Cocaine, Amphetamines, and Opioids: Neurochemistry and Effects

What is the source of cocaine?

alkaloid chemical found in the shrub Erythroxylon coca (indigenous to Colombia, Peru, and Bolivia)

Why is cocaine difficult to synthesize?

complex chemical structure

What is the typical concentration of cocaine in coca leaves?

~ 1%

How are coca leaves processed to extract cocaine?

ground and mixed with chemicals to form a paste

What is freebase cocaine?

smokable form of cocaine

What is crack cocaine?

cocaine mixing the paste with sodium bicarbonate (baking soda)

How is cocaine hydrochloride (HCl) formed?

mixing the cocaine paste with hydrochloric acid (making it water soluble)

What are the methods of using cocaine hydrochloride?

dissolved, injected, or snorted as a powder

Why can't cocaine HCl be smoked?

degraded by heat

What are the monoaminergic synapses, why?

DA, NE, and 5-ht (b/c one amine NH2 group of atoms)

How is dopamine synthesized?

Through a 2-step process from the amino acid tyrosine

How is norepinephrine synthesized?

Directly from dopamine (DA)

What is the role of presynaptic transporters in neurotransmitter regulation?

They remove neurotransmitters from the synapse; DAT for dopamine, NET for norepinephrine, and SERT for serotonin.

What is the neurochemical action of cocaine on dopamine?

Inhibits DAT, causing more dopamine in synapse

How does cocaine affect norepinephrine and serotonin levels?

It inhibits NET and SERT, resulting in elevated synaptic levels of norepinephrine and serotonin.

What are the effects of prolonged cocaine use on neurotransmitter receptors?

Causes overstimulation of receptors in nucleus accumbens, striatum, and frontal cortex

What is the rate-limiting enzyme in dopamine synthesis?

Tyrosine hydroxylase (TH).

What homeostatic changes occur in dopamine synapses with chronic cocaine use?

Lower levels of TH and dopamine autoreceptors, leading to decreased dopamine synthesis.

What can depleted dopamine terminals lead to?

Motor problems, fidelity issues, and tics.

What is the effect of cocaine on dopamine reuptake?

Cocaine blocks reuptake, keeping dopamine in the synapse.

What is sometimes referred to as an indirect agonist of dopamine, norepinephrine, or serotonin receptors?

Cocaine.

How does cocaine indirectly activate glutamate neurons?

Cocaine increases glutamate release in various regions of the reward circuit, affecting synaptic plasticity and producing maladaptive learning.

What role do PFC neurons play in cocaine's effects?

PFC contains glutamatergic neurons (that innervate many brain regions), including the NAc and VTA, neurons with D1-type dopamine receptors are indirectly activated by cocaine.

What happens to AMPA receptors with chronic cocaine use?

AMPA receptors are synthesized and inserted into the postsynaptic membrane, promoting synaptic plasticity (i.e., long-term potentiation).

What is the elimination half-life of cocaine?

The elimination half-life (t1/2) of cocaine is approximately 1 hour.

What is benzoylecgonine and half-life?

an inactive metabolite of cocaine with a half-life of about 12 hours

How does alcohol affect the effects of cocaine?

Alcohol intensifies and prolongs the effects of cocaine but greatly increases the risk of sudden death or other complications.

What autonomic effects does cocaine have on the cardiovascular system?

Cocaine blocks NET, increasing synaptic levels of norepinephrine, causing tachycardia and vasoconstriction, leading to hypertension.

What are some risks associated with cocaine use?

dilated cardiomyopathy, hemorrhagic stroke, rhabdomyolysis, paranoia, psychosis, perforated nasal septum, and seizures.

What are common adulterants found in cocaine?

other stimulants, local anesthetics, antihistamines

What were the historical medical uses of cocaine?

Cocaine was available over-the-counter as a remedy for toothaches and is currently FDA approved for use as a local anesthetic in various surgeries.

How does cocaine exert its local anesthetic effects?

Cocaine blocks the outside pore of voltage-gated sodium channels at high concentrations, leading to local anesthesia.

What is the effect of cocaine concentrations reached after snorting or smoking?

Concentrations of cocaine in the brain from these methods are not sufficient to block sodium channels in the brain.

What was Freud's stance on cocaine?

Freud published 'Uber Coca' advocating cocaine as an antidepressant and claimed there was no craving for further use after initial doses.

What is the historical significance of ephedrine?

Ephedrine, found in the herb ma huang, has a recorded history of use in China dating back to 3000 B.C. and is similar to amphetamines.

