env tox lecture 5: drug abuse and public health concerns

(final material)

drug abuse definition

• harmful or excessive use of psychoactive substances, such as alcohol, tobacco, marijuana, and prescription drugs

what can drug abuse cause

significant impairment in health, social, or occupational functioning

organ drugs target

central nervous system (CNS, brain)

explain the circled drugs

• nicotine → high dependence, relatively low toxicity

• alcohol → moderate dependence, high toxicity

• marijuana → moderate/low dependence, very low toxicity

• caffeine → moderate/low dependence, low toxicity

how do psychoactive drugs work in the brain/what are the mechanisms of action

1. mimic neurotransmitters and stimulate receptors (agonist)

2. inhibit neurotransmitters and/or receptors (antagonist)

3. block reuptake of neurotransmitters

adrenaline

fight or flight neurotransmitter

noradrenaline

concentration neurotransmitter

dopamine

pleasure neurotransmitter

serotonin

mood neurotransmitter

GABA

calming neurotransmitter

acetylcholine

learning neurotransmitter

glutamate

memory neurotransmitter

endorphins

euphoria neurotransmitter

neurons and synapses

• neurons transmit electrical signals along their axons and communicate with other neurons by releasing neurotransmitters at synapses

• GABA primarily inhibits neuronal activity, while glutamate primarily excites neuronal activity

neurotransmitter release process

1. action potential arrives at the presynaptic axon terminal

2. voltage-gated Ca²⁺ channels open, allowing calcium to enter

3. synaptic vesicles fuse with the presynaptic membrane, releasing neurotransmitters through exocytosis

4. neurotransmitters bind to receptors on the postsynaptic neuron, producing an excitatory or inhibitory response

5. neurotransmitters are removed through reuptake, enzymatic breakdown, or diffusion

excitatory neurotransmitter

glutamate

• increases neuronal activity → makes action potentials more likely

• glutamate binds to AMPA and NMDA receptors

• AMPA receptors allow Na⁺ to enter → depolarization

• NMDA receptors allow Ca²⁺ to enter → helps strengthen synapses and supports learning and memory

inhibitory neurotransmitter

GABA

• decreases neuronal activity → makes action potentials less likely

• GABA binds to GABA-A and GABA-B receptors

• GABA-A receptors typically allow Cl⁻ to enter → inhibits neuronal firing

• GABA-B receptors can open K⁺ channels → K⁺ exits, causing hyperpolarization

alcohol (ethanol) temporary effects (acute toxicity)

• relaxation and euphoria (CNS depressant)

• impaired coordination and balance

• slurred speech

• slowed reaction time

• may cause death is too much ethanol is ingested due to the CNA depression

is ethanol permeable

yeah cuz it small, uncharged molecule

alcohol (ethanol) delayed effects (chronic toxicity)

• hangover and headache

• dependency and withdrawal symptoms (mental and physical)

• GI damage

• liver damage (cirrhosis)

• cancer (IARC group 1 carcinogen)

mechanism of ethanol in the brain (acute toxicity)

• ethanol can penetrate the blood-brain barrier (BBB) and the following can happen:

  • alc enhances GABA (inhibitory) → ethanol enhances GABA-A receptor activity, more Cl- enters the neuron, increased inhibition (hyperpolarization) → neurons are less likely to fire APs

  • or alc can inhibit glutamate (excitatory) → ethanol inhibits NMDA receptors, less Na+ and Ca2+ enter the neuron, reduced depolarization → neurons are less likely to fire APs

what does CNS depression mean

reduced neuronal activity

metabolism of alcohol (ethanol — chronic toxicity)

• 1. ethanol → acetaldehyde (phase I oxidation)

  • enzyme (alcohol dehydrogenase)

  • oxidation removes hydrogen from ethanol, producing acetaldehyde (toxic metabolite) → can damage cells and tissues

  • occurs in liver and stomach

• 2. acetaldehyde → acetate (phase I oxidation)

