Module 3 | Source: A Brain-Mind Odyssey (UC Berkeley), Chapter 9
Tags: psychoactive drugs, caffeine, adenosine, nicotine, alcohol, ethanol, sedative-hypnotic, barbiturates, benzodiazepines, opioids, morphine, heroin, fentanyl, endorphins, cocaine, amphetamine, psychedelics, LSD, psilocybin, cannabis, THC, endocannabinoids, retrograde signalling
Chapter 9 surveys the major classes of psychoactive drugs, from everyday stimulants (caffeine, nicotine) through sedative-hypnotics (alcohol, barbiturates, benzodiazepines), opioids (morphine, heroin, fentanyl), stimulants (cocaine, amphetamines), psychedelics (mescaline, LSD, psilocybin, DMT), and cannabinoids (THC). Each class is linked to its receptor target and synaptic mechanism, with key historical figures and plant sources woven throughout.
Caffeine
Found in coffee (Coffea arabica, native to northeast Africa), tea (Camellia sinensis, native to East Asia), and cacao (Theobroma cacao, native to South and Central America). Acts as an antagonist at adenosine receptors, producing increased wakefulness and alertness.
Theophylline
Molecule closely related to caffeine; found in tea.
Theobromine
Molecule closely related to caffeine; found in cacao.
Adenosine
Neurotransmitter made from adenine by attachment of a ribose sugar. Caffeine acts as its antagonist. Adenosine receptors are GPCRs and have distinct roles by location:
Heart: mediate slowing of heart rate
Blood vessels: mediate vasodilation (opening of vessels)
Brain: decrease neuronal excitability
Nicotine
Primary psychoactive constituent of tobacco (Nicotiana tabacum, Nicotiana rustica). Binds as an agonist at nicotinic acetylcholine receptors (nAChRs). Behavioural effects include relaxation, alertness, and focused attention. Also disrupts heart rhythm, blood pressure, and respiration.
Ethanol (Ethyl Alcohol)
Refers specifically to two-carbon ethyl alcohol. All organic alcohols are poisons, but ethanol is the least poisonous to the human body. Produced by yeast fermentation of plant sugars.
Sedative-Hypnotic Drugs
A class of drugs (including ethanol) that produce sedative or relaxing effects at low doses and hypnotic (sleep-inducing) effects at higher doses. Act at ionotropic GABA receptors, facilitating GABA's action and increasing inhibition in the CNS by enhancing GABA-induced Cl- flow into cells. At sufficiently high doses: impaired movement and memory, loss of consciousness, death.
Barbiturates
Synthetic sedative-hypnotic drugs introduced in the early 20th century. Among the first synthetic drugs in medicine. Used to treat anxiety and insomnia.
Benzodiazepines
Another group of synthetic sedative-hypnotic drugs, introduced in the 1960s.
General Anaesthetics
A category of sedative-hypnotic used in medicine. Potent enough to reduce overall CNS neural activity, producing loss of consciousness and complete lack of awareness of sensory experience, including pain.
Opium Poppy (Papaver somniferum)
Source of psychoactive effects including relaxation, pain relief, and euphoria. Reduces perception of pain, suppresses cough, and slows motile muscle action of the intestines.
Opium
Resinous secretion obtained by carefully slitting unripe poppy seed pods. Contains the medicinal properties of the opium poppy.
Morphine
A more potent chemical substance purified from opium. Named after Morpheus, Greek god of dreams.
Friedrich Wilhelm Sertürner (1783–1841)
Isolated and purified morphine from opium, demonstrating that it produced the analgesic, soporific, and euphoric effects of opium but in a more potent manner.
Heroin (Diacetylmorphine)
Semi-synthetic opioid created by reacting morphine with acetic acid. Approximately twice as potent as morphine due to more efficient entry through the blood-brain barrier.
Semi-Synthetic Opioids
Chemical modifications made to a plant-derived compound to improve action or reduce toxicity while retaining opium-like effects.
Synthetic Opioids
Entirely synthetic compounds with opioid effects. First example: methadone, developed by German chemists during the early years of World War II.
Fentanyl
Synthetic opioid approximately 100 times more potent than morphine. Widely used in medicine. Certain fentanyl derivatives are among the most potent drugs presently known, naturally occurring or synthetic.
Endorphins
Endogenous molecules that function as agonists at opioid receptors. The first neuropeptides discovered. They are polypeptide chains: the shortest are five amino acids long (leu-enkephalin and met-enkephalin), the longest is thirty-one amino acids (beta-endorphin).
Opioid Receptors
Protein receptors (GPCRs) found in the brain and gut that bind opioids.
Erythroxylum Coca (Coca Plant)
Native to South America. Leaves are chewed or brewed into tea, producing increased wakefulness, focused attention, decreased fatigue, increased stamina, decreased appetite, increased positive mood, and sympathetic nervous system stimulation.
Cocaine
Primary stimulant molecule from the coca plant. Much more potent as a purified substance. Blocks reuptake transporters for norepinephrine and dopamine, slowing neurotransmitter clearance from the synaptic cleft and producing excessive activity at all noradrenergic and dopaminergic synapses.
