms: – tobacco leaf (cigarettes, cigars, pipes, hookahs,

chew / snuff) • also nicotine patches, gum, vaporizers

Nicotine

Nicotine• Effects: –1st stimulates nausea (brainstem / stomach receptors) • tolerance to this effect rapidly develops

– primarily a CNS stimulant • cross-generalization with amphetamine & cocaine

in drug discrimination trials • improves attention, speed of processing, working

memory • due to frontal lobe activation?

Nicotine• Effects (cont): –reduced appetite (weight loss) –anxiolytic / relaxing (counterintuitive for a stimulant) –sensorimotor gating deficits ameliorated for about 15m (self-medication in people with schizophrenia) – antidepressant (self-medication in people with depression) • nicotine patches may be effective antidepressants • stopping smoking can induce relapse of depression

relapse – sympathetic effects like increased heart rate & blood pressure

Nicotine• Effects (cont): – Too much - anxiogenic, nervousness, tremors – Highly addictive - only half of people who start smoking

eventually quit • only about 5% of the tobacco leaf is nicotine

– other ~4000 chemicals in the leaf + additives are responsible for most of the toxicity

– other stuff in tobacco slowly kills you, and the nicotine keeps you coming back for more

• rewarding effects quickly diminish - smokers typically smoke to relieve or avoid withdrawal symptoms

• withdrawal can last months (mostly “psychological”) •much easier to quit with nicotine replacement (patch,

gum, etc) – and/or the dopaminergic antidepressant

buproprion (“Zyban, “Wellbutrin”)

Nicotine

• Pharmacodynamics: – nicotinic ACh agonist

Nicotine

• Pharmacodynamics: – neurons with ACh receptors are widespread throughout CNS

– in midbrain, nicotine binds with ionotropic ACh receptors that allow Ca+, Na+, and K+ into the dendrites of neurons that release DA into the reward areas (nicotine movie)

– nicotinic ACh receptors also on found presynaptic axon terminals – facilitate release of DA, ACh, and glu

– increased levels of DA in nucleus accumbens & forebrain: – rewarding / addictive, stimulant, antidepressant

– increased activity at ACh receptors: – cognitive potentiation, memory facilitation (AD treatment?)

Nicotine

• Pharmacodynamics: – interacts with endogenous cannabinoid system

(“rewarding”) – increases blood flow to Reticular Activating

System in the brainstem leading to “sympathetic” PNS effects – increased blood pressure / heart rate, release

of adrenaline – other PNS effects: – inhibits sensory nerves innervating muscles

(leads to a relaxed muscle tone)

Nicotine

Nicotine• Pharmacokinetics: – Route of administration • generally inhalation (smoked or vaporized) • also transdermal / sublingual / nasal

Nicotine• Pharmacokinetics: – Absorption: rapidly absorbed through any route • lungs, mucous membranes, skin, GI

– 1 cigarette contains ~.5-2 mg nicotine – only ~20% (.1-.4 mg) is absorbed into bloodstream – smoking offers great ability to “self-titrate”

» users try to maintain a steady-state plasma concentration of ~15 ng/ml

– Distribution: freely & equally distributed throughout body

– Metabolism: 80-90% via CYP450 enzymes in the liver

– Elimination / Excretion: ½-life is ~1-2 hrs *

• Future developments: – AD effects and nornicotine (a metabolite) – antidepressant / antipyschotic – autism patch

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Nicotine

• Other name(s): benzoylmethylecgonine, coke, nose candy, crack, rock, blow, snow, rails, powder, bumps, etc.

• Class: phytochemical (tropane) alkaloid –primary psychoactive compound in the Coca

plant • Forms: leaves, powder, dissolved in water

solution, freebase (crack)

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Cocaine

• History: – Indigenous South Americans – Sherlock Holmes injected it – Used, abused, endorsed (“Uber Coca”), and

ultimately reviled by Freud – Once in Coca-Cola (60 mg / cup) – Current clinical usage:

• primarily illicit recreational euphoriant / stimulant • also legit use as surgical topical anesthetic

– still comes from Coca-Cola company • 2nd most popular illegal recreational drug in U.S.

– 1st now that marijuana is “mostly” legal?

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Cocaine

• Effects (cont):

• topical anesthetic properties (like procaine, “Novocaine”)

• primarily a stimulant:

• low doses (25-75 mg powdered intranasal, 1-3 “lines”):

• CNS effects: mood elevation, euphoria / more alert / confident / fast, clear flow of thoughts / arousal, wakefulness, reduced fatigue / improved task performance

• self-medication for ADHD?

• PNS effects: similar to sympathetic “fight or flight”

• increased blood pressure, heart rate / dilated pupils

• vasoconstriction

• peaks in ~30 min, lasts up to 2 hrs (then want more)

Cocaine

• Effects (cont):

• too much

• acutely “toxic” at ~2 mg/kg (~150 mg / 6 lines for a 150 lb person)

• anxiety, nervousness, irritability

• toxic paranoid psychosis - psychotic behavior indistinguishable from schizophrenia

• cocaine overdose used as a model of schizophrenia

Cocaine

• Effects (cont):

• long-term / chronic use:

• even after abstinence for 1 year, reaction times are slowed (but attention may be improved?)

