Source: MCB C61, UC Berkeley
Tags: cocaine, amphetamine, opioids, morphine, heroin, fentanyl, general anesthetics, GABA, microtubules, schizophrenia, antipsychotics, dopamine hypothesis, depression, MAOIs, tricyclics, SSRIs, monoamine hypothesis, psychedelics, LSD, psilocybin, DMT, mescaline, serotonin, Schedule One, controlled substances
This section covers the major classes of psychoactive drugs, from stimulants (cocaine, amphetamines) to opioids, general anesthetics, antipsychotics, antidepressants, and psychedelics. The recurring theme is that most of these compounds work by interfering with specific neurotransmitter systems, particularly dopamine, norepinephrine, and serotonin. Understanding the synaptic mechanism of each drug class is the backbone of this material.
Cocaine
An alkaloid from the coca plant (Erythroxylum coca) that blocks reuptake transporters for norepinephrine and dopamine, causing these neurotransmitters to remain in the synaptic cleft longer than normal. Originally used as a local anaesthetic.
Amphetamine
A stimulant that makes norepinephrine and dopamine reuptake transporters "leaky," allowing neurotransmitters to stay in the cleft. Examples include Adderall, Dexedrine, and methamphetamine (speed).
Sympathomimetic
A substance that mimics the effects of the sympathetic nervous system. Both cocaine and amphetamines are sympathomimetic because they increase norepinephrine activity.
Opioid
A class of compounds (natural, semi-synthetic, or synthetic) that bind to opioid receptors in the brain. Derived originally from the opium poppy (Papaver somniferum).
Morphine
The first substance isolated from a plant (opium poppy) that was responsible for its medicinal properties. Discovered by Friedrich Wilhelm Sertürner in 1803.
Heroin
The acetylated form of morphine, a semi-synthetic opioid with increased potency.
Endorphins (endogenous morphine)
The body's own neuropeptide neurotransmitters that bind to opioid receptors. They are the reason opioid receptors exist in the brain in the first place.
General anaesthetic
A chemical that produces a global loss of sensation by affecting the brain and altering consciousness. Works by facilitating GABA at ionotropic GABA receptors and by disrupting microtubule function inside neurons.
Local anaesthetic
A chemical that produces loss of sensation only in the region of the body where it is applied. Cocaine was the original local anaesthetic.
Pharmakon
Greek word meaning both medicine and poison, reflecting the dual nature of drugs.
Reductionist equation
The approach of breaking complex biological effects into simpler subunits: plant → single chemical → specific neurotransmitter interaction.
Schizophrenia
A chronic psychotic condition (prevalence ~1%) involving a breakdown in the relation between thought, emotion, and behaviour. Characterised by delusions, hallucinations, and withdrawal from reality. Has both genetic and environmental risk factors.
Psychosis
A disruption of perceived reality characterised by delusions (fixed false beliefs) and/or hallucinations (perceptual experiences not generated by ordinary sensory stimuli).
Dopamine hypothesis of psychosis
The theory that psychotic symptoms are related to overactivity in dopaminergic neurotransmission, and antipsychotic medications reduce symptoms by blocking some of that overactivity.
Antipsychotic medications (dopamine receptor antagonists)
Drugs that reduce delusions and hallucinations by blocking dopamine receptors. Example: Chlorpromazine (Thorazine). Second-generation antipsychotics also block certain serotonin receptors and have fewer side effects.
Rauwolfia serpentina (snakeroot)
An ancient Chinese and Indian medicine that serves as an anti-anxiety, antipsychotic, and antihypertensive drug.
Clinical depression (major depression)
A prolonged and dysfunctional dysphoric mood. Symptoms span feelings (low mood, loss of interest), thoughts (guilt, suicidal ideation), actions (disordered eating, suicide attempts), and somatic complaints (sleep disturbance, fatigue). Lifetime prevalence ~17%, current prevalence ~5%.
MAOIs (monoamine oxidase inhibitors)
Antidepressants that inhibit monoamine oxidase, the enzyme that normally inactivates norepinephrine and serotonin by oxidising them. This allows more of these neurotransmitters to remain active at synapses.
Tricyclics (TCAs)
Antidepressants that block or slow the reuptake of norepinephrine and serotonin back into the axons that released them.
SSRIs (selective serotonin reuptake inhibitors)
Antidepressants that selectively block serotonin reuptake. Fluoxetine (Prozac) was the first SSRI, reaching the market in 1988. Not more effective than MAOIs or TCAs, but with fewer side effects.
Monoamine hypothesis of depression
The theory that depression is related to a deficit of norepinephrine and/or serotonin, and that increasing the efficiency of these neurotransmitters is therapeutically important. Monoaminergic nerve fibres emerge from small clusters in the brainstem and innervate the entire brain. All their receptors are GPCRs.