Psychosis
Discombobulation of the perception of reality, characterised by delusions and/or hallucinations. Can result from CNS overarousal by stimulant drugs.
Amphetamine-Type Stimulant Drugs
Related to cocaine in their nervous system and behavioural effects. Synthetic pharmaceutical drugs including amphetamine, methamphetamine, methylphenidate (commercial names Dexedrine, Adderall). Interact with reuptake transporters for norepinephrine and dopamine and cause them to become leaky, producing overstimulation of those neural circuits.
Ephedrine
Present in plants of the genus Ephedra. Used to treat asthma; known as ma huang in Chinese medicine.
Psychedelics (Hallucinogens)
Produce complex effects on the brain and mind: intensified thoughts and feelings, altered sensory perception, experiences ranging from awe and connection to anxiety and panic. Bind as agonists to various serotonin receptor subtypes, especially 5-HT2A receptors, and to dopamine and norepinephrine receptors.
Mescaline
First psychedelic substance to be chemically identified. From the peyote cactus (Lophophora williamsii). Identified by Arthur Heffter (1859–1925) in 1897.
LSD (Lysergic Acid Diethylamide)
Derived from ergotamine, produced by the fungus Claviceps purpurea (ergot). One of the most potent psychoactive substances known, active in quantities of a few micrograms. Synthesised and tested by Albert Hofmann (1906–2008) in 1943.
Psilocybin and Psilocin
Two psychedelically active chemicals from Psilocybe mushrooms. Molecular structure is extremely similar to serotonin. Their ritual use was shared by Mazatec healer Maria Sabina (1894–1985) and documented by Gordon Wasson (1898–1986).
DMT (Dimethyltryptamine)
Structurally similar to serotonin and psilocin. Can be readily synthesised by enzymes from the amino acid tryptophan in many organisms. May serve as an endogenous neurotransmitter.
Ayahuasca
A brew made from the vine Banisteriopsis caapi (which increases DMT's effects) combined with DMT-containing plants such as Psychotria viridis.
Cannabis
Plants of the genus Cannabis, believed to have originated in central Asia. Diverse applications: analgesic, muscle relaxant, appetite stimulant, sedative, stimulant, psychedelic-like consciousness alteration. When cultivated for fibre, referred to as hemp.
Tetrahydrocannabinol (THC)
Delta-9-tetrahydrocannabinol. The major psychoactive chemical constituent of cannabis. Very hydrophobic.
Endocannabinoids
Endogenous agonists at cannabinoid (CB) receptors. Include anandamide and 2-arachidonylglycerol (2-AG). Function as retrograde neurotransmitters.
Anandamide
Endogenous ligand for the CB receptor. Functions as a neurotransmitter at CB receptor synapses.
Cannabinoid (CB) Receptor
A GPCR. Appears to be the most abundant of all known GPCR receptor types in the vertebrate brain.
Retrograde Signalling
Molecules that carry signal information in the direction opposite to the conventional direction of neural signal transmission (i.e. from postsynaptic back to presynaptic cell).
Caffeine, theophylline, and theobromine are structurally related methylxanthines found in coffee, tea, and cacao respectively.
Caffeine competitively antagonises adenosine receptors (GPCRs), blocking adenosine's inhibitory and vasodilatory effects.
The result is increased wakefulness, alertness, and stimulatory cardiovascular effects (raised heart rate and blood pressure).
Alcohol, barbiturates, benzodiazepines, and general anaesthetics all act at ionotropic GABA receptors.
They facilitate GABA's action, increasing Cl- influx into neurons and thereby increasing inhibition throughout the CNS.
Dose-dependent progression: relaxation and anxiolysis at low doses, impaired movement and memory at moderate doses, unconsciousness at high doses, death at very high doses.
Natural source: opium from Papaver somniferum.
Morphine is purified from opium (isolated by Sertürner).
Heroin (diacetylmorphine) is a semi-synthetic modification, roughly twice morphine's potency due to better BBB penetration.
Synthetic opioids (methadone, fentanyl) are entirely laboratory-made. Fentanyl is approximately 100x more potent than morphine.
Opioid receptors are GPCRs in the brain and gut. Endogenous ligands are endorphins (polypeptide neuropeptides).
Cocaine blocks reuptake transporters for norepinephrine and dopamine, prolonging neurotransmitter presence in the synaptic cleft.
Amphetamines interact with those same transporters but cause them to become leaky, producing a similar net effect: overstimulation of noradrenergic and dopaminergic circuits.
CNS effects (both classes): increased wakefulness, alertness, focused attention, decreased appetite, elevated mood.
Sympathomimetic effects: increased heart rate and blood pressure, bronchodilation, pupil dilation.
Risks: anxiety, irritability, impaired judgement, psychosis, seizures, cardiovascular damage, stroke, heart attack, addiction.
Classical psychedelics (mescaline, LSD, psilocybin/psilocin) bind as agonists primarily at 5-HT2A serotonin receptors, with additional activity at dopamine and norepinephrine receptors.
LSD is active at microgram doses, making it one of the most potent psychoactive substances known.