What was the purpose of the amphetamine inhaler Benzedrine in the 1930s?

Benzedrine was sold as a bronchodilator for asthma.

What is the relationship between methamphetamine and World War II?

used for it’s stimulant effects.

What are the neurochemical actions of cocaine?

Cocaine acts as an indirect dopamine agonist, releases dopamine, and dopamine reuptake blocker

What type of ion channels does cocaine block to exert local anesthetic effects?

Cocaine blocks voltage-gated sodium channels.

What was the historical use of amphetamines by the Japanese and German militaries?

counter fatigue measure

What era saw the marketing of amphetamine-containing products as weight loss aids?

The 1940s to 1960s, often referred to as the misogyny era.

What are the current approved uses for amphetamines like Adderall?

They are approved for ADHD, severe narcolepsy, and obesity.

How does chronic meth use affect aging?

It is associated with accelerated aging, evidenced by skin-picking and dental erosion.

What is the increased risk of dementia or Parkinson's disease for individuals with amphetamine use disorder?

3-5 times more likely to develop these conditions than non-users

What effect does methamphetamine have on cellular aging according to in vitro studies?

Meth increases cellular aging (senescence).

What is the role of monoamine oxidase (MAO) in the neurochemistry of amphetamines?

At low concentrations, amphetamines inhibit MAO, increasing the availability of dopamine, norepinephrine, and serotonin.

What are MAO inhibitors (MAOIs)?

Drugs that inhibit monoamine oxidase, leading to increased levels of monoamines in the synapse.

What happens to dopamine, norepinephrine, and serotonin at low doses of amphetamines?

Amphetamines block their transporters (DAT, NET, SERT).

What occurs at higher doses of amphetamines regarding neurotransmitter transporters?

They compete with neurotransmitters for their transporter substrates, acting as false neurotransmitters.

How do amphetamines affect synaptic vesicles?

They displace neurotransmitters from vesicles into the cytoplasm, causing reverse transport into the synapse.

How do the actions of cocaine differ from those of amphetamines?

Cocaine is a reuptake inhibitor, while amphetamines are MAO inhibitors and also act as substrates and releasers.

What are the effects of chronic amphetamine use on synapses?

downregulation and desensitization of postsynaptic receptors and increased synthesis of DA, NE, and 5-HT.

What is the plasma elimination half-life of methamphetamine?

Approximately 10-30 hours.

How does methamphetamine differ from regular amphetamines in terms of lipophilicity?

more lipophilic, crosses BBB easier

What is the bioavailability of meth and amphetamine when taken orally?

About 67% for oral use and 90% when smoked.

What are synthetic cathinones (bath salts)?

derivatives of cathinone, stimulant found in the khat plant, have effects similar amphetamine or cocaine

Why are stimulants used to treat ADHD?

Cognitive ability lies along an arousal spectrum, and ADHD patients may have an underactive prefrontal cortex

What is the significance of the inverted U shape in relation to cognitive ability and arousal?

Cognitive performance is best at moderate arousal levels (which stimulant medications can help achieve.)

What is the relationship between chronic amphetamine use and MAO levels?

Chronic use may lead to increased MAO levels due to prolonged inhibition.

What is the mechanism of action of Methylphenidate (Ritalin)?

It weakly blocks the dopamine transporter (DAT) and norepinephrine transporter (NET), increasing synaptic levels of dopamine (DA) and norepinephrine (NE).

How does Lisdexamfetamine work?

Lisdexamfetamine is a prodrug that is inactive until it is cleaved in the gastrointestinal tract to form dextroamphetamine.

What is the purpose of Lisdexamfetamine's formulation?

long-lasting and less abused version of dextroamphetamine

What are Guanfacine and Clonidine used for?

They are selective agonists at norepinephrine receptors, specifically the alpha-2A receptors.

Which ADHD medication is sold in an abuse-deterrent formulation?

Lisdexamfetamine (Vyvanse) is conjugated to lysine to deter abuse.

What are common street names for MDMA?

Common street names include ecstasy, E, X, XTC, Hug Drug, and Molly.

What psychological effects does MDMA have?

increases energy, openness, empathy, increases sensory experiences, and may cause visual distortions.

What physiological effects are associated with MDMA use?

Physiological effects include tachycardia, hyperthermia, dehydration, teeth grinding (bruxism), and jaw clenching (trismus).

What was MDMA originally synthesized for?

MDMA was first synthesized as a hemostatic (blood clotting) agent by Merck in 1912.