Psychedelics / hallucinogens
Compounds that produce intensified thoughts and feelings and altered sensory perception. Their effects are heavily influenced by "set and setting." Classic psychedelics bind as agonists to serotonin receptor subtypes, especially 5-HT2A receptors.
Set and setting
"Set" refers to psychological factors (expectations, mood, memories). "Setting" refers to the physical environment. Psychedelics are highly affected by both; alcohol is less so.
Mescaline
The first identified psychedelic substance, found in the peyote cactus (Lophophora williamsii). The peyote cactus grows primarily in Mexico and was used by native peoples of the Americas in rituals.
LSD (lysergic acid diethylamide)
Synthesised and self-tested by Albert Hofmann in 1943. Derived from ergotamine, produced by the fungus Claviceps purpurea (ergot). Structurally resembles serotonin.
Psilocybin / psilocin
Active compounds in "magic mushrooms" (Psilocybe genus). Both structurally resemble serotonin. Knowledge of their use was brought to contemporary society by Gordon Wasson in 1957, who learned from the Mazatec healer Maria Sabina. The active chemicals were identified by Albert Hofmann.
DMT (dimethyltryptamine)
Structurally similar to serotonin and psilocin. Can be synthesised from tryptophan. Possibly functions as an endogenous neurotransmitter in animal nervous systems. Found in many plants. The Amazonian preparation ayahuasca combines Psychotria viridis (contains DMT) with the ayahuasca vine (Banisteriopsis caapi), which amplifies DMT's effects.
Schedule One controlled substance
Under the U.S. Controlled Substances Act, these are substances deemed to have no accepted medical use, high potential for abuse, and are outlawed. Marijuana, LSD, psilocybin, and DMT are all Schedule One.
Cocaine blocks or inhibits reuptake transporters for norepinephrine (NE) and dopamine (DA), keeping these neurotransmitters in the synaptic cleft for longer than normal
This produces excessive postsynaptic activity
Effects on NE pathways: sympathomimetic (mimics the sympathetic nervous system)
Effects on CNS: stimulant, wakefulness, increased stamina, appetite suppression, elevated mood, potential for overstimulation
High addiction potential
Routes of administration: injection, intranasal, smoking (crack cocaine)
Amphetamines work similarly but through a slightly different mechanism: they make the NE and DA reuptake transporters "leaky" rather than blocking them outright. The downstream effects are comparable.
Examples: Adderall, Dexedrine (oral administration)
Methamphetamine (speed)
Methylphenidate (Ritalin) (oral administration)
NE and DA pathways project broadly across the entire brain
Opium poppy (Papaver somniferum), native to the Mediterranean
Medicinal effects of opioids: analgesia (reduced pain perception), anxiolytic (anti-anxiety), sedation, cough suppression, decreased intestinal motility (used to treat diarrhoea), pupil constriction
Friedrich Wilhelm Sertürner (1803, Germany) isolated morphine from opium, the first time a single active compound was extracted from a plant
He also found codeine
Increasing potency through chemical modification:
Acetylation of morphine produces heroin
Oxycodone and etorphine are semi-synthetic and synthetic variants
Carfentanyl (Wildnil) is 10,000x more potent than morphine, used to sedate large animals
Overdose risk comes from depression of respiratory control centres in the brainstem
Lethal overdoses have increased dramatically in recent years, driven by synthetic opioids
Endogenous opioid system:
The body produces its own opioid neurotransmitters, called endorphins (endogenous morphine)
Endorphins are neuropeptides
They bind to the same opioid receptors that morphine and heroin target
General anaesthetics produce a global loss of sensation by acting on the brain
They facilitate GABA at ionotropic GABA receptors, making GABA more sensitive and producing a stronger inhibitory effect
Additionally, psychoactive drugs enter the lipid bilayer of neurons and act intracellularly
Microtubules (dense within axon interiors) regulate intracellular processes; general anaesthetics bind to microtubules and disrupt their function
This microtubule disruption is an example of molecular-level mechanisms that remain under-studied
Schizophrenia: chronic psychotic condition, ~1% prevalence, genetic and environmental risk factors
Common symptoms: delusions, hallucinations
Antipsychotic drugs: Chlorpromazine (Thorazine), discovered in France, was among the first
All first-generation antipsychotics act as dopamine receptor antagonists (they block DA receptors)
Second-generation (serotonin-dopamine antagonists) also block certain serotonin receptors, with fewer problematic side effects
The dopamine hypothesis: psychotic symptoms arise from overactivity in dopaminergic pathways, and antipsychotics work by reducing that overactivity
Depression symptoms span mood (dysphoria, loss of interest), cognition (guilt, suicidal ideation), behaviour (eating changes, suicide attempts), and somatic (sleep, fatigue, agitation)
Lifetime prevalence ~17%, current ~5%
Three main classes of antidepressants:
MAOIs: inhibit the enzyme monoamine oxidase, which normally breaks down NE and serotonin
Tricyclics (TCAs): block reuptake of NE and serotonin
SSRIs: selectively block serotonin reuptake. Fluoxetine (1988) was the first; SSRIs are not more effective than older drugs but have fewer side effects
The monoamine hypothesis: depression is linked to a deficit of NE and/or serotonin. All monoaminergic receptors are GPCRs. Monoaminergic fibres originate from small brainstem clusters and innervate the entire brain.