Psilocybin and psilocin are structurally very similar to serotonin.
DMT is also structurally similar to serotonin and may function as an endogenous neurotransmitter.
Non-classical psychedelics include MDMA (ecstasy), MDA, and salvinorin.
THC is very hydrophobic, crossing the BBB readily.
CB receptors are GPCRs and may be the most abundant GPCR type in the vertebrate brain.
Endocannabinoids (anandamide, 2-AG) are retrograde neurotransmitters: they carry signals from the postsynaptic neuron back to the presynaptic neuron, the reverse of conventional signal flow.
⚠️ Know the receptor type and mechanism for each drug class. Sedative-hypnotics facilitate GABA at ionotropic receptors. Opioids act at GPCR opioid receptors. Psychedelics agonise 5-HT2A receptors. Cannabinoids act at CB receptors (GPCRs).
⚠️ Cocaine blocks reuptake transporters; amphetamines make them leaky. Different mechanism, similar downstream effect.
⚠️ Dose-dependent effects of sedative-hypnotics form a clear continuum from relaxation through to death. This is a common exam sequence to reproduce.
⚠️ Fentanyl potency relative to morphine (approximately 100x) is a frequently tested figure.
⚠️ Endocannabinoids are retrograde neurotransmitters. This is an unusual and distinctive signalling direction that examiners like to ask about.
⚠️ Endorphins were the first neuropeptides discovered. Shortest: five amino acids (leu-enkephalin, met-enkephalin). Longest: thirty-one amino acids (beta-endorphin).
⚠️ LSD active at microgram quantities; psilocybin/psilocin structurally similar to serotonin; DMT may be endogenous. These are distinct, testable facts.
Q: How does caffeine produce its stimulant effects?
A: Caffeine acts as an antagonist at adenosine receptors (GPCRs), blocking adenosine's normal inhibitory effects on neuronal excitability, its slowing of heart rate, and its vasodilatory action.
Q: What receptor type do sedative-hypnotic drugs act on, and what is the ionic mechanism?
A: Ionotropic GABA receptors. These drugs facilitate GABA's action, increasing chloride ion (Cl-) flow into neurons, which enhances inhibition in the CNS.
Q: How does heroin differ from morphine in terms of chemistry and potency?
A: Heroin (diacetylmorphine) is morphine reacted with acetic acid. It is approximately twice as potent as morphine because it crosses the blood-brain barrier more efficiently.
Q: Compare the synaptic mechanisms of cocaine and amphetamines.
A: Cocaine blocks (inhibits) reuptake transporters for norepinephrine and dopamine. Amphetamines interact with those same transporters and cause them to become leaky. Both result in excess norepinephrine and dopamine remaining in the synaptic cleft and overstimulation of those circuits.
Q: At which serotonin receptor subtype do classical psychedelics primarily act, and as agonists or antagonists?
A: Classical psychedelics (mescaline, LSD, psilocybin) bind as agonists primarily at 5-HT2A serotonin receptors.
Q: What is retrograde signalling, and which endogenous neurotransmitters use it?
A: Retrograde signalling is the transmission of signals from the postsynaptic neuron back to the presynaptic neuron, opposite to the conventional direction. Endocannabinoids (anandamide, 2-AG) are the primary retrograde neurotransmitters discussed.
Q: What are endorphins, and what is their receptor type?
A: Endorphins are endogenous polypeptide neuropeptides that function as agonists at opioid receptors (GPCRs) in the brain and gut. They range from five amino acids (enkephalins) to thirty-one amino acids (beta-endorphin).
psychoactive drugs, caffeine, theophylline, theobromine, methylxanthines, adenosine, adenosine antagonist, GPCR, nicotine, nAChR, tobacco, Nicotiana tabacum, ethanol, ethyl alcohol, sedative-hypnotic, GABA, GABA receptor, ionotropic, chloride channel, barbiturates, benzodiazepines, general anaesthetics, opium, opium poppy, Papaver somniferum, morphine, Sertürner, heroin, diacetylmorphine, semi-synthetic opioid, synthetic opioid, methadone, fentanyl, endorphins, enkephalin, beta-endorphin, neuropeptide, opioid receptor, Erythroxylum coca, cocaine, reuptake transporter, norepinephrine, dopamine, sympathomimetic, amphetamine, methamphetamine, methylphenidate, Dexedrine, Adderall, ephedrine, Ephedra, psychosis, psychedelics, hallucinogens, psychotomimetics, mescaline, peyote, Lophophora williamsii, Arthur Heffter, LSD, ergotamine, Claviceps purpurea, ergot, Albert Hofmann, psilocybin, psilocin, Psilocybe, Maria Sabina, Gordon Wasson, serotonin, 5-HT2A, DMT, dimethyltryptamine, ayahuasca, Banisteriopsis caapi, Psychotria viridis, MDMA, cannabis, hemp, THC, delta-9-tetrahydrocannabinol, cannabinoid receptor, CB receptor, endocannabinoids, anandamide, 2-AG, 2-arachidonylglycerol, retrograde signalling, retrograde neurotransmitter