Source: Chapter 9, Lecture slides
Tags: psychoactive drug, caffeine, adenosine, nicotine, alcohol, GABA, sedative-hypnotic, barbiturate, benzodiazepine, general anesthetic, opium, morphine, opioid, fentanyl, endorphin, cocaine, reuptake blocker, amphetamine, psychedelic, LSD, psilocybin, mescaline, DMT, cannabis, THC, endocannabinoid, anandamide, retrograde signaling
This chapter surveys the major classes of psychoactive drugs, from stimulants (caffeine, nicotine, cocaine, amphetamines) through depressants (alcohol, barbiturates, benzodiazepines) to opioids and psychedelics. It covers their mechanisms of action at the synaptic level, their historical context, and the endogenous systems they interact with (adenosine receptors, opioid receptors, endocannabinoid system).
Psychoactive drug
A chemical substance that acts primarily on the central nervous system, altering brain function and producing temporary changes in perception, mood, consciousness, and behaviour.
Caffeine
The most widely used psychoactive drug globally. Found in coffee, tea, chocolate. Discovered in 1820. A potent stimulant. Works as an antagonist at adenosine receptors, blocking the inhibitory effects of adenosine and producing an overall excitatory effect.
Theophylline
Found in tea. Similar psychoactive effects to caffeine due to similar chemical structure. Also an adenosine receptor antagonist.
Theobromine
Found in chocolate. Similar psychoactive effects to caffeine due to similar chemical structure. Also an adenosine receptor antagonist.
Adenosine
An inhibitory neurotransmitter. Caffeine, theophylline, and theobromine are all antagonists at adenosine receptors, which is why they produce stimulating effects.
Nicotine
The primary psychoactive compound in tobacco (Nicotiana tabacum). An agonist at nicotinic acetylcholine receptors. Overall CNS effect: both stimulation and relaxation. Likely exists in the plant to protect against insects. Adverse effects in humans include disruptions in heart rate, blood pressure, and breathing.
Alcohol (ethyl alcohol)
A member of the sedative-hypnotic family. Effects progress from relaxation to impaired actions and decisions, memory loss, loss of consciousness, and potentially death. Works by facilitating GABA action, producing an overall inhibitory effect on the brain and body.
Sedative-hypnotic drugs
Named from Hypnos, Greek god of sleep. In low doses: sleep-inducing, relaxing effects. In higher doses: impaired function, memory loss, unconsciousness, and potentially death. All thought to work through GABA-related mechanisms.
Barbiturates
Among the first synthetic drugs in the pharmaceutical world. Prescribed for anxiety and insomnia. Examples: phenobarbital, pentobarbital.
Benzodiazepines
Developed in the 1960s. Examples: diazepam (Valium), lorazepam, alprazolam (Xanax). Librium and Valium quickly became the best-selling drugs in history after their release.
General anaesthetics
Drugs that reduce CNS neural activity to create a complete loss of sensory awareness, used for surgery. Often volatile liquids inhaled by patients (e.g. diethyl ether, later replaced by other agents).
Opium
Derived from the opium poppy (Papaver somniferum). Medicinal properties include analgesia (pain relief), cough suppression, and slowing intestinal motility (diarrhoea treatment). Produces intense feelings of euphoria and relaxation.
Morphine
The isolated active chemical of the opium poppy. Named after Morpheus, Greek god of sleep. Produces the same effects as crude opium. Its isolation by Friedrich Wilhelm Sertürner was the first time a single chemical substance was shown to account for the medicinal and psychoactive properties of a plant.
Friedrich Wilhelm Sertürner
Isolated morphine from the opium poppy and proved the isolated chemical produced the same effects as the whole plant substance. A landmark moment in pharmacology.
Heroin (diacetylmorphine)
The first semi-synthetic opioid. About twice as potent as morphine because its less-polar acetyl group allows faster crossing of the blood-brain barrier. Originally marketed by Bayer as a cough medicine and analgesic.
Semi-synthetic opioid
A compound that starts with a plant-derived molecule and is chemically modified to be more potent or less toxic. Heroin was the first example.
