Source: Chapter 9, A Brain-Mind Odyssey
Tags: psychoactive drugs, caffeine, nicotine, alcohol, opioids, cocaine, amphetamine, LSD, psilocybin, cannabis, THC, endocannabinoids, dopamine hypothesis, GABA, serotonin, schedule I, sedative hypnotic
Psychoactive drugs alter brain function by interacting with specific neurotransmitter systems, either mimicking, blocking, or modulating endogenous signalling molecules. This chapter covers the major drug classes (stimulants, depressants, opioids, psychedelics, cannabinoids), their receptor targets, historical context, and the concept of endogenous ligands such as endorphins and endocannabinoids. Understanding the synaptic mechanism of each drug is the backbone of exam questions here.
Adenosine receptor antagonist
A molecule that binds to adenosine receptors and blocks the natural ligand from acting. Caffeine is the classic example: it prevents the sleep-promoting effects of adenosine.
Sedative hypnotic
A class of drugs that depress CNS activity, producing calming and sleep-inducing effects. Includes alcohol, barbiturates, and benzodiazepines. All facilitate GABA signalling.
Therapeutic index (TI)
The ratio between the lethal dose and the therapeutic dose of a drug. A low TI means there is a narrow margin between an effective dose and a dangerous one. Barbiturates have a notably low TI.
Anxiolytic
A substance that reduces anxiety. Alcohol and benzodiazepines both have anxiolytic properties via GABA facilitation.
Sympathomimetic
A drug or effect that mimics activation of the sympathetic nervous system, e.g. increased heart rate, dilated pupils. Cocaine and amphetamines produce sympathomimetic effects.
Endorphins
Endogenous morphines: polypeptide molecules produced in the brain that act as agonists at opioid receptors. They are the body's own pain-relief system.
Endocannabinoids
Endogenous molecules that bind to cannabinoid (CB) receptors. The first discovered was anandamide. They are involved in retrograde signalling at synapses.
Retrograde signalling
A process in which signalling molecules (endocannabinoids) travel backwards across the synaptic cleft, from the postsynaptic dendrite to the presynaptic axon terminal, modulating neurotransmitter release and tuning synaptic strength.
Dopamine hypothesis of psychosis
The theory that psychosis results from excess activity in particular dopamine pathways in the brain. Supported by the fact that antipsychotics are dopamine receptor antagonists, and that cocaine and amphetamines (which activate dopamine pathways) can produce psychosis.
Schedule I controlled substance
A drug classification indicating no currently accepted medical use, high potential for abuse, and lack of accepted safety under medical supervision. Psychedelics fall into this category.
Psychotomimetic
A substance that mimics symptoms of psychosis. THC has psychotomimetic properties, whereas CBD has antipsychotic properties.
Caffeine is found in coffee (Coffea arabica, northeast Africa), tea (Camellia sinensis, East Asia), cacao (Theobroma cacao, Central/South America), kola, guarana, and yerba mate
Caffeine works as an adenosine receptor antagonist, blocking the sleep-promoting signal of adenosine
Nicotine (from Nicotiana tabacum, named after Jean Nicot) is an agonist at nicotinic acetylcholine receptors
Ethanol is produced through yeast fermentation and was the first general anaesthetic used in medicine
Alcohol is a sedative hypnotic: it facilitates GABA, increasing chloride (Cl⁻) flow into cells, producing anxiolytic effects
Barbiturates are synthetic sedative-hypnotic pharmaceuticals with a low therapeutic index, making overdose relatively easy
Benzodiazepines (e.g. Valium, Xanax) are also sedative hypnotics but have a wider safety margin than barbiturates
Both drug classes, along with alcohol and general anaesthetics such as sevoflurane, amplify the effect of GABA at its receptor
GABA receptor facilitation means chloride channels remain open longer, strengthening the inhibitory effect
Opium comes from the opium poppy (Papaver somniferum), used for thousands of years around the Mediterranean
Active compounds are concentrated in the seed pod after petals fall; opium acts as a pain reliever, cough suppressant, and anti-diarrhoeal
Friedrich Wilhelm Sertürner isolated and purified morphine from opium in 1803, naming it after the Greek god Morpheus
This was a turning point: it introduced the idea that the medicinal properties of plants could be attributed to specific chemical compounds
Morphine is a powerful opioid because it acts directly on the CNS
Brand-name opioids include Vicodin, oxycodone, and Percocet
Heroin (diacetylmorphine) was first produced by Bayer in 1898 as an analgesic and cough medicine
It is less hydrophilic than morphine (fewer OH groups), so it crosses the blood-brain barrier faster
Opioid receptors are GPCRs; their discovery prompted the search for the endogenous ligand, leading to the identification of endorphins
Endorphins are polypeptides that act as agonists at opioid receptors
Opioid toxicity: respiratory depression is the primary cause of overdose death; addiction potential is very high
Fentanyl is approximately 10,000 times more potent than morphine
Derived from the coca plant (Erythroxylum coca), native to South America, where the plant uses cocaine as an insecticide
Illustrates how a whole plant can differ profoundly in effect from a purified chemical constituent
At the synapse: blocks reuptake of norepinephrine and dopamine, increasing activity of those neurotransmitters
CNS effects: increased wakefulness, decreased fatigue, positive mood, decreased appetite
Autonomic effects: increased heart rate, dilation of nasal passages and pupils (sympathomimetic)
