💊 Neurotransmitters on drugs: How alcohol, medications & other substances affect the CNS

Every action in the brain - whether catching a ball, calming a panic attack, or waking from anaesthesia - starts at the synapse. In physiology, you’ve already met the major neurotransmitters: GABA, glutamate, dopamine, serotonin, acetylcholine, and noradrenaline.

Now it’s time to see these in clinical action. If you haven't already read it, go back and check out the Neurotransmitters 101 post, it will help it all make sense. 

Many drugs and substances - from prescription medications to recreational drugs - alter the brain’s electrochemical balance. They dial neurotransmitter signalling up or down, leading to effects that are therapeutic, recreational, harmful, or all three. Understanding how they work builds your clinical intuition - and helps you spot mechanisms behind both therapeutic effects and side effects.

 We’ll explore how each class works, what effects they trigger, and where they act in the neural circuit. Consider this your pharmacological map of the CNS - designed for clarity, clinical context, and curiosity.

🍷 Alcohol – The broad-spectrum dampener

Primary effect: Enhances the action of GABA, the brain’s main inhibitory neurotransmitter.

GABA binds to GABA_A receptors, opening chloride channels and hyperpolarizing neurons, making them less likely to fire.

• Alcohol amplifies this effect, leading to sedation, reduced anxiety, motor impairment, and eventually unconsciousness.

Other effects:

• Inhibits glutamate transmission (excitatory), blunting cognition and reflexes.
• Boosts dopamine release transiently—hence the early feelings of euphoria.

🔬 That’s why someone intoxicated may be relaxed (GABA), disinhibited (frontal cortex suppression), but also clumsy and slow (motor system inhibition).

🧪 Naltrexone: Blocking the buzz to break the cycle

Naltrexone is an opioid receptor antagonist: it binds to receptors but doesn’t activate them. Instead, it blocks the effects of opioids and alcohol at the brain’s reward centres – no high, no reinforcement.

🧠 How It Works:

• Opioids: Naltrexone blocks the euphoric effects of drugs like heroin, oxycodone, and morphine.
• Alcohol: It reduces the pleasurable reinforcement of drinking by dampening dopamine release in the mesolimbic pathway.

💊 Clinical Use:

• Used after detox: patients must be opioid-free for 7–10 days to avoid precipitated withdrawal.
• Available as daily tablets or monthly injections (e.g. Vivitrol).
• Helps reduce cravings, relapse risk, and heavy drinking episodes.
• Patients often report that alcohol or opioids “just don’t feel the same” on naltrexone.

🔬 Think of naltrexone as a “mute button” on the brain’s reward speakers—it doesn’t erase the signal, but it stops the buzz from being heard.

💊 Opioids – Pain relief via mu-receptor signalling

Examples: Morphine, Fentanyl, Heroin, Oxycodone

How they work:

• Bind to mu-opioid receptors: a type of metabotropic receptor found in the brain, spinal cord, and gut.
• This triggers G-protein cascades that:

• Block pain signal transmission in the dorsal horn
• Suppress GABA release, which paradoxically increases dopamine in reward pathways → euphoria

Clinical effects:

• Analgesia, sedation, respiratory depression, constipation, euphoria
• In overdose: brainstem suppression → slowed breathing, unconsciousness

🔬 Imagine pain pathways dimming, but so does respiratory drive—that’s the danger zone.

🔁 Why so many CNS drugs are addictive—and what is addiction?

Many CNS-active drugs (e.g. opioids, stimulants, alcohol) hijack the brain’s reward system, flooding it with dopamine in the mesolimbic pathway. This creates intense reinforcement, making the brain associate the drug with survival-level importance. 

🧠 Over time, tolerance builds, the brain adapts, making natural rewards feel dull and requiring higher doses just to feel “normal,” not high. Compulsive use emerges not from pleasure-seeking, but from avoiding withdrawal and emotional flatlining

🧠 Addiction isn’t just craving, it’s a rewiring of motivation and control circuits.
It’s a chronic brain condition, not a failure of willpower.

🧠 Imagine your brain’s reward system being reprogrammed to treat the drug like oxygen- it feels essential to survive, even when it’s harming you.

😌 Benzodiazepines – GABA’s helpful sidekick

Examples: Diazepam, Lorazepam, Midazolam

Mechanism:

• Bind to a modulatory site on the GABA_A receptor, making it more responsive to GABA.
• Doesn’t open channels directly, but enhances the inhibitory effect → calming, anxiolytic, anticonvulsant actions

Used in:

• Anxiety, insomnia, seizures, procedural sedation
• Can cause sedation, reduced coordination, and memory impairment

🔬 They’re like a backstage crew helping GABA keep the lights dimmed across the cortex.