Fentanyl
A fully synthetic opioid, approximately 100 times as powerful as morphine. Used in human medicine. Carfentanil, a derivative, is 10,000 times as powerful as morphine and is used for sedating elephants.
Synthetic opioid
An opioid produced entirely by chemical synthesis, not derived from plant material. Methadone (made by German chemists during WWII) was the first. Fentanyl is another example.
Endorphins
Endogenous (produced within the body) opioid peptides. The name combines "endogenous" and "morphine." They are the natural neurotransmitter ligands that bind opioid receptors. Their principal function is to inhibit pain signal transmission; they may also produce feelings of euphoria. All opioid receptors are GPCRs. Types include enkephalins, dynorphins, and beta-endorphin.
Opioid receptor
Found in the brain and the gut. All types are GPCRs (metabotropic). Endorphins are their endogenous agonists; exogenous opioids (morphine, heroin, fentanyl) also activate them.
Cocaine
Derived from the coca plant (Erythroxylum coca), used by native South Americans for thousands of years. Effects: decreased appetite, increased positive mood, sympathetic nervous system stimulation (increased heart rate, vasoconstriction, bronchial and nasal passage opening, pupil dilation). Mechanism: blocks neurotransmitter reuptake at synapses.
Psychosis
A severe mental state involving loss of contact with reality, sometimes induced by high doses of stimulant drugs.
Amphetamine
A class of stimulant drugs that act at synapses. Related molecules share similar effects.
Psychedelics / hallucinogens
Substances that produce altered perception, thought, and feeling. Include mescaline (from peyote cactus, isolated by Arthur Heffter), LSD (synthesised by Albert Hofmann), psilocybin (from Psilocybe mushrooms, famously used by Maria Sabina and investigated by Gordon Wasson), and DMT (found in ayahuasca).
Mescaline
The psychoactive compound in the peyote cactus. Isolated by Arthur Heffter.
LSD (lysergic acid diethylamide)
Synthesised by Albert Hofmann. One of the most potent known psychedelics.
Psilocybin
The psychoactive compound in Psilocybe mushrooms. Maria Sabina, a Mazatec healer, introduced their ceremonial use to the Western world through Gordon Wasson.
DMT (dimethyltryptamine)
A powerful psychedelic compound found in ayahuasca, a traditional brew from South America.
Cannabis
A plant containing multiple psychoactive compounds.
THC (tetrahydrocannabinol)
The primary psychoactive compound in cannabis.
Endocannabinoids
Endogenous molecules that bind cannabinoid receptors. Anandamide is the best known. These are the body's own cannabis-like signalling molecules.
Anandamide
An endocannabinoid, the body's endogenous ligand at cannabinoid receptors. Named from the Sanskrit word ananda, meaning "bliss."
Retrograde signalling
Endocannabinoids are unusual neurotransmitters because they are released by the postsynaptic neuron and travel backwards across the synapse to act on the presynaptic terminal. This is the reverse of typical neurotransmitter signalling.
Caffeine, theophylline, theobromine: antagonists at adenosine receptors, producing excitation by blocking an inhibitory NT
Nicotine: agonist at nicotinic ACh receptors, causes both stimulation and relaxation; highly toxic and addictive
Cocaine: blocks reuptake of neurotransmitters (especially dopamine) at synapses, prolonging their effects; stimulates the sympathetic nervous system
Amphetamines: act at synapses to increase neurotransmitter activity (related mechanisms to cocaine)
Alcohol: facilitates GABA action (overall inhibitory effect); progressive dose-dependent effects from relaxation to death
Barbiturates: early synthetic sedatives for anxiety and insomnia (phenobarbital, pentobarbital)
Benzodiazepines: developed 1960s, safer profile than barbiturates (diazepam, lorazepam, alprazolam)
General anaesthetics: reduce CNS activity for surgical loss of sensation; often volatile liquids (diethyl ether and successors)
All sedative-hypnotics are thought to work through GABA-related mechanisms
Opium (from Papaver somniferum): analgesia, euphoria, cough suppression, slowed intestinal motility
Morphine: isolated by Sertürner, first pure drug from a plant
Semi-synthetic opioids: heroin (twice morphine's potency, crosses BBB faster)
Synthetic opioids: methadone (first, WWII era), fentanyl (~100x morphine), carfentanil (~10,000x morphine)
Endorphins: endogenous opioid peptides (enkephalins, dynorphins, beta-endorphin), inhibit pain, produce euphoria
All opioid receptors are GPCRs, found in the brain and gut
Mescaline: peyote cactus, isolated by Arthur Heffter
LSD: synthesised by Albert Hofmann
Psilocybin: Psilocybe mushrooms, Maria Sabina, Gordon Wasson
DMT: found in ayahuasca
All produce altered perception, thought, and feeling
THC is the primary psychoactive compound in cannabis
Endocannabinoids (e.g. anandamide) are the body's own cannabinoid signalling molecules
Endocannabinoids use retrograde signalling: released by the postsynaptic neuron, they travel backwards to act on the presynaptic terminal
⚠️ Know caffeine's mechanism: antagonist at adenosine receptors (blocks an inhibitory NT, producing net excitation).
