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Nicotine: Origin

• north and south america

• used by mayan priests for rituals

• formally introduced to Europe as a medicinal herb

• Sir walter raleigh introduced the English court to tobacco and tobacco smoking

• english began to grow nicotiana tobacum in the colonies

Nicotine: Plant

• Nicotiana tobacum

  • indigenous to S. america

• Nicotiana rustica

  • small leafed species

    • indigenous to E. North America, West Indies

    • sometimes mixed into ayahuasca

• Nicotine (from plants)

  • potent poison, most bugs will keep away from it

  • leaves have 6-9% nicotine

Nicotine: Drug preparation

• plants are cut at the base and stacked onto tobacco sticks before being dried in tobacco barns and sold

• most often packed into cigarettes, cigars, pipes, etc

Nicotine: Route of Administration

• cigar, patch, cigarette, dip, ENDS, pipe, etc

Nicotine Half-life

• 90-150 min

• 16-25% have problem metabolizing nicotine

Nicotine Absorption

• differences in absorption contributes to the dependence potential

  • 90% inhaled nicotine is absorbed

  • 60 mg is lethal

  • cigars contain enough nicotine for two lethal doses, but burning the product destroys most of the nicotine

    • absorbed through the mouth

• nicotine is readily absorbed through the skin as well

Cigarettes

• need to inhale deeply for the nicotine to hit the lungs, most cigarettes contain 8-9 mg, ~1 mg is inhaled

Nicotine Distribution/Concentration

• high initial concentration in the brain

• concentrated in the liver, kidneys, salivary glands, and stomach

• readily distributed across placental barrier into mother’s milk

Nicotine Excretion/Metabolism

• majority of metabolism takes plave in liver

• major metabolite is cotinine

• another metabolite being studied is nornicotine

Replacement Pharmacotherapies for Nicotine

• ENDS, patch, gum, inhaler, nasal spray

• Zyban, Chantix, NicVax

Zyban

• wellbutrin

• NE and DA uptake inhibitor (antidepressant effects)

• has partial nAChR antagonist activity

  • alters rewarding effects of nicotine and the aversive effects of withdrawal

Chantix

• varenicline

• partial nAChR

• stimulates most common nAChR (a4b2)

• blocks nicotine from acting at the receptor

NicVax

• prevents majority of nicotine from crossing the BBB

• antibodies bind to nicotine and prevent them from crossing into the brain

• currently in clinical trials

• not all nicotine is prevented from crossing into BBB

Nicotine PNS Effects

• muscle tremors, decrease in patellar reflex, increased HR and BP, constriction of blood vessels in the skin (release of epinephrine), inhibits stomach secretions, acts as a laxative

Nicotine CNS effects

• general arousal (nicotine stimulates release of epinephrine), respiratory arrest, nausea, euphoria, increase in dopamine release produced

  • withdrawal disrupts sleep

Nicotine effects on behavior

• decreased hunger (diuretic) and increased weight reduction weight reduction (appetite suppressant)

What receptors does nicotine bind to?

• Nicotinic and muscarinic ACh receptors

Muscarinic Receptors

• muscarine binds the muscarinic ACh receptor with a very high affinity (agonist)

  • muscarine: AGONIST at muscarinic receptors

  • Atropine: ANTAGONIST, blocks muscles that constrict pupils, poisonous when ingested

  • Dendrotoxin, 1, 3, 7, K: ANTAGONIST

    • prevents ACh from stimulating muscle on lungs and heart

Nicotinic Receptors

• nicotine is an agonist that binds with an extremely high affinity

• exist in periphery at NMJ and on neurons throughout the brain

Neuronal Nicotinic ACh Receptors (nAChRs)

• nicotinic receptors are formed as different pentameric combinations of distinct subunits

• Subunits confer nAChRs with distinct functional and structural properties

  • subunits are labeled either alpha or beta

  • at least 10 nAChR subunits have been found to be expressed in vertebrate neurons

3 states of nAChRs

1. basal state: ion channel closed

   • no agonist (or ACh)

2. Active state: ion channel open

   • agonist (or ACh)

3. Desensitized State

   • receptor sites are occupied, but repeated stimulations “desensitize it”

     • leads to upregulation of receptors

     • may be responsible for nicotine withdrawal

nAChR Agonists

• ACh, nicotine, nornicotine, cytosine, epibatidine

nAChR Antagonists

• mecamylamine binds to all known subtypes

Epibatidine

• stimulates neuronal and peripheral nicotinic AChRs

• agonist

• skin of ecuadorian frog

Curare

• antagonist from South American Plant

• irreversible antagonist

• target NMJ in skeletal muscle

• produces paralysis

A-bungarotoxin

• irreversible nicotinic AChR antagonist

• target: neuromuscular junction (skeletal muscle)

