Depression

What is the general impact of stimulants on the sympathetic nervous system?

In general, stimulants cause activation of the sympathetic nervous system (the "fight or flight" response), leading to effects like increased heart rate, blood pressure, and alertness. Prolonged chronic use can lead to hypertension and cardiovascular issues.

How do cocaine and amphetamines specifically impact dopamine signaling in the mesolimbic pathway?

Cocaine and amphetamines directly increase mesolimbic dopamine signaling to supraphysiological levels. This leads to a strong motivation for the reward and the formation of very strong drug-associated memories and behaviors, contributing to high potential for disordered use.

What roles do glutamate and GABA play in drug memory and addiction?

While dopamine is crucial in early drug use for reward learning, glutamate and GABA play significant roles in encoding drug memories, habitual compulsive behavior, and driving relapse.

What is cocaethylene and why is it dangerous?

Cocaethylene is a compound formed in the liver when cocaine and alcohol are consumed together. It is a psychostimulant with a longer half-life and is a more potent DAT inhibitor than cocaine, also increasing hepatotoxicity.

What non-psychological mechanism of action does cocaine possess, and what is its clinical relevance?

Cocaine acts as a local anesthetic by blocking voltage-gated sodium channels (VGSCs) in the heart and sensory neurons, which can contribute to cardiac arrest. This property was historically used in surgery.

What is the historical significance of the Harrison Act of 1914 for cocaine?

The Harrison Act of 1914 made the production and sale of cocaine illegal in the United States, following President Taft's declaration of it as "Public Enemy No. 1" in 1910.

Why did the introduction of "crack" cocaine lead to increased use in the 1980s?

Crack" is cocaine base, which can be smoked. Smoking cocaine allows for a much more rapid and intense onset of effects compared to snorting cocaine HCl, increasing its abuse potential.

What is the historical context of amphetamine use?

Amphetamines were synthesized in 1887 and found various medical uses including for asthma, narcolepsy, ADHD, obesity, nasal/sinus congestion, and hypotension.

How does nicotine affect caffeine metabolism?

Nicotine stimulates the CYP1A2 enzyme, which metabolizes caffeine, leading to faster caffeine metabolism. This is why smokers often consume more caffeine. When someone quits smoking, CYP1A2 activity decreases, which can lead to higher caffeine levels and side effects like anxiety, sleep loss, and tachycardia.

Is nicotine itself carcinogenic?

No, nicotine is likely not a carcinogen. The carcinogenicity and lung disease associated with tobacco use are primarily driven by tar and other chemicals produced when tobacco is burned.

What is unique about caffeine's status as a psychoactive drug?

Caffeine is the most commonly consumed psychoactive drug worldwide

What specific interaction can occur between caffeine and SSRI antidepressants?

Some SSRI antidepressants can inhibit CYP1A2, which is the primary enzyme metabolizing caffeine. This can lead to decreased caffeine metabolism and significant side effects.

How was MDMA originally classified and synthesized?

MDMA was synthesized in 1914 and popularized in the 1970s. It is classified as a stimulant, empathogen, and hallucinogen/sympathomimetic.

How do depressants generally reduce neuronal activity?

Depressants generally reduce neuronal activity by agonizing inhibitory signaling (primarily through GABA receptors) or antagonizing excitatory signaling (e.g., glutamate receptors).

Why is withdrawal from many depressants particularly challenging and potentially fatal?

Depressants, especially ethanol and barbiturates, reduce baseline neuronal activity. During withdrawal, the brain experiences a rebound of heightened neuronal activity which can lead to severe symptoms like seizures, tremors, vomiting, cardiac arrhythmia, and delirium tremens (DTs), which has a 2% lethality rate for alcohol.

What is the "drunken monkey hypothesis" related to ethanol?

The "drunken monkey hypothesis" suggests that our primate ancestors were drawn to ripe, fermenting fruit, which contains ethanol, as a readily available source of calories. This exposure may have shaped our ability to metabolize alcohol.

What is distinct about ethanol's metabolism at higher doses?

At higher doses, ethanol metabolism follows zero-order kinetics, meaning a fixed amount of ethanol is metabolized per unit of time, rather than a fixed percentage. This means the body can only process a certain amount, regardless of how much more is consumed.

Why are barbiturates used less frequently in modern medicine compared to benzodiazepines?

Barbiturates have a much narrower therapeutic window than benzodiazepines, meaning the dose required for therapeutic effects is much closer to the dose that causes dangerous side effects like fatal respiratory depression. This makes their overdose risk significantly higher.

What historical event led to the term "soldier's disease" in relation to opioids?

"Soldier's disease" was a term used post-Civil War to describe opioid addiction among soldiers who were administered morphine for pain.

What is Naloxone (Narcan) and its significance?

Naloxone (Narcan) is a high-affinity opioid antagonist with rapid action. It is a critical medication used to reverse opioid overdose by blocking opioid receptors.

Why is opioid withdrawal, despite being severe, generally not fatal?

Unlike withdrawal from GABAergic depressants (alcohol, barbiturates, benzodiazepines) which can cause deadly seizures, opioid withdrawal primarily manifests as extremely unpleasant flu-like symptoms, muscle cramps, vomiting, and diarrhea. While agonizing, it is typically not directly fatal.

What is opioid-induced hyperalgesia?

Opioid-induced hyperalgesia refers to a phenomenon where chronic opioid use actually leads to an increased sensitivity to pain, making pain feel worse than before. This is a form of sensitization to pain, rather than tolerance to the drug's effects.

MOA of Ethanol (Alcohol)

Positive Allosteric Modulator (PAM) of GABA-A receptors and inhibitor of NMDA glutamate receptors.

Ethanol Neurotransmitters Systems Affected

GABA, Glutamate, Dopamine (indirectly)

ROA of Ethanol

Oral

ADME of Ethanol

Absorption: Rapid oral absorption.

Metabolism: By alcohol dehydrogenase and CYP2E1.

Ethanol Half-life

Varies; typically follows zero-order kinetics at higher doses (fixed amount metabolized per unit time).

Short term effects of ethanol

Reduced anxiety and awareness, disinhibition, lethargy, amnesia, hypnosis, anesthesia.

Long term effects of ethanol

Liver damage (cirrhosis), Korsakoff syndrome, various cancers, cardiomyopathy, gastritis.

Dynamic Responses of Ethanol

Tolerance: Common.

Sensitization: Less common outside of reward behavior.

Dependence: High risk.

Withdrawal: Severe and potentially fatal (e.g., delirium tremens, seizures, vomiting, cardiac arrhythmia).

Medical uses of Ethanols

None