Classic psychedelics: mescaline, LSD, psilocybin, DMT
All classic psychedelics bind as agonists at serotonin receptors, especially 5-HT2A; they can also bind to NE and DA receptors
Non-classic psychedelics: MDMA (ecstasy), MDA, salvinorin, ketamine, anticholinergic hallucinogens (atropine, scopolamine)
Key historical figures:
Arthur Heffter: proposed the term "psychedelic" (psyche = mind, delos = visible); identified mescaline from peyote
Albert Hofmann: synthesised and self-tested LSD in 1943; identified psilocybin and psilocin with Wasson
Gordon Wasson: brought knowledge of psilocybin mushrooms to contemporary society (1957), learned from Maria Sabina
Richard Evans Schultes: ethnobotanist and Amazon explorer who studied DMT
Legal history:
First laws against LSD: 1966; globally outlawed in 1971
In the 1990s, psychedelics again investigated for therapeutic purposes
All classic psychedelics are Schedule One under the U.S. Controlled Substances Act
⚠️ Know the specific synaptic mechanism for each drug class: cocaine blocks reuptake, amphetamines make transporters leaky, MAOIs block enzymatic breakdown, TCAs block reuptake, SSRIs selectively block serotonin reuptake.
⚠️ Distinguish between dopamine hypothesis (psychosis/schizophrenia) and monoamine hypothesis (depression). Both involve monoamines, but the specific neurotransmitter emphasis differs.
⚠️ Endorphins are neuropeptides, not small-molecule neurotransmitters. They are the endogenous ligands for opioid receptors.
⚠️ General anaesthetics have two known mechanisms: GABA facilitation at ionotropic receptors AND microtubule disruption. The microtubule mechanism is less well studied.
⚠️ "Set and setting" is a core concept for psychedelics. Psychedelics are heavily influenced by both; alcohol is less so.
⚠️ All classic psychedelics are 5-HT2A agonists. LSD, psilocybin, psilocin, and DMT all structurally resemble serotonin.
Q: How does cocaine produce its stimulant effects at the synapse?
A: Cocaine blocks or inhibits reuptake transporters for norepinephrine and dopamine, keeping these neurotransmitters in the synaptic cleft longer and producing excessive postsynaptic activity.
Q: What distinguishes the mechanism of amphetamines from that of cocaine?
A: Both increase NE and DA in the cleft, but cocaine blocks reuptake transporters while amphetamines make the transporters leaky, allowing neurotransmitter to flow back out into the cleft.
Q: Why is respiratory depression the primary danger in opioid overdose?
A: Opioids depress the respiratory control centres in the brainstem, which can lead to cessation of breathing and death.
Q: What are endorphins, and why do opioid receptors exist in the brain?
A: Endorphins are endogenous neuropeptide neurotransmitters (endogenous morphine) that bind to opioid receptors. These receptors evolved to respond to the body's own endorphins, not to external opioids.
Q: How do general anaesthetics work at the molecular level?
A: They facilitate GABA at ionotropic GABA receptors (increasing inhibition) and also enter the lipid bilayer of neurons to disrupt microtubule function intracellularly.
Q: What is the dopamine hypothesis of psychosis?
A: It proposes that psychotic symptoms (delusions, hallucinations) are related to overactivity in dopaminergic neurotransmission, and antipsychotics reduce symptoms by blocking dopamine receptors.
Q: Name the three classes of antidepressants and state the mechanism of each.
A: MAOIs inhibit monoamine oxidase (the enzyme that breaks down NE and serotonin). TCAs block NE and serotonin reuptake. SSRIs selectively block serotonin reuptake.
Q: What does "set and setting" mean in the context of psychedelics?
A: "Set" is the user's psychological state (expectations, mood, prior experience). "Setting" is the physical environment. Both strongly influence the psychedelic experience.
Q: Which serotonin receptor subtype is most associated with classical psychedelic effects?
A: The 5-HT2A receptor.
Q: What does Schedule One mean under the U.S. Controlled Substances Act?
A: The substance is not legally available, not seen to have any accepted medical use, and has a high potential for abuse.
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