⚠️ Alcohol facilitates GABA (inhibitory). All sedative-hypnotics are thought to work through GABA mechanisms.
⚠️ Cocaine blocks reuptake at synapses, prolonging neurotransmitter action.
⚠️ Understand the opioid progression: opium (plant), morphine (isolated chemical), heroin (semi-synthetic), fentanyl (fully synthetic), each more potent.
⚠️ All opioid receptors are GPCRs. Endorphins are the endogenous ligands.
⚠️ Retrograde signalling by endocannabinoids is unique: postsynaptic to presynaptic, the reverse of normal transmission.
⚠️ Nicotine is an agonist at nicotinic ACh receptors (ionotropic). Know the distinction from muscarinic receptors (metabotropic, covered in Ch. 8).
Q: How does caffeine produce its stimulating effect?
A: Caffeine is an antagonist at adenosine receptors. By blocking adenosine (an inhibitory neurotransmitter), caffeine removes inhibition, resulting in a net excitatory effect.
Q: What is the mechanism of alcohol's effect on the brain?
A: Alcohol facilitates the action of GABA, the brain's primary inhibitory neurotransmitter, producing an overall inhibitory effect. At increasing doses this progresses from relaxation to impairment, memory loss, unconsciousness, and potentially death.
Q: What makes heroin more potent than morphine?
A: Heroin (diacetylmorphine) has a less-polar acetyl group that allows it to cross the blood-brain barrier faster than morphine, making it about twice as potent.
Q: What are endorphins, and what type of receptor do they bind?
A: Endorphins are endogenous opioid peptides (produced within the body). They bind opioid receptors, all of which are GPCRs. Their main function is inhibiting pain signal transmission, and they can also produce euphoria.
Q: What is unique about endocannabinoid signalling?
A: Endocannabinoids use retrograde signalling: they are released by the postsynaptic neuron and travel backwards across the synapse to act on the presynaptic terminal, the reverse of typical neurotransmitter signalling.
Q: How does cocaine work at the synapse?
A: Cocaine blocks the reuptake of neurotransmitters (particularly dopamine) from the synaptic cleft, prolonging their action at the postsynaptic receptor.
Psychoactive drug, caffeine, theophylline, theobromine, adenosine, adenosine receptor, antagonist, nicotine, nicotinic receptor, tobacco, Nicotiana tabacum, alcohol, ethanol, sedative-hypnotic, GABA, barbiturate, benzodiazepine, diazepam, Valium, Xanax, general anaesthetic, diethyl ether, opium, Papaver somniferum, morphine, Morpheus, Sertürner, heroin, diacetylmorphine, semi-synthetic opioid, synthetic opioid, methadone, fentanyl, carfentanil, endorphin, enkephalin, dynorphin, opioid receptor, GPCR, cocaine, Erythroxylum coca, reuptake blocker, amphetamine, psychosis, psychedelic, hallucinogen, mescaline, peyote, Arthur Heffter, LSD, Albert Hofmann, psilocybin, Psilocybe, Maria Sabina, Gordon Wasson, DMT, ayahuasca, cannabis, THC, tetrahydrocannabinol, endocannabinoid, anandamide, retrograde signalling, MCB C61, UC Berkeley