Table of Contents
Overview: How Chemicals Influence the Nervous System
Psychoactive substances and neurotoxins are chemical agents that alter how the nervous system works.
- Psychoactive substances mainly change mental states: perception, mood, consciousness, thinking, and behavior.
- Neurotoxins damage or block the normal function of nerve cells and can cause paralysis, convulsions, pain, or death.
Both act by interfering with the mechanisms of signal transmission and processing already discussed in the parent chapters: action potentials, synaptic transmission, neurotransmitters, and receptors. Here, the focus is on typical mechanisms and examples.
Psychoactive Substances
What Makes a Substance “Psychoactive”?
A substance is called psychoactive if, in small amounts, it:
- Crosses the blood–brain barrier (enters the central nervous system).
- Interacts with neurotransmitter systems, e.g.:
- Mimics a neurotransmitter (agonist).
- Blocks a neurotransmitter’s action (antagonist).
- Changes release, reuptake, or degradation of transmitters.
- Leads to subjective mental effects: euphoria, sedation, hallucinations, altered thinking or motivation.
The same neurotransmitter systems are used for normal information processing; psychoactive substances “hack” these systems.
Major Functional Classes of Psychoactive Substances
1. Depressants (Sedatives)
Depressants reduce the overall activity of the central nervous system.
Typical effects:
- Calming, reduced anxiety, drowsiness.
- Slowed reflexes and thinking.
- At higher doses: respiratory depression, unconsciousness, coma.
Mechanisms (often multiple):
- Enhance inhibitory GABAergic transmission, e.g.:
- Increase opening frequency or duration of GABA\(_A\) receptor Cl\(^-\) channels.
- Inhibit excitatory transmission (e.g. glutamate receptors).
- Alter membrane fluidity and ion channel function (especially alcohols).
Examples:
- Alcohol (ethanol):
- Potentiates GABA\(_A\) receptors; inhibits some glutamate (NMDA) receptors.
- Disturbs coordination, judgment, and memory (hippocampus).
- Benzodiazepines (e.g. diazepam):
- Bind allosterically to GABA\(_A\) receptors and increase their effect.
- Used therapeutically as anxiolytics, hypnotics, anticonvulsants.
- Barbiturates:
- Strong GABA\(_A\) potentiation; narrow therapeutic window; high overdose risk.
- Opiates/Opioids (also analgesics; see below).
2. Stimulants
Stimulants increase activity in the central nervous system.
Typical effects:
- Increased alertness, attention, and wakefulness.
- Elevated heart rate and blood pressure.
- Reduced appetite, decreased need for sleep.
- At high doses: anxiety, agitation, psychosis-like symptoms.
Mechanisms:
- Increase release of monoamine neurotransmitters (dopamine, noradrenaline, sometimes serotonin).
- Block reuptake transporters, prolonging transmitter action.
- Less commonly: inhibit monoamine-degrading enzymes (MAO).
Examples:
- Caffeine:
- Blocks adenosine receptors (which normally promote sleepiness).
- Indirectly increases dopamine and noradrenaline signaling.
- Nicotine:
- Agonist at nicotinic acetylcholine receptors.
- Increases dopamine release in reward pathways; also stimulates autonomic ganglia.
- Amphetamines:
- Promote release and inhibit reuptake of dopamine and noradrenaline.
- Strong effects on mood, focus, drive; high addiction potential.
- Cocaine:
- Blocks dopamine, noradrenaline, and serotonin reuptake.
- Marked euphoria; high risk of cardiovascular events and addiction.
3. Hallucinogens (Psychedelics and Related Substances)
Hallucinogens mainly alter perception, thinking, and self-experience.
Typical effects:
- Visual and auditory distortions (not always true hallucinations).
- Intensified emotions, changes in sense of time and self.
- Synesthesia (“hearing colors”) in some users.
Mechanisms:
- Many act as agonists or partial agonists at serotonin 5-HT\(_{2A}\) receptors (especially in cortex).
- Some affect glutamate systems (e.g. NMDA receptors).
Examples:
- LSD (lysergic acid diethylamide):
- Potent 5-HT\(_{2A}\) receptor agonist.
- Extremely active in microgram doses; long-lasting effects.
- Psilocybin (from “magic mushrooms”):
- Converted to psilocin; also acts at 5-HT receptors.
- Mescaline:
- Phenethylamine hallucinogen; affects 5-HT and other receptors.
- Ketamine, PCP (dissociatives):
- NMDA receptor antagonists; cause detachment from body, altered pain perception.
4. Analgesics with Psychoactive Effects: Opiates/Opioids
Opiates/opioids relieve pain and can strongly influence mood.
Typical effects:
- Strong analgesia (pain relief).
- Euphoria, sedation, “warmth”.