⚡ Ionotropic Receptors – Fast, direct, short-lived

• Remember we discussed two main kinds of receptors - Ionotropic vs metabotropic receptors? 
  
  
• Ionotropic receptors are ligand-gated ion channels.
• When a neurotransmitter binds, the channel opens immediately → ions flow in or out → rapid change in membrane potential.
• Effects last milliseconds.

🧠 Clinical relevance:

• Used for quick responses like muscle contraction, reflexes, and seizure activity.
• Drugs that act here tend to have rapid onset and short duration.

Examples:

• Benzodiazepines (e.g. diazepam) enhance GABA_A ionotropic receptors → fast anxiolytic and sedative effects.
• NMDA antagonists (e.g. ketamine) block glutamate ionotropic receptors → rapid anaesthesia or antidepressant effects.

🔬  Ionotropic receptors are like automatic doors: step on the mat (neurotransmitter binds), and the door opens instantly.

🧠 Why This Distinction Matters in Practice

• Emergency meds (e.g. midazolam for seizures) target ionotropic receptors for speed.
• Side effects differ: ionotropic drugs may cause abrupt sedation or motor changes; metabotropic drugs may alter mood, appetite, or long-term neural plasticity.

🔥 Stimulants – Cranking up dopamine and noradrenaline

Examples: Methamphetamine, Cocaine, Methylphenidate

Mechanism:

• Increase synaptic dopamine and noradrenaline via multiple routes:

• Blocking reuptake transporters
• Promoting neurotransmitter release
• Inhibiting breakdown enzymes

Effects:

• Heightened alertness, mood elevation, reduced appetite
• High doses → agitation, paranoia, seizures

🔬 They flood the synapse with excitatory drive—great for attention, risky for balance

🧩 Why Stimulants Calm ADHD: The Paradox Explained

Stimulants like methylphenidate and amphetamine increase dopamine and noradrenaline in the prefrontal cortex, improving attention and impulse control.

In neurotypical brains, this boost can cause hyperactivity and agitation. But in ADHD, where baseline dopamine is low, stimulants restore balance, leading to calm focus rather than overstimulation.

🧠  It’s like turning up the volume on a quiet radio—not to make it loud, but to finally hear the music clearly.

😷 Anaesthetics (e.g. Propofol) – Switching off awareness

Mechanism:

• Potentiates GABA_A receptors, leading to widespread inhibition
• Reduces glutamate release and inhibits voltage-gated sodium channels

Effects:

• Rapid induction of unconsciousness
• Depresses cortical and brainstem activity
• Commonly used in surgery and ICU settings

🧪 Anaesthetic Pharmacology: Induction vs Maintenance

Anaesthesia has two key phases: induction (getting the patient unconscious) and maintenance (keeping them there safely). Different drugs are used for each, and they differ in pharmacokinetics and receptor targets.

🚀 Induction Agents – Fast in, fast out

• Highly lipophilic → rapidly cross the blood–brain barrier
• Bolus dose → quick peak in CNS concentration
• Rapid redistribution → short duration of action
• Often act on GABA_A receptors to cause immediate CNS depression

🧠 Why? We need fast unconsciousness, so drugs like propofol or thiopental flood the brain quickly, then redistribute to fat and muscle, wearing off within minutes.

🔄 Maintenance Agents – Steady state, titratable

• Given as continuous infusion or inhaled gas
• Designed for slow onset, longer duration, and precise control
• Maintain a stable plasma concentration over time
• Often act on multiple targets (GABA_A, NMDA, K⁺ channels) for balanced anaesthesia

🧠 Why? We need to sustain unconsciousness without overshooting. These agents are chosen for predictable clearance, low accumulation, and adjustability during surgery.

🔬 Analogy: Induction agents are like flipping a light switch - fast and decisive. Maintenance agents are like a dimmer - adjustable and sustained.
Watch this video to see just how fast propofol works !

🌿 Cannabinoids – Neurotransmission with a retrograde twist

Examples: THC, CBD, marijuana

Mechanism:

• THC activates CB₁ receptors on presynaptic terminals, suppressing neurotransmitter release (especially GABA, glutamate, dopamine)
• Signals often move retrograde, from postsynaptic to presynaptic cell
• CBD modulates these effects without directly activating CB₁

Effects:

• Euphoria, altered perception, anxiolysis, impaired memory and coordination
• Variable sedation depending on dose and individual response

🔬 Imagine the postsynaptic neuron sending a ‘quiet down’ signal back upstream, like a student asking their teacher to lower their voice so they can concentrate. It’s backward signalling that rewrites the usual rules.