What neurochemical action does MDMA have on serotonin?

MDMA enters 5-HT terminals and vesicles, displacing serotonin (5-HT) and causing reversal of the serotonin transporter (SERT) direction.

What is the primary action of MDMA in the brain?

MDMA primarily acts as a 5-HT releasing and reuptake inhibiting amphetamine, favoring serotonin over other monoaminergic systems.

What was the initial use of MDMA by the U.S. military in the 1950s?

truth serum

What are the effects of MDMA on appetite?

MDMA reduces appetite.

What are the common side effects of MDMA use during raving or partying?

Common side effects include teeth grinding (bruxism) and jaw clenching (trismus), which is why people often use pacifiers.

How does MDMA differ from SSRIs in its effect on serotonin?

MDMA blocks 5-HT reuptake and also causes 5-HT release via displacement from vesicles and reversal of SERT.

What indirect effect does MDMA have on dopamine (DA) release?

MDMA can indirectly affect DA release by inhibiting MAO activity, leading to increased cytoplasmic levels of DA and reversal of DAT function.

What are the symptoms of the post-MDMA crash?

depression, insomnia, fatigue, anxiety, and irritability for several days.

What did a 1995 study suggest about the serotonergic toxicity of MDMA?

The study was retracted due to the drug used containing methamphetamine, not MDMA, but PET imaging shows reduced SERT levels in MDMA users.

What is the elimination half-life of MDMA?

8-9 hours

How is MDMA metabolized in the body?

About 80% is metabolized by liver cytochrome P450 enzymes into active metabolites like MDA, DHMA, DHA, and HMMA; 20% is excreted unchanged via the renal route.

Which cognitive domains are impacted by MDMA overuse?

Working memory, spatial working memory, declarative memory, prospective memory, and complex problem solving.

What can cause MDMA-induced hyponatremia?

5-HT overstimulation increases ADH release, causing water retention; combined with hyperthermia and polydipsia, this leads to low blood Na+ levels.

What are potential therapeutic uses of MDMA, why (what does it do)?

may aid in psychotherapy for PTSD (and other anxiety and depression forms) enhancing empathy, awareness, and self-acceptance.

How does MDMA affect fear extinction in psychotherapy?

MDMA may help extinguish negative emotional memories associated with traumatic events.

What percentage of participants no longer met PTSD qualifications after MDMA therapy?

843% of participants no longer met PTSD qualifications at the 2-month follow-up.

What is the role of the Multidisciplinary Association for Psychedelic Studies (MAPS) in MDMA research?

MAPS advocates for the therapeutic uses of MDMA

What is the effect of MDMA on the frontal cortex?

enhances activity

What is the relationship between MDMA and antidiuretic hormone (ADH)?

MDMA overstimulation causes increased release of ADH, leading to water retention.

What are the active metabolites produced from MDMA metabolism?

Active metabolites include methylenedioxyamphetamine (MDA), dihydroxymethamphetamine (DHMA), dihydroxyamphetamine (DHA), and hydroxy-methoxy-methamphetamine (HMMA).

What is the impact of MDMA on working memory?

overuse impairs working memory, the information needed to complete tasks

What is a potential consequence of disrupted electrolyte levels due to MDMA use?

Disrupted electrolyte levels can cause potentially fatal brain swelling (cerebral edema).

How does MDMA affect the release of serotonin?

MDMA causes serotonin release by displacing it from vesicles and reversing SERT function.

What are the primary locations of 5-HT producing neuron cell bodies in the brainstem?

The raphe nuclei.

What factors contributed to the opioid epidemic?

Overprescription and overmarketing of prescription opioids, restrictions on opioid dispensing, and the infiltration of the drug market with potent opioids like fentanyl.

What is 'goofballing' in the context of opioid use?

co-abuse of opioids and psychostimulants, especially meth, to counteract sedation and increase euphoria

What is a speedball?

A combination of cocaine and heroin.

Where is most opium produced?

In the Middle East and Southeast Asia, particularly known as the Golden Triangle (Thailand, Laos, Myanmar).

How did opium smoking come to the U.S.?

It was largely brought by Chinese immigrants in the 1870s.

What is the process of harvesting opium?

poppies cut to allow raw latex to come out

What are the main alkaloids found in raw opium latex?

Approximately 10% morphine, 2% codeine, and 1% thebaine.

Who discovered heroin and how is it formed?

Charles Alder Wright discovered heroin by boiling morphine with acetic acid