- At high doses: respiratory depression, pinpoint pupils, unconsciousness.
Mechanism:
- Agonists at opioid receptors (µ, κ, δ), which normally bind endorphins/enkephalins.
- Inhibit neurotransmitter release; modulate pain pathways and reward circuits.
Examples:
- Morphine, heroin, fentanyl, oxycodone.
- Endogenous endorphins and enkephalins.
5. Anxiolytics, Hypnotics, and Antipsychotics
These include several drug classes used therapeutically to alter mental states.
- Anxiolytics/hypnotics:
- Often benzodiazepines or related GABAergic drugs.
- Decrease anxiety, induce sleep; risk of dependence.
- Antipsychotics:
- Block dopamine D\(_2\) receptors (and sometimes serotonin receptors).
- Reduce hallucinations and delusions in psychotic disorders.
- Can cause movement disorders (extrapyramidal side effects) due to basal ganglia dopamine blockade.
Tolerance, Dependence, and Addiction
Repeated exposure to psychoactive substances often leads to physiological and psychological changes.
Tolerance
- Pharmacodynamic tolerance:
- Neurons adapt: receptor number or sensitivity changes, signaling pathways adjust.
- Pharmacokinetic tolerance:
- Liver enzymes increase; the substance is metabolized faster.
- Result: Higher doses are needed to achieve the same effect.
Dependence
- Physical dependence:
- Nervous system adapts to presence of the substance.
- Abrupt cessation leads to withdrawal symptoms (e.g. tremors, anxiety, pain, seizures).
- Psychological dependence:
- Strong craving and perceived need to take the substance for well-being or normal functioning.
Addiction and Reward Pathways
Addiction is closely linked to the brain’s reward system, especially:
- Dopamine pathways from the ventral tegmental area (VTA) to the nucleus accumbens and prefrontal cortex.
- Drugs of abuse typically cause rapid, strong dopamine release in these regions, reinforcing drug-taking behavior.
- Learning processes connect drug cues (places, people, paraphernalia) with intense reward signals, making relapse likely.
Neurotoxins
What Is a Neurotoxin?
A neurotoxin is a substance that damages nerve cells or disrupts their function, often without intending to cause subjective “pleasure” or desirable mental effects.
- Many neurotoxins are defensive or offensive molecules produced by animals, plants, fungi, or bacteria.
- Some are environmental pollutants or synthetic chemicals.
- Doses may be extremely low: nanograms can be lethal.
Neurotoxins primarily affect:
- Ion channels (Na\(^+\), K\(^+\), Ca\(^{2+}\)).
- Synaptic vesicle release machinery.
- Neurotransmitter receptors.
- Metabolic processes required for neuron survival.
Mechanisms of Action of Neurotoxins
1. Blockage of Voltage-Gated Ion Channels
Since action potentials depend on voltage-gated Na\(^+\) and K\(^+\) channels, blockers can stop nerve conduction.
- Tetrodotoxin (TTX):
- Found in pufferfish, some newts, octopus.
- Blocks voltage-gated Na\(^+\) channels in nerves and muscles from the outside.
- Symptoms: numbness, paralysis, respiratory failure; consciousness can remain intact.
- Saxitoxin:
- Produced by some marine dinoflagellates; accumulates in shellfish (paralytic shellfish poisoning).
- Mechanism similar to TTX.
- Local anesthetics (e.g. lidocaine) as controlled “neurotoxins”:
- Also block Na\(^+\) channels but are used at carefully controlled doses and locations.
2. Disruption of Synaptic Vesicle Release
Neurotransmitter release depends on vesicle fusion machinery (SNARE proteins). Some toxins selectively target these proteins.
- Botulinum toxins (from Clostridium botulinum):
- Proteases that cleave SNARE proteins at cholinergic synapses.
- Block acetylcholine release at neuromuscular junctions.
- Result: flaccid paralysis; lethal through respiratory failure.
- In tiny amounts used medically (e.g. for muscle spasms, cosmetic treatments).
- Tetanus toxin (from Clostridium tetani):
- Taken up at neuromuscular junctions and transported to inhibitory interneurons in the spinal cord.
- Blocks release of inhibitory transmitters (GABA, glycine).
- Result: uncontrolled muscle contractions and rigidity (spastic paralysis).
3. Overactivation or Blockade of Neurotransmitter Receptors
Neurotoxins can also act at postsynaptic receptors:
- Nicotinic acetylcholine receptor antagonists:
- Examples: curare alkaloids from plants.
- Block nAChRs at neuromuscular junctions.
- Result: flaccid paralysis with preserved consciousness.
- Nicotine (already mentioned as a stimulant):
- Acts as agonist at nAChRs; in large doses can be neurotoxic (seizures, respiratory paralysis).