  • enzyme (aldehyde dehydrogenase)

  • another oxidation reaction turns toxic acetaldehyde into less toxic acetate

  • occurs in mitochondria in muscle, liver, brain, and heart

• 3. acetate → acetyl-coA

  • enzyme (acetyl-coA synthetase)

  • acetate is converted into acetyl-coA which can be used for energy production

  • this is an activation reaction

toxic mechanism of acetaldehyde

1. acetaldehyde binds to a protein

• acetaldehyde reacts with an amino group (–NH₂) on a protein

• water s removed, forming a Schiff base

• creates a chemical attachment between acetaldehyde and the protein

2. cross-linking occurs

• acetaldehyde-derived structure can react with another protein

• creates a cross-link, connecting two proteins together

• cross-linking can interfere with the proteins' normal structure and function.

why is cross-linking harmful

• damaged proteins may no longer function properly

• acetaldehyde can also react with DNA and lipids

• over time, these reactions contribute to cellular damage, inflammation, and chronic toxicity, particularly in the liver

how does acetaldehyde promote DNA mutation

• DNA adduct formation and cross-linking

  • monoadduct, interstand crosslink, DNA protein crosslink, intrastand cross link

  • disruption of DNA replication and repair → possible mutations → tumorigenesis/increased cancer risks

alcohol consumption and liver damage (clinical consequences)

major metavolism of alc takes place in LIVER

• DNA adduct formation → DNA mutation (tumor development, functional impairment)

• RNA adduct formation → loss of protein synthesis (functional impairment)

• protein-protein crosslink → loss of enzyme function (functional impairment)

• protein-lipid crosslink → loss of enzyme function, loss of membrane integrity (functional impairment)

• lipid-lipid crosslink → loss of membrane integrity (functional impairment)

***functional impairment → necrosis (cell death)

stages of alc-induced liver damage

healthy liver → fatty liver (reversible with abstinence) → alcoholic hepatitis (partial reversibility possible) → cirrhosis (irreversible)

methanol mechanism

phase I oxidation:

• methanol → formaldehyde → formic acid (formate)

• ADH converts methanol to formaldehyde

• ALDH coverts formaldehyde into formic acid

is methanol more toxic than ethanol? why so?

methanol is significantly more toxic than ethanol

• formaldehyde: highly reactive and can damage proteins and DNA through chemical cross-linking (fixing agent, IARC group 1)

• formic acid (formate): inhibits mitochondrial cytochrome c oxidase, disrupting ATP production

  • causes severe acidosis (increased blood acidity).

  • can damage the optic nerve and retina, potentially causing blindness

cough syrup deaths

more than 300 children died after taking a cough syrup in Gambia, Indonesia, and Uzbekistan

• cause of death → acute renal failure

• suspected toxic agent → diethylene glycol (DEG)

recall of cough syrup

occurred in Nigeria → cough syrup was made in South Africa

• fatal level of diethylene glycol was found in benylin syrup

• toxic effects may lead to death → Nigeria regulator says

• South Africa’s health regulator recalled batches of J&J’s children cough syrup due to high levels of DEG

• affected batches sold in South Africa, Eswatini, Rwanda, Kenya, Tanzania, and Nigeria

  • but no deaths reported

WHO and DEG-contaminated cough syrups in India

WHO was informed that at least 3 oral cough syrups were contamined with diethylene glycol (DEG)

• first cluster of acute illness and child fatalities identified on 9/30/2025 → ~23 children died after consuming the cough syrup

timeline of outbreak of diethylene glychol (DEG) poisoning

• 1937 (USA) → DEG was improperly added to sulfonamide (antimicrobial drug) → 100+ people died

• 1985 (Austria) → DEG intentionally added to wines to make sweet and smooth texture, no death reported

• 1990-1996 (Nigeria, Bangladesh, Haiti) → DEG was used as sub for propylene glycol and added to acetaminophen syrup → over 100 children died