A-cobra toxin

• reversible nicotinic AChR antagonist

• target: NMJ (skeletal muscle)

AChE Inhibitors

• insectisides and nerve gas (like sarin gas)

• inhibits AChE induced breakdown of ACh

• results in increased ACh levels

  • overstimulation of muscles at NMJ

Nicotine Tolerance/Withdrawal

• Psychological

  • anxiety, irritability, frustration, stress, nervousness, shortened attention span, restlessness, craving, urge to use

• Physical

  • lower heart rate, tremors, headaches, insomnia, dizziness, increased appetite, light-headedness, drowsiness

Cessation of Smoking

• both behavioral therapies and pharmacotherapy are both important for smoking cessation

• most surveys show that the majority of smokers want to quit, but success rate is low and requires multiple attempts

FDA Family Smoking Prevention and Tobacco Control Act of 2009

• allowed the FDA to regulate the marketing and promotion of tobacco products

Cigarette Smoking

• declined in the US, but prevalence is rising in developing countries

• ENDS are becoming more common in the US

  • some debate on whether or not they help stop smoking or encourage smoking in adolescents

Benowitz and Henningfield Hypothesis (1994)

• “there is a threshold of nicotine concentration to acquire tobacco addiction”

• if you lower the nicotine concentration to below this threshold, fewer, if any, adolescents or new smokers will become nicotine addicted

nAChRs modulate all other NT systems

• homeostatic adaptations that occur on other NT systems are also disrupted when nicotine is removed

• suggests multiple NT systems undergo states of dysregulation

Health Benefits of Nicotine

• produces beneficial effects on fine motor performance, attention, and short-term memory

Methylxanthines

1. caffeine (coffee)

2. Theophylline (tea)

3. Theobromine (chocolate)

Caffeine

• most commonly consumed psychoactive drug in the world

• found in many prescription and OTC medications

• safe, added to just about anything that we can ingest

• average consumption per day is 70 mg

Caffeine: Coffee Origin

• native to Ethiopia

• Arabica (60-80% of coffee consumed)

• psychoactive effects first discovered in Ethiopia between 12th and 15th centuries

• William Harvey advocated for therapeutic effects

  • cured drunkenness

• first coffee house

  • Oxford, England 1650

Caffeine: Tea Origins

• emperor Chen Nung

• claimed to discover tea around 2700 BCE

• Dutch were shipping tea around ~1630

Caffeine: Chocolate Origins

• mayas, aztecs, incas called it a gift to the Gods

• Cortes introduced the drink to Spain with sugar and vanilla

Caffeine Plant Origins (Coffee)

• coffee: bean is a seed kernel from the coffee berry

  • caffeine in a cup of coffee varies widely

Caffeine Plant Origins (Tea)

• black tea: leaves dried and crushed for oxidation

• oolong tea: oxidation is stopped before it is complete

  • green tea: leaves are steamed to prevent oxidation

    • oxidation: chlorophyll in the leaves is enzymatically broken down

      • phenols and tannins are release

Other Caffeine Plant Origins

• chocolate: caffeine and theobromine are the methylxanthines found in chocolate

• yaupon holly: north american, native peoples in the southeast regions drank a beverage called youpon

• guarana: used in soft drinks and energy shots

• kola nut: chew the kola nut to extract caffeine, originally used in coca-cola

Caffeine route of administration

• oral

Caffeine Half-Life

• ~5 hours

• infants do not metabolize caffeine well

  • 85% left unchanged in urine

  • ½ life = 4 days

  • adult pattern begins 7-9 months of age

• less than 2% is unchanged in urine

How do methylxanthines exert their effects?

• relax smooth muscle (especially bronchial muscles)

• stimulate CNS and cardiac muscle

• produce diuresis in kidneys

• used to treat a variety of disorders

  • asthma, narcolepsy, migraines, headaches, other pain syndromes

Caffeine Absorption

• oral caffeine is rapidly and completely absorbed

• absorbed by intestine, some in stomach

• coffee and tea, peak blood levels within 45-75 minutes

Distribution of Methylxanthines

• freely and equally distributed throughout the body

• present in all bodily fluids

  • crosses placenta to fetus, breast milk

Excretion of Methylxanthines

• metabolites

  • paraxanthine- 80%

  • theobromine- 12%

  • Theophylline 4%

Adenosine

• methylxanthines alter the effect of adenosine

• when adenosine binds to one of its receptors, usually produces inhibition and decreases firing rate of other neurons

• methylxanthines are adensoine ANTAGONISTS

• 4 adenosine receptors: A1, A2a, A2b, A3

Dopamine (methylxanthines effect)