🧬 Metabotropic Receptors – Slow, indirect, long-lasting

• Remember we discussed two main kinds of receptors – ionotropic vs metabotropic receptors? 

• Metabotropic receptors are G-protein-coupled receptors (GPCRs).
• Binding triggers a cascade of intracellular signals → can open ion channels indirectly or change gene expression.
• Effects last seconds to minutes or longer.

🧠 Clinical relevance:

• Used for modulation, long-term changes, and fine-tuning of neural activity.
• Drugs here often have slower onset, but sustained effects.

Examples:

• Opioids (e.g. morphine) bind mu-opioid metabotropic receptors → pain relief, euphoria, respiratory depression.
• SSRIs (e.g. fluoxetine) act on serotonin metabotropic receptors → gradual mood improvement over weeks.
• Cannabinoids (e.g. THC) act on CB₁ metabotropic receptors → altered perception and coordination.

🔬 Metabotropic receptors are like sending a message through a chain of people—slower, but the effects ripple widely and last longer.

🧠 Why This Distinction Matters in Practice

• Chronic treatments (e.g. antidepressants, antipsychotics) often target metabotropic receptors for sustained modulation.
• Side effects differ: ionotropic drugs may cause abrupt sedation or motor changes; metabotropic drugs may alter mood, appetite, or long-term neural plasticity.

💨 Inhalants – Messy chemistry meets CNS disruption

Examples: Nitrous oxide, Toluene, Solvents

Mechanism:

• Disrupt neuronal membranes and ion channels nonspecifically
• Depress overall CNS activity, not targeted at particular receptors

Effects:

• Transient euphoria, dizziness, impaired coordination
• Long-term use → white matter damage, cognitive decline

🔬 Imagine trying to operate a delicate circuit board with a sticky oily rag: it’s messy, non-specific, and over time it ruins the wiring

🧪 Hallucinogens – Perception rewired via serotonin

Examples: LSD, Psilocybin, MDMA

Mechanism:

• Stimulate 5-HT_2A receptors, especially in sensory cortices and frontal association areas
• MDMA also floods the synapse with serotonin, dopamine, noradrenaline, creating stimulant and empathogenic effects

Effects:

• Sensory distortion, emotional intensity, altered cognition
• MDMA can produce euphoria and prosocial feelings, but risk of serotonin toxicity at high doses

🔬 These drugs crank up the brain’s “special effects department”, like editing real life with psychedelic Photoshop filters and ambient emotion boosters

🧬 Antidepressants & Antipsychotics – Modulating serotonin and dopamine clinically

🧠 Antidepressants

Examples: SSRIs, SNRIs, MAOIs, Tricyclics

Mechanism:

• SSRIs block serotonin reuptake
• SNRIs extend effect to noradrenaline
• MAOIs prevent monoamine breakdown
• TCAs target multiple reuptake systems

Effects:

• Improved mood regulation, reduced anxiety
• Side effects depend on off-target actions (e.g. sedation, weight gain)

🔬 Think of the synapse like a bathtub, reuptake inhibitors plug the drain so serotonin “fills up” and bathes the brain longer, soothing low mood

🧠 Antipsychotics

Examples: Haloperidol, Risperidone, Clozapine

Mechanism:

• Typical drugs block D₂ receptors, dampening dopamine transmission
• Atypicals also block serotonin receptors, aiming for fewer motor side effects

Effects:

• Reduced hallucinations and delusions
• Can cause movement disorders or metabolic shifts

🔬 Antipsychotics act like dimmer switches for dopamine, necessary in conditions where the ‘volume’ of reality is turned up too high.

🕺 Antipsychotics and movement disorders: Dopamine’s double-edged sword

Antipsychotics also block D₂ receptors in the nigrostriatal pathway, which controls movement.

This can lead to extrapyramidal side effects (EPSEs) like:

• Parkinsonism (rigidity, tremor, slow movement)
• Akathisia (restlessness, urge to move)
• Acute dystonia (painful muscle spasms)
• Tardive dyskinesia (involuntary facial or limb movements)

🧠 It’s like trying to quiet a noisy neighbour (dopamine in the limbic system) but accidentally cutting power to your own house (dopamine in the motor system).

