Source: A Brain-Mind Odyssey, Ch. 9
Tags: psychoactive drugs, caffeine, nicotine, alcohol, opioids, cocaine, amphetamines, psychedelics, cannabis, THC, endocannabinoids, dopamine hypothesis, sedative-hypnotic, GABA, serotonin
Psychoactive drugs alter brain function by interacting with neurotransmitter systems, either mimicking, blocking, or modulating endogenous signalling molecules. This chapter covers the major drug classes (stimulants, sedative-hypnotics, opioids, psychedelics, cannabinoids), their mechanisms of action at the synapse, and the endogenous receptor systems they hijack. Understanding the receptor type each drug targets (GPCR, ion channel, reuptake transporter) is the backbone of this material.
Adenosine receptor antagonist
A molecule that blocks adenosine receptors, preventing the normal sleep-promoting effect of adenosine. Caffeine is the classic example.
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 the margin between an effective dose and a dangerous one is narrow.
Sympathomimetic
A drug effect that mimics activation of the sympathetic nervous system: increased heart rate, dilated pupils, raised blood pressure. Cocaine and amphetamines produce sympathomimetic effects.
Endorphins (endogenous morphines)
Polypeptides produced naturally 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. Anandamide was the first to be discovered.
Retrograde signalling
A signalling direction in which a chemical messenger travels backwards, from the postsynaptic neuron to the presynaptic terminal. Endocannabinoids use this mechanism to tune synaptic strength.
Psychotomimetic
A substance that mimics symptoms of psychosis. THC has psychotomimetic properties.
Schedule I controlled substance
A drug classification indicating no currently accepted medical use, high abuse potential, and lack of accepted safety under medical supervision. Psychedelic drugs fall into this category.
Found in coffee (Coffea arabica, northeast Africa), tea (Camellia sinensis, East Asia), cacao (Theobroma cacao, Central/South America), kola, guarana, yerba mate
Mechanism: adenosine receptor antagonist
Blocks the receptor that normally promotes drowsiness
Named after Jean Nicot; derived from Nicotiana tabacum
Mechanism: agonist at nicotinic acetylcholine receptors (nAChRs)
Directly activates the receptor that acetylcholine normally binds
Produced by yeast fermentation
Historically the first general anaesthetic
Mechanism: sedative-hypnotic
Facilitates GABA activity, increasing chloride (Cl⁻) ion flow into cells
Anxiolytic (reduces anxiety)
Synthetic sedative-hypnotic pharmaceuticals
Low therapeutic index, meaning overdose risk is high
Facilitate GABA receptor activity (same general mechanism as alcohol)
Examples: Valium, Xanax
Sedative-hypnotic pharmaceuticals
Amplify GABA's inhibitory effect at the receptor, keeping chloride channels open longer
Higher therapeutic index than barbiturates (safer margin)
Ethanol was the first used in medicine
Modern inhalation anaesthetics include sevoflurane
All amplify GABA receptor function
Opium: derived from the opium poppy (Papaver somniferum), used for thousands of years in the Mediterranean region
Concentrated in the seed pod after petals fall
Functions: pain relief, cough suppression, slows diarrhoea
Morphine: crystallised from opium
Friedrich Wilhelm Sertürner isolated and named it in 1803, after the Greek god Morpheus
Far more potent than raw opium
Acts directly on the CNS
Gave birth to the idea that purified chemical constituents carry a plant's medicinal properties
Semi-synthetic opioids and heroin
Heroin (diacetylmorphine) was first marketed in 1898 by Bayer as an analgesic and cough medicine
Less hydrophilic than morphine (fewer OH groups), so it crosses the blood-brain barrier faster
Opioid receptors: G-protein coupled receptors (GPCRs)
Their discovery prompted the search for the endogenous ligand, leading to the identification of endorphins
Endorphins: endogenous polypeptides that act as agonists at opioid receptors
Toxicity: respiratory depression is the primary danger; overdose death results from suppressed breathing. Highly addictive.
Fentanyl: roughly 10,000 times more potent than morphine
Derived from the coca plant (Erythroxylum coca), native to South America
The plant uses cocaine as a natural insecticide
A good example of how a whole plant differs profoundly from its purified chemical constituent
Mechanism at the synapse: blocks reuptake of norepinephrine and dopamine, increasing their concentration in the synaptic cleft
CNS effects: increased wakefulness, decreased fatigue, positive mood, decreased appetite
Autonomic effects: increased heart rate, dilated nasal passages and pupils (sympathomimetic)
Risks: increased anxiety, impaired judgement, stimulant psychosis, disconnection from reality. Genetic components influence duration and intensity of effects. Highly addictive; affects frontal lobe and limbic system.