• may be “self-medication” for people with ADHD

• down-regulation of DA receptors

• brains show evidence of chronic ischemia

• from vasoconstriction

Cocaine

Cocaine• Pharmacodynamics: – blocks DA, NE, and 5-HT re-uptake receptors on

pre-synaptic axon terminals • potentiates actions of these NTs • especially in the nucleus accumbens and ventral

tegmental area (reward circuit) – responsible for euphoric / addictive effect

– probably also effects glutamate system (AMPA receptors) •withdrawal upregulates AMPA-type glu receptors in the

nucleus accumbens

Cocaine

• Pharmacokinetics: – Routes of administration: – oral (tea / chew), nasal,

injectable, inhalation

Cocaine

Cocaine• Pharmacokinetics (cont): – Coca leaves – chewed or brewed into tea as a coffee-like

stimulant – treated with solvents (e.g., hydrochloric acid) to

form cocaine hydrochloride powder (water soluble) –most often snorted – 1 “line” ~25 mg – typical dose is 2-4 lines (50-100 mg)

– may also be injected, typically in doses of 100-1000+ mg

Cocaine• Pharmacokinetics (cont): – Cocaine hydrochloride powder is destroyed by

heating – mixing with baking soda converts the acidic

cocaine hydrochloride powder to a base form (aka, freebase cocaine, or crack) – water insoluble – can’t be snorted or injected – heated vapors must be inhaled (typical

dose is 250+ mg)

• Pharmacokinetics: – Absorption: – easily absorbed from all sites (mucous,

stomach, lungs) – chewing leaves / drinking tea: ~25%

absorbed – peak plasma levels ~150 ng/ml – peaks ~ 5-10 min, lasts ~1 hr

– snorting powder: ~25% absorbed – peak plasma levels ~150 ng/ml – peaks ~ 2-3 min, lasts ~ 40 min

Cocaine

• Pharmacokinetics: – Absorption: – injecting dissolved powder: 100% absorbed – peak plasma levels 350+ ng/ml – peaks ~ 30s, lasts ~15 min

– inhaling freebase vapors: ~25% absorbed – peak plasma levels 850 ng/ml – peaks ~ 10s, lasts ~7 min

Cocaine

Cocaine• Pharmacokinetics: – Distribution: – concentrates in brain – distributed evenly throughout rest of body

– Metabolism: – almost completely metabolized by enzymes in the liver and

within the blood – CYP3A4 > norcocaine – when used with alcohol, metabolite is cocaethylene – as

active as cocaine – more toxic & long-lasting

– potentiates effects and toxicity – Elimination / Excretion - via kidneys – 1/2 life ~50 min – metabolites detectable in urine up to 48 hrs / weeks later

Cocaine• Drugs that counteract / synergize: – Alcohol – cross-tolerance w/ nicotine, amphetamine, Ritalin – Commonly used in combination with opiates

(“speedballs”)

• Future developments: – antibodies for addicts

• Other name(s): alpha-methylphenethylamine, speed, crank, crystal, meth, etc.

• Class: synthetic phenethylamine –generally exists as two

“enantiomers” (molecular mirror images) • levo-amphetamine and dextro-amphetamine • “amphetamine” formally refers to a specific

combination of equal parts of each, but informally can imply any combo or either alone – “meth”amphetamine has a methyl group (CH3) added onto

the amphetamine molecule (which makes it easier to pass through blood brain barrier > more potent)

– Forms: powder, dissolved in water solution, freebase (ice)

Amphetamines

• Effects: –primarily a CNS stimulant very similar to cocaine with similar potency – Ricaurte, et al. (Science 2002) - methamphetamine (not MDMA) is neurotoxic in monkeys – long-term use:

•metabolic abnormalities & reduced neuronal density – frontal lobe / basal ganglia / nucleus accumbens

• at low doses (e.g., ADHD treatment), may be preferential for 5-HT – not toxic?

Amphetamines

Amphetamines

Amphetamines• Pharmacodynamics: – presynaptic g-protein receptor

• augments DA & NE release from the synapse by entering terminal

• result is the same as cocaine (more NT in synapse)

Amphetamines• Pharmacokinetics: – Routes of administration: – oral, nasal, intravenous, inhalation

– ADME: • 40% excreted unchanged • “ice” = freebase form with long ½-life (~12 hrs)

• Similar in action to amphetamine:

• ephedrine (Mini-thins, Trucker’s Buddy)

• khat / cathinone

• Ecstacy / MDMA

•Similar in action to cocaine:

• methylphenidate (Ritalin)

• Unique (unknown) mechanism:

• modafinil (Provigil) (glu / GABA?)

Other Stimulants