🧾 Summary Matrix – Drug Effects on Neurotransmission

Drug Class	Examples	Main Target(s)	Effect on Neurotransmission	Clinical/Neurological Effects
Alcohol	Ethanol	GABAA, Glutamate, Dopamine	↑ GABA, ↓ Glutamate, transient ↑ Dopamine	Sedation, disinhibition, motor impairment
Opioids	Morphine, Fentanyl, Heroin	Mu-opioid receptors (↓ GABA → ↑ DA)	Inhibitory signalling, ↑ dopamine in reward paths	Analgesia, euphoria, respiratory depression
Benzodiazepines	Diazepam, Lorazepam	GABAA (modulatory site)	Enhanced GABA effect	Anxiolysis, sedation, anticonvulsant
Stimulants	Methamphetamine, Cocaine	Dopamine, Noradrenaline transporters	↑ release, ↓ reuptake, ↓ breakdown	Alertness, euphoria, seizures at high dose
Anaesthetics	Propofol, Ketamine	GABAA, Glutamate	↑ inhibition, ↓ excitation	Unconsciousness, CNS depression
Cannabinoids	THC, CBD	CB1 receptors	↓ NT release (GABA, Glu, DA), retrograde signalling	Euphoria, anxiolysis, altered cognition
Hallucinogens	LSD, Psilocybin, MDMA	5-HT2A, DA, NA	↑ serotonin signalling, mixed DA/NA effects	Sensory distortion, emotional intensity
Antidepressants	SSRIs, MAOIs, SNRIs	Serotonin transporters, monoamine oxidase	↑ serotonin (& NA/DA depending on class)	Mood elevation, anxiety reduction
Antipsychotics	Haloperidol, Risperidone	D2, 5-HT2A	↓ dopamine (± serotonin modulation)	Antipsychotic, extrapyramidal effects
Inhalants	Nitrous oxide, solvents	Membrane and ion channels	Non-specific CNS suppression	Euphoria, neurotoxicity, motor dysfunction

Why these mechanisms matter

Knowing the receptor targets and neurotransmitters involved helps you predict:

• What symptoms might emerge with overdose or withdrawal
• Why certain drugs interact or produce paradoxical effects
• How similar symptoms (e.g. sedation or agitation) arise from vastly different pathways

🧑‍⚕️ Case: Jacob, 19-year-old with escalating oxycodone use

Jacob was prescribed oxycodone after a sports injury. Initially, he felt intense relief from the pain but also relaxed and a euphoric “lift.”

But within a few weeks, he noticed the same dose didn’t work as well, it didn’t bring the same high, and the pain seemed to be getting worse. Instead of two pills, Jacob began taking four to six. Not for a high - but just to feel normal and take the pain away.

He tried stopping once but experienced sweats, anxiety, and cravings so severe he gave up within a day.

Now, he doesn’t feel pleasure from hanging out with friends or playing music—only the drug seems to “switch life back on.”

💡 Clinical takeaway:
This isn’t about chasing pleasure—it’s the brain adapting and recalibrating its baseline. Jacob’s mesolimbic pathway now treats oxycodone like a survival cue, and his prefrontal cortex’s control circuits are struggling to keep up.

🧭 Final Thought: It’s All About Signal Tuning

Whether the goal is pain relief, sleep, stimulation, or anaesthesia, drugs work by dialling neurotransmission up or down. Once you understand the circuit, the pharmacology becomes a form of neural storytelling, one receptor at a time.

Understanding their mechanism shows you more than how they work, it teaches you how delicate, dynamic, and interconnected the CNS really is.

So next time you encounter a clinical case, whether it’s a patient with altered consciousness, withdrawal symptoms, or paradoxical reactions, ask:
💬 Which neurotransmitter is being tuned?
💬 Which receptor is being targeted?
💬 What network effect is emerging?

Grab a piece of paper or a whiteboard - can you draw the synapses and neurotransmitters and draw the action of the drug classes?

Because once you can see the signal behind the symptom, the synapse starts speaking your language.

📦 Want to learn more?

• 📝 All posts on the nervous system →
• 📝 Structure and function of the CNS →
• 📝 Pathophysiology of seizures →
• 📝 Understanding seizure classification →
• 📝 Localisation of seizures →
• 📝 Neurotransmitters 101 →
• 📝 Consciousness and how we can lose it →
• 📝 Clinical cases in seizure localisation →
• 📝Principles of seizure management →
• 📝Neurotransmitters on drugs! →
• 📝A beginner's guide to EEG →
• 📝A beginner's guide to neuroimaging →