Examples: Adderall, Ritalin
Mechanism: cause neurotransmitter vesicles to become "leaky," spilling norepinephrine and dopamine into the synaptic cleft
Results in increased arousal, stamina, attention, focus
Sympathomimetic effects
Slower excretion than cocaine (longer duration of action)
Similar overall effects to cocaine
Affect thoughts, perception, and the psyche
Strongly influenced by set (expectation) and setting (physical environment)
All interact with serotonin, particularly in the raphe nuclei, amplifying sensory phenomena
LSD (lysergic acid diethylamide)
One of the most potent psychoactive substances known
Derived from ergot fungus
Albert Hofmann discovered its psychoactive effects in 1943
Hofmann also proposed serotonin as a neurotransmitter, a turning point in neurobiology
Maria Sabina: Mazatec curandera who introduced Western researchers to the ritual use of psilocybin mushrooms
Psilocybin: primary psychoactive component of "magic mushrooms," also identified by Hofmann in 1958
DMT (dimethyltryptamine): occurs widely in Amazonian jungle plants; used in spiritual rituals by Amazonian shamans; also found endogenously in the brain
Mescaline: the most powerful psychoactive compound in the peyote cactus; used in Mexican rituals; intensifies thoughts, feelings, and perceptions
Cannabis has long been valued for its fibre (hemp)
THC (delta-9-tetrahydrocannabinol): the major psychoactive constituent, one of approximately 60 cannabinoids
Very hydrophobic, crosses membranes easily
Cannabinoid receptors (CB receptors): GPCRs found throughout the brain; the most abundant of all GPCRs
Anandamide: the first endocannabinoid discovered; an endogenous agonist at cannabinoid receptors
Retrograde signalling: endocannabinoids are released from the postsynaptic dendrite and travel backwards across the synaptic cleft to CB receptors on the presynaptic terminal, tuning synaptic strength
THC is psychotomimetic; CBD is antipsychotic (important contrast)
Proposes that psychosis results from excess dopamine activity in certain brain pathways
Supporting evidence:
Antipsychotic drugs are dopamine receptor antagonists
Cocaine and amphetamines activate dopamine pathways and can produce psychosis
Symptoms span feelings (low mood, loss of interest/pleasure), thoughts (guilt, suicidal ideation), actions (changes in eating, suicide attempts), and somatic complaints
Current prevalence roughly 5%; lifetime prevalence roughly 17%
Depressed mood is linked to underactivity (hypofunction) in monoamine neurotransmitter systems, especially serotonin
Traditional Chinese and Indian medicine
Source of reserpine, used as an anti-anxiety, antipsychotic, and antihypertensive agent
⚠️ Know which receptor type each drug targets: GPCR (opioids, cannabinoids, bitter taste), ion channel (nicotinic ACh), or reuptake transporter (cocaine, amphetamines).
⚠️ Distinguish cocaine's mechanism (blocks reuptake) from amphetamine's mechanism (causes vesicle leakage). Both raise dopamine and norepinephrine, but by different routes.
⚠️ Barbiturates have a low therapeutic index (dangerous); benzodiazepines are safer by comparison.
⚠️ Endorphins are the endogenous ligands for opioid receptors; anandamide is the endogenous ligand for cannabinoid receptors. Both receptor families are GPCRs.
⚠️ Retrograde signalling by endocannabinoids is a distinctive mechanism: postsynaptic to presynaptic.
⚠️ THC is psychotomimetic, CBD is antipsychotic. Don't confuse them.
⚠️ The dopamine hypothesis of psychosis ties together antipsychotic drugs (dopamine antagonists) and stimulant-induced psychosis (cocaine/amphetamine activate dopamine pathways).
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 normal sleep-promoting signal.
Q: How does heroin differ from morphine in terms of pharmacokinetics, and why does this matter?
A: Heroin (diacetylmorphine) is less hydrophilic than morphine because it has fewer hydroxyl groups. This allows it to cross the blood-brain barrier faster, producing a more rapid and intense effect.
Q: Compare the synaptic mechanisms of cocaine and amphetamines.
A: Cocaine blocks the reuptake of dopamine and norepinephrine, leaving more neurotransmitter in the cleft. Amphetamines cause vesicles to leak neurotransmitter into the cleft. Both increase synaptic dopamine and norepinephrine, but through different mechanisms.
Q: What is retrograde signalling in the context of endocannabinoids?
A: Endocannabinoids are synthesised in the postsynaptic neuron and travel backwards across the synaptic cleft to bind CB receptors on the presynaptic terminal. This modulates (tunes) the strength of the synapse.
Q: What evidence supports the dopamine hypothesis of psychosis?
A: Antipsychotic drugs work by blocking dopamine receptors. Conversely, cocaine and amphetamines, which increase dopamine activity, can produce psychotic symptoms. Both observations implicate excess dopamine signalling in psychosis.
Q: What is the therapeutic index, and why is it clinically important for barbiturates?
A: The therapeutic index is the ratio of the lethal dose to the therapeutic dose. Barbiturates have a low TI, meaning the effective dose and the lethal dose are dangerously close together, making overdose a significant risk.
psychoactive drugs, caffeine adenosine antagonist, nicotine acetylcholine agonist, ethanol GABA, sedative-hypnotic, barbiturate therapeutic index, benzodiazepine Valium Xanax, opioid GPCR, morphine Sertürner, heroin diacetylmorphine blood-brain barrier, endorphins endogenous morphine, fentanyl potency, cocaine reuptake blocker, amphetamine vesicle leakage, sympathomimetic, LSD Hofmann serotonin, psilocybin Maria Sabina, DMT dimethyltryptamine, mescaline peyote, Schedule I, THC delta-9-tetrahydrocannabinol, cannabinoid receptor CB GPCR, anandamide endocannabinoid, retrograde signalling, dopamine hypothesis psychosis, reserpine Rauwolfia, psychotomimetic, CBD antipsychotic, monoamine depression serotonin