Unit 4: Drugs from Nature

Question 1

What are natural drugs?

Answer 1

Herbal medicines/natural drugs are those with active ingredients derived from plant parts (roots, leaves, flowers, etc.)

“Natural” doesn’t mean SAFE

Question 2

Alcohol Facts

Answer 2

• Alcohol (ethanol) is the byproduct of yeast metabolism.
• Evidence of production, storage and consumption from prehistoric civilizations as early as 7000BCE
• Fermented cider was safer than tap water in the 1800’s (before sanitation)
• Alcohol = lipophilic (soluable in both water and oil)—allowing quick absorption into the bloodstream and passage through the blood-brain barrier

Question 3

Alcohol Molecule

Answer 3

Alcohol = CH₃CH₂OH—two carbons and a hydroxyl group
- the carbon is not charged, so it passes easily through fats and cell membranes (rapid absorption)
- OH gives alcohol a weak (-) charge, making it quickly soluble i water

Alcohol = lipophilic (soluable in both water and oil)—allowing quick absorption into the bloodstream and passage through the blood-brain barrier

Question 4

Alcohol Metabolism Enzymes

Answer 4

Alcohol is metabolized in a two step process in the liver by two enzymes:
(a) alcohol dehydrogenase (ADH)
(b) aldehyde dehydrogenase (ALDH)
There are genetic variants of these enzymes affecting the speed of alcohol metabolism.

Ethanol → (a) → acetaldehyde → (b) → acetate

Question 5

Alcohol Metabolism

Answer 5

Ethanol → [ADH] → acetaldehyde → [ALDH] → acetate

Ethanol : active drug; active distribution to all body tissues

[ADH] : (alcohol dehydrogenase); converts ethanol to acetaldehyde

Acetaldehyde: toxic intermediate metabolite in the liver and brain; similar to formaldehyde—damages protein, DNA lipids, causes cancer

[ALDH] : (aldehyde dehydronase); breaks acetaldehyde down into acetate

Acetate: final metabolite; excreted in urine

Question 6

ADH/ALDH Metabolism Variants

Answer 6

Fast ADH (alcohol dehydrogenase):
- ethanol is not enjoyable as the body quickly produces acetaldehyde, causing flushing and nausea
- people with fast ADH variants are more protected from alcohol use disorder and cancer (through abstinence)

Slow ALDH (aldehyde dehydrogenase):
- ethanol = enjoyable, but acetaldehyde accumulates in system due to slow ALDH, causing sickness
- genetic variant associated with East Asia (“Asian glow”)
- more acetaldehyde in system; higher cancer risk

Question 7

Alcohol:
Target, Mechanism of Action

Answer 7

Target: GABA and NMDA receptors
Mechanism of Action: alcohol is an/a
(a) agonist of major inhibitory neurotransmitter GABA, enhancing inhibition
- endorphins are released and activate mu opioid receptors on GABA neurons—this keeps ion channel open, allowing more chloride in to hyperpolarize the neuron

(b) antagonist of major excitatory neurotransmitter glutamate (NDMA), diminishing its effects
- blocks the NDMA receptors—keeps ion channel closed, stopping entry of sodium (Na+) and calcium (Ca+), preventing depolarization

(c) disinhibitor of dopamine (DA); by enhancing inhibition of GABA, dopamine is free to fire more—positive reinforcement feeling

Drug Class: CNS depressant
- 1st neurons to “go offline” are ones that work all the time
- numerous central and peripheral nervous system effects

Question 8

Alcohol: Acute Effects

Answer 8

Acute (short-term) effects:
Increased
- euphoria
- behavioural disinhibition (cortex neurons inhibited)
- nausea, vomiting
- vasodilation (flushing); loss of body heat
- gastric secretion; GI ulceration

Reduced
- anxiety (amydala neurons inhibited)
- reaction time, balance, speech, vision, hearing, motor coordination (cerebellum inhibited)

Lethal
- coma
- acidosis (accumulation of acid in bloodstream; change in blood PH level)
- respiratory depression

Question 9

Acute Alcohol Poisoning

Answer 9

Acute alcohol poisoning effects:
- motor impairment
- amnesia
- vomiting
- loss of consciousness
- breathing suppression
- coma
- death

No medicine to counteract; supportive medical measures (eg: breathing and body temperature regulation) used to prevent death

Question 10

Alcohol: Chronic Effects

Answer 10

Chronic (long-term) effects:
- Dependence—abrupt withdrawal can cause seizures and death
- Addiction—compulsive use despite consequences
- Wernicke-Korsakoff syndrome—amnesia and cognitive impairments due to severe thiamine (vitamin B1) deficiency
- B1 suppliments will prevent neuron death of existing neurons, but won’t promote new neuron generation
- impaired memory, movement, vision, coordination