• 2006 → counterfeit toothpaste worldwide → containing DEG and sold as brand names

• 2019 (Brazil) → DEG was accidentally added to beer through leak from coolant equipment during production → 10 people died

public health concerns on diethylene glycol (DEG)

C4H10O3 → colorless, odorless thick liquid with sweet taste

• available info about toxicity to humans is limited → LD50 is estimated to be ~1.6g/kg

• DEG not allowed to be added to food and drugs → used as a replacement for glycerol (LD50 ~8/12 g/kg in mice and rats) and propylene glycol (LD50 ~20 g/kg in rats) in drugs, toothpaste, and wine to add sweet taste and smooth (viscous) texture

DEG exposure clinical symptoms

• nausea, vomiting, abdominal pain, diarrhea → followed by acidosis, acute kidney failure, and anuria (1-3 days after ingestion)

• neurological symptoms including lethargy, blurred vision, paralysis, dysphonia, and coma appear at late stage (<10 days)

DEG exposure treatment

• prevent metabolism of diethylene glycol → Fomepizole (alc dehydrogenase inhibitor) and ethanol

• hemodialysis → remove DEG from the body

DEG prognosis

• depends on the amount of ingestion, prompt diagnosis and treatment

• can be fatal, survivors may have to remain dialysis-dependent rest of life

DEG metabolism

1. DEG → 2-Hydroxyethoxyacetaldehyde

• enzyme: alcohol dehydrogenase (ADH)

• reaction: phase I oxidation

• DEG is converted into an aldehyde

2. 2-Hydroxyethoxyacetaldehyde → 2-Hydroxyethoxyacetic acid

• enzyme: aldehyde dehydrogenase (ALDH)

• reaction: phase I oxidation

• the aldehyde is converted into an organic acid

step 3: formation of diglycolic acid (DGA)

• further oxidation produces diglycolic acid (DGA)

• DGA is a major toxic metabolite responsible for kidney injury and potentially acute kidney failure

role of fomepizole

• fomepizole inhibits ADH, preventing DEG from being converted into its toxic metabolites

  • reduces the formation of DGA and helps prevent further toxicity

where does DEG metabolism take place primarily

liver

proposed toxic mechanism of action for DEG

1. DEG is metabolized into DGA

• DEG undergoes oxidation in the liver

• produces diglycolic acid (DGA), a toxic metabolite

2. DGA interferes with the krebs cycle

• DGA is structurally similar to oxaloacetate, an important molecule in the Krebs cycle

• DGA is proposed to interfere with reactions involving oxaloacetate, disrupting normal krebs cycle activity

3. reduced ATP production

• disruption of the Krebs cycle decreases energy production

• kidney cells are particularly vulnerable because they require large amounts of ATP

• contributes to kidney damage and potentially acute kidney failure

energy production in the cell

• glycolysis (takes place in cytosol) → anaerobic respiration, producing a small amount of ATP (2 ATP from one molecule of glucose)

• citric acid cycle and ETC (takes place in mitochondria) → aerobic respiration, produces a large amount of ATP (~30 ATP from one molecule of glucose)

what does DGA damage

proximal tubules of kidneys

how does DGA damage the proximal tubules of kidneys

1. DGA enters kidney cells

• enters proximal tubule cells through Na⁺-dependent dicarboxylate (NaDC) transporters

  • transporters normally help reabsorb certain organic acids

2. DGA damages proximal tubules

• the proximal tubules are responsible for most reabsorption of:

  • glucose and amino acids

  • Na⁺ and bicarbonate

  • phosphate and much of the filtered Ca²⁺

• DGA disrupts cellular energy production and damages these cells.