• A1 and A2a modulates dopamine tone

• adenosine, or any adenosine agonist, contributes to synaptic dopamine levels

• it is these receptors that mediate the reinforcing effects of caffeine

Ephedrine

• caffeine releases ephedrine (adrenaline) from brain tissue

• likely the origin of stimulatory effects

Methylxanthine Pyschostimulant Effects

• caffeine- effective psychostimulant

• heavy consumption (1.5g) causes agitation, anxiety, tremors, rapid breathing, insomnia

• lethal dose 5-50 g

• people with anxiety disorders are especially sensitive to caffeine

Caffeineism

• clinical syndrome characterized by both CNS and PNS symptoms

  • CNS Symptoms: anxiety, low-grade fever, irritability

  • PNS symptoms: tachycardia, hypertension, cardiac arrhythmias, GI Disturbances

  • usually dose related (1g, 5-10 cups of coffee)

  • cessation of caffeine ingestion usually resolves this

Caffeine Tolerance/Dependence

• chronic administration of caffeine results in up-regulation of adenosine receptors

• caffeine has less effect on heavy coffee drinkers compared to non-drinkers

• withdrawal = headache

  • usually starts within 12-24 hours after cessation of caffeine

Health Benefits of Caffeine

• decreased risk of developing type 2 diabetes, obesity, coronary heart disease, stroke, and cancer

• risk of mortality in general is lower in caffeine consumers

• good evidence that caffeine intake protects against neurodegenerative disease, including Alzheimer’s and Parkinson’s

MDMA Origins

• created by Alexander “Sasha” Shulgin in a legal lab in his basement, tested the drugs on himself and other willing participants

• named “ADAM” to denote an entheogeneic effect

How does MDMA exert its effects?

• releaser, like amphetamine and methamphetamine

• meth-like structure

• produces release of serotonin

  • 5-HT > DA > NE

  • hence psychoactive effect

Harmful/Neurotoxic Effects of MDMA

• high dose exposure of MDMA usage results in damage to serotonin neurons, particularly regarding SERT expression

• MDMA decreases in SERT are reported, and some studies suggest that SERT expression may resolve after a long period of abstinence

  • changes in SERT expression tend to be use dependent

  • higher frequency of use is associated with more reduction in SERT expression

Cocaine Origins

• coca plant, naturally occurring psychomotor stimulant

• south america

  • pre-columbian (2500 BC)

• 1800s

  • Freud, first local anesthetic, added to various beverages

Harrison Narcotic Act of 1914

• made cocaine illegal in the US along with morphine

Cocaine HCl preparation

• organic solvent is added to coca plant

• high concentration, snort, intravenous

Crude Cocaine

• coca plant leaves are chewed, low concentration

Freebase

• cocaine HCl is treated with alkaloid, then petroleum ether, or ammonia

• high concentration (smoke)

Crack Cocaine

• cocaine HCl is treated with baking soda and water added

• high concentration (smoke)

Cocaine Routes of Administration

• Chewed: coca leaves chewed with lime from wood ash or seashells

• Insufflation: snorting as salt (HCl)

• Smoking: cocaine HCl

• IV injection

• Freebase

  • more lipid soluble

  • for smoking, separates the cocaine molecule from the HCl

• Crack

  • cocaine HCl with sodium bicarbonate

  • baking soda solution separates HCL from cocaine and leaves the base (same as freebase)

Cocaine Half-Life

• excreted much faster than ampehtamines

• half-life of about 60 minutes, averaged across routes of administration

  • IV ranges from 15 minutes to 3.5 hours

  • Intranasally from 30 minutes to 4 hours

  • oral around 50 minutes

How does cocaine exert its effect?

• cocaine does not bind to a post-synaptic receptor, alter membrane potential, or release DA

• cocaine blocks the dopamine transporter (DAT) and prevents reuptake of DA

• DA levels increase because cocaine blocks reuptake

What transporter does cocaine block?

• blocks DAT at the terminal end of VTA axon and synaptic DA levels increase because it can’t be taken back up into the cell to be repackaged

Cocaine Function in the synapse

• all cocaine’s activity is in the synapse

• does not have a receptor, blocks DAT

Harmful/Neurotoxic Effects of Cocaine

• mild liver disease

• inflammation and ulceration of the mucous membranes in the nose

• expensive

Cocaine Overdose

• those who take large doses commonly experience muscle weakness and respiratory depression

• lethality depends on route of administration

• caine reaction

  • initial excitement followed by severe headache, nausea, vomiting, and severe convulsions

  • followed by loss of consciousness, respiratory depression and cardiac failure, resulting in death

Methamphetamine/Amphetamine Origins

• ephedrine used in China for 5,000 years

• similar to ephedrine, amphetamine synthesized (1887)

• effects not widely grasped until 1927

• medical use sanctioned by AMA (1937)