Can produce stimulant psychosis and disconnection from reality
Genetic components influence duration and intensity of effects
Highly addictive; affects the frontal lobe and limbic system
Includes Adderall and Ritalin
Mechanism: cause neurotransmitter vesicles to become "leaky," spilling norepinephrine and dopamine into the synaptic cleft
Result: extra stimulation producing increased arousal, stamina, attention, focus, and sympathomimetic effects
Takes longer to be excreted from the body than cocaine
Amphetamines have similar effects to cocaine at the synaptic level
Psychedelics affect the mind, psyche, and perception; effects are strongly shaped by set (expectation) and setting (environment)
All interact with serotonin, particularly in the raphe nuclei, and amplify sensory phenomena
LSD (lysergic acid diethylamide): one of the most potent psychoactive substances known; derived from ergot fungus; Albert Hofmann discovered its effects in 1943; Hofmann also proposed serotonin as a neurotransmitter, a major turning point in neurobiology
Maria Sabina: Mazatec curandera who introduced the Western world to the ritual ethnobotanical use of psilocybin mushrooms in her culture
Psilocybin: primary psychoactive component of psychedelic mushrooms; also identified by Hofmann in 1958
DMT (dimethyltryptamine): occurs widely in Amazonian plants; used in shamanic rituals; also present endogenously in the brain; produces powerful perceptual changes
Mescaline: the most powerful psychoactive compound in the peyote cactus; used in Mexican rituals; intensifies thoughts, feelings, and perceptions
Psychedelics are classified as Schedule I controlled substances
Cannabis has long been valued for its fibre (hemp)
THC (delta-9-tetrahydrocannabinol) is the major psychoactive cannabinoid, one of roughly 60 cannabinoids in the plant
THC is very hydrophobic, so it crosses cell membranes easily
Cannabinoid receptors (CB receptors) are GPCRs, among the most abundant GPCRs in the brain
Endocannabinoids are endogenous molecules that activate CB receptors; anandamide was the first to be discovered
Retrograde signalling: endocannabinoids are synthesised in the postsynaptic neuron and travel backwards across the synaptic cleft to CB receptors on the presynaptic terminal, tuning synaptic strength
THC is psychotomimetic; CBD is antipsychotic
The dopamine hypothesis of psychosis: excess dopamine pathway activity produces psychotic symptoms
Antipsychotic drugs are dopamine receptor antagonists
Cocaine and amphetamines activate dopamine pathways and can induce psychosis
Rauwolfia serpentina ("snakeroot"): a traditional Chinese and Indian medicine; source of reserpine, which has anti-anxiety, antipsychotic, and anti-hypertensive properties
Depression symptoms span mood, interest, pleasure, guilt, suicidal thoughts, changes in eating, and somatic complaints
Current prevalence roughly 5%, lifetime prevalence roughly 17%
Depressed mood is linked to underactivity (hypofunction) in monoamine neurotransmitter systems, especially serotonin
⚠️ Know the specific receptor target for each drug class: caffeine (adenosine antagonist), nicotine (nAChR agonist), alcohol/barbiturates/benzodiazepines (GABA facilitation), opioids (opioid GPCRs), cocaine (reuptake blocker), amphetamines (vesicle leakage), psychedelics (serotonin), cannabinoids (CB GPCRs).
⚠️ Distinguish between agonist, antagonist, and reuptake blocker mechanisms.
⚠️ Therapeutic index: barbiturates have a low TI (easy to overdose), benzodiazepines are safer.
⚠️ Heroin crosses the BBB faster than morphine because it is less hydrophilic (fewer OH groups).
⚠️ Retrograde signalling by endocannabinoids is a distinctive mechanism, often tested.
⚠️ The dopamine hypothesis ties together cocaine, amphetamines, antipsychotics, and psychosis.
⚠️ THC is psychotomimetic, CBD is antipsychotic: know this contrast.
Q: What is the mechanism by which caffeine promotes wakefulness?
A: Caffeine is an adenosine receptor antagonist. It blocks adenosine from binding to its receptors, preventing the sleep-promoting effects of adenosine accumulation.
Q: Why is heroin more potent than morphine when injected?
A: Heroin (diacetylmorphine) is less hydrophilic than morphine because it has fewer hydroxyl groups. This allows it to cross the blood-brain barrier more quickly, reaching the CNS faster and at higher concentrations.
Q: How do barbiturates and benzodiazepines differ in terms of safety?
A: Both facilitate GABA signalling, but barbiturates have a low therapeutic index (small gap between effective and lethal dose), making overdose more likely. Benzodiazepines have a wider margin of safety.
Q: What is retrograde signalling in the context of the endocannabinoid system?
A: Endocannabinoids are produced in the postsynaptic neuron and travel backwards across the synaptic cleft to bind CB receptors on the presynaptic terminal. This modulates neurotransmitter release and tunes synaptic strength.
Q: What evidence supports the dopamine hypothesis of psychosis?
A: Antipsychotic drugs that block dopamine receptors reduce psychotic symptoms. Cocaine and amphetamines, which increase dopamine activity, can produce psychosis. Together, these observations suggest excess dopamine pathway activity underlies psychosis.
Q: Cocaine and amphetamines both increase dopamine in the synaptic cleft. How do their mechanisms differ?
A: Cocaine blocks the reuptake transporter for dopamine and norepinephrine, preventing clearance from the cleft. Amphetamines cause vesicles to become leaky, spilling dopamine and norepinephrine directly into the cleft and then into the synapse.
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