3. Kidney function decreases

• damaged proximal tubules cannot properly reabsorb essential substances

• severe damage can cause acute kidney injury or kidney failure

magic mushroom contains what

psilocybin and psilocin

symptoms of magic mushroom consumption

• visual hallucination appears within 4-5 mg of psilocybin ingestion (within 15 min)

• 10 mg/kg → increase blood sugar, body temp, blood pressure, dilation of pupil, rapid breathe, and heart rate

• may cause memory impairment, inability to concentrate

• recovery in 4-10 hours

LSD/psilocybin active/lethal dose ratio and dependence potential

• very low dependence potential

• very low active/lethal dose ratio

california and magic mushroom

CA tried to decriminalize magic mushroom possession and personal and therapeutic use in adults

• senate bill 58 → the bill passed legislature but vetoed by gov newsom

• bill was supported by mental health professionals and military veteran groups

• may provide the way for better treatment options to alleviate substance use disorders and other health issues → such as depression, PTSD, anxiety disorders

magic mushroom public health concerns

possible public health safety risks associated with hallucinogens

US government and psychedelic drugs

US gov is moving towards development of psychedelic drugs to treat severe mental illness

• april 18, 2026 → trump signed executive order to accelerate medical research and access to psychedelics (ibogaine, psilocybin, MDMA) to treat mental health conditions like PTSD and depression

• allows FDA to speed up reviews of psychedelic-based treatments

• $50 million federal funds will be allocated to research on psychedelic drugs

serotonin vs dopamine (similarities)

happy neurotransmitters controlling mood, happiness, motivation

serotonin vs dopamine

• serotonin → happiness, long-term pleasure, feeling of well-being, feeling of relaxation (stable, healthy, happiness, and calm)

• dopamine → motivation, reward, short-term pleasure, feeling of pleasure, feeling of alertness (actively seeking pleasure)

dopamine vs serotonin signaling in brain

• dopamine pathways originate in the midbrain (VTA and substantia nigra) → project to reward and movement-related brain regions

• serotonin pathways originate in the brainstem (raphe nuclei) and → project widely throughout the brain to regulate mood and other functions

psilocybin, psilocin, serotonin, and LSD (how do they cause effects)

effect/symptom are due to interaction with serotonin receptors in the brain

• psilocybin: converted into psilocin in the body

• psilocin: activates serotonin receptors (5-HT) → producing psychedelic effects and altered perception

• serotonin: natural neurotransmitter involved in mood, sleep, and emotional regulation

• LSD: also activates serotonin receptors (5-HT2A) → producing hallucinations and altered perception

when you are clinically depressed, doctors usually prescribe what

antidepressants → SSRIs (selective serotonin reuptake inhibitors).

• SSRIs block serotonin reuptake → increasing serotonin availability in the synaptic cleft

• examples include fluoxetine (Prozac) and sertraline (Zoloft)

psilocybin metabolism

1. psilocybin → psilocin: psilocybin is converted into psilocin, its active form, by removing a phosphate group

2. psilocin crosses the BBB: enters the brain and produces hallucinogenic effects by activating serotonin receptors (especially 5-HT2A)

3. psilocin is metabolized through two pathways:

• phase I: psilocin undergoes oxidation, forming 4-hydroxyindole-3-acetaldehyde, which is further oxidized into 4-hydroxyindole-3-acetic acid

• phase II: psilocin undergoes glucuronidation (glucuronic acid is added), making it more water-soluble for elimination

mechanism of action psilocin vs ssris

1. normal serotonin signaling: serotonin (5-HT) is released from the presynaptic neuron, binds to receptors on postsynaptic neuron, and is then taken back up through reuptake transporters

2. SSRIs (antidepressants): block serotonin reuptake (serotonin transporter (SERT) on the presynaptic neuron is responsible for reuptaking serotonin from the synaptic cleft) allowing more serotonin to remain in the synaptic cleft and continue stimulating receptors

3. psilocin (active form of psilocybin):dDirectly activates serotonin receptors, especially 5-HT2A, producing psychedelic effects

what is the key difference between psilocin vs ssris

• SSRIs: increase serotonin availability by preventing its reuptake

• psilocin: mimics serotonin by directly activating certain serotonin receptors

serotonin release vs depletion

• release promotes stable happiness, calm, well-being

• depletion promotes depression and anxiety

psilocybin anti-depressant effects longevity

long-lasting compared to other drugs such as fluoxetine (ssri) and ketamine

• psilocybin → produces rapid improvements in depression symptoms that can persist for weeks after just two doses

public health concerns on hallucinogen use (individuals)

• can this be gateway or entry-point for healthy individuals (including young, teens) to start recreational drug use?