• (1943) used for weight reduction, antidepressant, stimulant, extended periods of alertness

• currently used for narcolepsy and hyperactivity in children, ADHD of all ages

Methamphetamine/Amphetamine Plant origins

• ephedra plant (Ma Huang)

Methamphetamine/Amphetamine Route of Administration

• absorbed poorly from digestive paper

• more potent when administered by injection or inhalation

Amphetamine Half-Life

• excretion depends on pH of urine

• also excreted in sweat and saliva

• half-life between 10-14 hours for mixed salts

• 10-11 hours for d-amphetamine

• 11.5-14 hours for l-amphetamine

Methamphetamine Half-life

• 9 hours oral or injected IV

• 11-13 hours when snorted or smoked

Methamphetamine/Amphetamine Synaptic function

• all of amphetamine’s activity is in the synapse

• does not have a receptor

Methamphetamine/Amphetamine Harmful Effects

• restlessness, excessive talking, confusion, and dizziness

• paranoid psychotic behavior (chronic use) due to lack of sleep

• increased BP, stroke

• depression, suicidal tendencies, lethargy, and sleep disturbances occur with cessation of use

• skin picking

Monoamine Psychosis

• amphetamine psychosis (MA psychosis)

• paranoid schizophrenia

• formication violence

Methamphetamine/Amphetamine Neurotoxic Effects

• experiments with non-human primates and rodents show neurotoxic effects in dopamine and serotonin-rich brain areas

• models of binge-taking brain levels in these animals reflect alterations of neurons (changes in DAT or SERT expression)

• humans: long-time METH users exhibit decreased DAT expression in the basal ganglia

  • part of the mesocorticolimbic dopamine system

Cathinone/Methcathinone Origin

• derived from African Shrub (catha edulis)

• alexander the great, europe, US soldiers

Synthetic cathinone/methcathinones

• referred to as bath salts

• MDPV and mephedrone are examples

• mephedrone is now known as 4-MMC

• newest popular version is 3-MMC

cathinone/methcathinone half-life

• 2.6-6 hours

How do cathinone/methcathinones exert their effects?

• cause monoamine NT to be released, rather than accumulating by just blocking MAT like DAT (cocaine), NET, or SERT

• promotes leaking of NT from vesicles (via VMAT2)

• inhibits MAO, which prevents metabolism

• reverses direction of DAT function

  • reverse transport (out)

• results in more transmitter release with every action potential

T/F: cathinone/methcathinone do not alter metabolism

• false

• they completely prevent metabolism

Do cathinone/methcathinones cause psychoses?

• yes, two types

• manic

  • hyperactivity, talkativeness, shouting, grandiose, mood fluctuations

• Schizophreniform

  • same as amphetamine or cocaine-induced psychoses

Psychedelics

• psychedelic is any event or stimulus that produces a mind-manifesting event

• LSD, ibogaine, psilocybin, harmine/harmaline, DMT

• these drugs are associated with ego dissolution

Non-classical psychedelics

• MDMA, synthetic cathinones, salvinorin A, ketamine, PCP, dextromethorphan

• not necessarily associated with ego dissolution

Plant-based psychedelics

• ibogaine

• psilocybin

• ayahuasca

  • teas containing DMT and harmine/harmaline

    • harmine/harmaline: tropical vine, south america

    • DMT: plant, south America

• 5-MeO-DMT: sonoran desert toad

• salvinorin A

• mescaline: peyote cactus

Laboratory synthesized psychedelics

• LSD

• DMT (N,N-dimethyltyptamine)

• MDPV (3-MMC)

• MDMA (ectasy)

• ketamine: dissociative anesthetic

• dextrophethorphan: cough medicine

Duration of Psychedelic Effects

• oral, smoked, IV

• duration depends on route of administration

  • smoked or IV DMT: 10-15 minutes

  • oral DMT: lasts hours

• LSD potency

  • potency matters for LSD because it is one of the most potent drugs known

  • experience lasts for hours (8-12)

Psychedelic

• mind manifesting

Phantasticant

vivid perceptual effects

Entheogen

generating god from within

entactogen

touching within

Empathogens

empathy enhancer

Psychomimetic or hallucinogen

has a negative psychiatric association

Uses of Psychedelics

1. party drugs

   • relatively low doses, non-classic psychedelics

2. Religious/Spiritual

   • relatively high doses of classic psychedelics

   • ego dissolution: common with high doses of DMT, 5-MeO-DMT, ibogaine

3. Medicinal

   • doses depend on outcome/effect

   • classic or non-classic psychedelis

   • ego dissolution not necessary (PTSD and MDMA)

Ego Dissolution

• receive information about the self from “other beings”

• elves, faces, jokers, animals, etc