- Atropine (from deadly nightshade) and related alkaloids:
- Block muscarinic acetylcholine receptors (mainly in parasympathetic system and CNS).
- Lead to tachycardia, dry mouth, hallucinations, hyperthermia.
- Kainic acid, domoic acid:
- Glutamate receptor agonists causing excitotoxic damage (overactivation leading to neuron death).
4. Interference with Neurotransmitter Metabolism
Some neurotoxins affect synthesis or breakdown of transmitters:
- Organophosphate nerve agents and some insecticides (e.g. sarin, VX):
- Irreversibly inhibit acetylcholinesterase.
- Acetylcholine accumulates at synapses:
- Continuous stimulation of muscles (fasciculations, paralysis).
- Excessive secretions, bronchoconstriction, bradycardia.
- Death by respiratory failure.
- Physostigmine, neostigmine:
- Reversible acetylcholinesterase inhibitors used therapeutically (e.g. in myasthenia gravis), but in higher doses are toxic.
5. Metabolic Poisons Targeting Neurons
Some toxins interfere with energy metabolism or structural components particularly critical for nerve cells.
- Cyanide:
- Inhibits cytochrome c oxidase in the mitochondrial electron transport chain.
- Neurons, with high energy demand, are rapidly affected.
- Methylmercury, lead:
- Environmental neurotoxins that disrupt neuronal development and synaptic function.
- Can cause cognitive deficits, motor disturbances, and sensory problems.
Selected Examples from Different Organisms
Animal Venoms
Animal venoms often contain complex mixtures of peptides and proteins targeting the nervous system.
- Cone snail toxins (conotoxins):
- Highly specific blockers of various ion channels and receptors.
- Some variants used as powerful analgesics.
- Scorpion and spider toxins:
- Often affect Na\(^+\), K\(^+\), or Ca\(^{2+}\) channels.
- Can cause pain, convulsions, or paralysis.
- Snake neurotoxins:
- α-neurotoxins (e.g. from cobras) bind nAChRs and block neuromuscular transmission.
Plant and Fungal Neurotoxins
- Nicotine, atropine, scopolamine:
- Plant alkaloids that modulate acetylcholine receptors or central signaling.
- Muscimol (from fly agaric, Amanita muscaria):
- Potent GABA\(_A\) agonist; hallucinogenic and neurotoxic effects.
- Ibotenic acid:
- Glutamate receptor agonist; causes excitotoxic damage.
Bacterial Neurotoxins
- Botulinum and tetanus toxins (already described):
- Among the most potent toxins known.
- Their extreme toxicity illustrates how critical properly functioning synapses are for life.
Therapeutic Uses vs. Toxic Effects
Many substances can be both medicine and poison, depending on dose, context, and route of administration.
- Opioids:
- Essential in pain management; high overdose risk.
- Local anesthetics:
- Safe when used locally and in controlled doses; systemic overdose can cause seizures, arrhythmias.
- Botulinum toxin:
- Used in tiny doses in neurology and dermatology; systemically is a lethal neurotoxin.
- Antipsychotics, antidepressants, anxiolytics:
- Act on the same receptors and pathways as many abused drugs; require careful dosing and monitoring.
This dual nature underlines a central principle: the nervous system is so sensitive that small chemical changes can have profound effects—beneficial, harmful, or both.
Long-Term Effects on the Nervous System
Repeated or chronic exposure to psychoactive substances and neurotoxins can cause lasting changes:
- Structural changes:
- Loss of neurons (neurodegeneration) in specific brain areas.
- Altered dendritic branching and synaptic density.
- Functional changes:
- Modified receptor expression and sensitivity.
- Persistent alterations in neurotransmitter systems (e.g. dopamine in addiction).
- Behavioral/cognitive effects:
- Memory impairments, mood disorders, reduced impulse control.
- Increased vulnerability to mental illnesses in susceptible individuals.
Many of these changes involve processes also relevant for normal learning, memory, and plasticity, but driven abnormally by chemical exposure.
Protective Mechanisms and Risk Reduction
Organisms possess several mechanisms to limit neural damage:
- Blood–brain barrier (BBB):
- Restricts access of many toxins to the CNS.
- Detoxification systems:
- Liver and kidneys metabolize and excrete many xenobiotics.
- Homeostatic regulation:
- Receptor downregulation, transporter upregulation, etc., help rebalance signaling—but can also contribute to tolerance and withdrawal.
From a human health perspective, risk reduction involves:
- Limiting exposure to known environmental neurotoxins (e.g. heavy metals, pesticides).
- Informed, cautious use of therapeutic psychoactive drugs.
- Prevention and treatment of substance use disorders, given their basis in altered neural information processing and reward learning.
Understanding psychoactive substances and neurotoxins therefore provides insight not only into disease and poisoning, but also into the normal function and plasticity of the nervous system.