• addiction and substance abuse → escalating the use of more potent illegal drugs?

• hallucinogen → would it be ok to have in normal daily activities?

• long-term health concerns → is it really no adverse health effects?

public health concerns on hallucinogen use (community)

• increase risk of DUI-related violation, criminals, accidents, injuries → public safety concerns

• impact on communities → increasing medical cost, hospital visits, lost productivity (up unemployment?), decreasing real estate values, etc…

fentanyl definition

a powerful synthetic opioid that is 50-100x stronger than heroin and morphine

fentanyl LD50 and half-life

• LD50 ~0.03 mg/kg (2 mg for adults)

• half-life in the body → 2-4 hours

is heroin synthetic or not

semi-synthetic, 2x stronger than morphine

is morphine synthetic or not

natural opioid from opium poppy

morphone and heroin active/lethal dose ratio and dependence potential, also does this make fentanyl concerning

high dependence potential and relatively high overdose risk → AND fentanyl is 50-100x than heroin and morphine

effects and clinical symptoms of fentanyl use

• relaxation, euphoria, pain relief, sedation

• confusion, drowsiness, dizziness, nausea, and vomiting, pulpillary constriction, respiratory depression

• extremely addictive

acute toxic mechanism of action for fentanyl (overdose)

• shuts down communication between neurons in the brain

• respiratory failure (stop breathing) = death

  • bind to opioid receptors in the BRAIN STEM and inhibit respiratory function (stop breathing)

fentanyl withdrawal symptoms

chronic pain, unpleasant feelings, anxiety, irritability, tremor, etcm

fentanyl effects on different brain regions

• anterior cingulate cortex: alters the emotional experience of pain

• insula: reduces awareness and perception of pain

• amygdala: influences emotional responses to pain, fear, and anxiety

• ventral tegmental area (VTA): increases dopamine signaling in reward pathways

• nucleus accumbens: involved in reward and euphoria, contributing to addiction

• brainstem: suppresses respiratory activity, potentially causing respiratory depression and death

molecular mechanism of action of fentanyl

1. fentanyl binds to μ-opioid receptors, which are Gi/o-coupled GPCRs

2. inhibits adenylyl cyclase → decreases cAMP (second messenger)

3. closes voltage-gated Ca²⁺ channels in presynaptic neurons → reduces neurotransmitter release

4. opens K⁺ channels in postsynaptic neurons → hyperpolarizes the neuron, making it less likely to fire

5. neuronal signaling is inhibited, including pain transmission

what does dopamine release do

gives you sense of reward, pleasure, and euphoria → drives motivation, rewards, and pleasure (active “motivation” or “seeking”)

what happens when fentanyl binds to opioid receptor in GABA neurons in ventral tegmental area (VTA)

GABA release inhibited, stimulates the dopaminergic neurons in VTA and releases more dopamine in NAc (nucleus accumbens) → causes euphoria

fentanyl overdose in the UK

• fentanyl-related overdose deaths increased dramatically after 2013

• orescription opioid and heroin deaths without fentanyl eventually declined

• fentanyl deaths increased both with and without stimulants (stimulants = things like cocaine or meth)

• fentanyl became a major driver of opioid overdose deaths, especially when combined with stimulants

fentanyl overdose deaths per year in the US

has increased rapidly → in 2023, deaths = ~75,000

public health concerns on fentanyl use

• extremely addictive

• adverse physical and mental health effects

• increasing criminal activity

• decreasing productivity, real estate values

• money to purchase fentanyl may go to mafia or other criminal groups