• Fetal Alcohol syndrome (FAS)—in utero exposure causes craniofacial abnormalities, cognitive and behavioural deficits and stunted growth
• Endocrine effects—reduced production of testosterone and increased production of glucocorticoids (corticosterone)
• Liver—fatty liver, alcoholic hepatitis, cirrhosis
• Heart—hypertension, high risk of cardiac arrest
• Cancer—mouth, stomach, liver, breast, colon

Question 11

Alcohol Withdrawal Symtoms

Answer 11

Withdrawal symptoms:
- nausea
- vomiting
- muscle tremors
- headache
- anxiety
- delirium
- seizures (when quit cold turkey); death

Question 12

Alcohol Use Disorder: Treatments

Answer 12

AUD Treatments:
(1) Benzodiazepines for alcohol withdrawal
- benzos target and agonize GABA receptors (enhance inhibition) to promote calmness, sedation
- treats and prevents: headaches, nausea, vomiting, insomnia, aggravation/irritability, chills/sweats, seizures
- can be used during the detox stage of AUD recovery

(2) Naltrexone for alcohol cravings
- naltrexone is an antagonist of mu opioid receptors—binds to MORs controlling the inhibition of GABA, modulates how much dopamine is released (thus reducing cravings)
- should not be used during the detox stage

Question 13

Nicotine Facts

Answer 13

• Nicotine is a naturally-occurring pesticide of the tobacco plant—acts as a neurotoxin for insects
• Tobacco field workers can become ill due to overexposure (causes confusion, difficulty breathing, blurred vision, nausea, vomiting)
• Nicotine is highly potent
  
  • one cigarette dose: 1mg
  • lethal dose: 50 mg

Question 14

Nicotine:
Target, Mechanism of Action, Drug Class

Answer 14

Target: nicotinic acetylcholine receptors

Mechanism of Action: nicotine is an
(a) agonist of the excitatory acetylcholine receptor; activation opens ion channel, allowing Na+ into neuron, causing depolarization

Drug Class: stimulant

Question 15

Nicotinic Acetylcholine Receptors (nAChRs)

Answer 15

Nicotinic acetylcholine receptors (nAChRs) are located throughout the brain—mostly concentrated in the thalamus, cortex and basal ganglia. The neurotransmitter acetylcholine is important for:
- wakefulness
- memory and attention → learning (cognition)

Alzheimer’s patients lack acetylcholine

Question 16

Nicotine: Low Doses

Answer 16

Nicotinic acetylcholine receptors are located on:

(a) dopamine neurons—nicotine binds directly to DA, allowing increased dopamine firing, which induces:
- increased focus, attention, improved cognitive performance
- serenity, calmness
- reduced anxiety
- mild euphoria
- addiction

(b) autonomic nervous system—major effects on organs:
- respiratory system (lungs): breathing rate
- circulatory system (heart): heart rate, blood pressure, blood vessel dialation
- digestive system (stomach/intestines): GI tract secreation; nausea and vomiting at higher doses

(c) neuromuscular junctions—where neurons connect to muscles to facilliate voluntary movement

Question 17

Nicotine: High Doses

Answer 17

High doses of nicotine causes:
(a) Overactivation of the parasympathetic nervous system, resulting in:
- confusion
- nausea
- vomiting
- difficulty breathing
- blurred vision
- delirium
- excessive mucus production

(b) Desensitization—as a result of overactivation, receptors will no longer open and stop working altogether, leading to:
- weak muscles
- mild paralysis

Question 18

Nicotine: Toxic Doses

Answer 18

Toxic doses of nicotine leads to:
- slowed heartbeat and breathing
- muscle weakness and paralysis
- seizures

Question 19

Smoking/Chewing Tobacco

Answer 19

Smoking tobacco is the primary cause of:
- lung cancer
- chronic obstructive pulmonary disease (COPD)
- atherosclerosis—hardening/plaque build-up in the arteries; increases risk for heart attack

Chewing tobacco associated with
- mouth cancer

Question 20

Nicotine Withdrawal Symptoms

Answer 20

Nicotine withdrawal symptoms:
- anxiety
- irritability
- aggression
- attention deficit
- insomnia
- depressed mood

Question 21

Nicotine Cessation Methods

Answer 21

Treatments to improve smoking cessation:
(1) Nicotine replacement (slow release patch)—reduces withdrawal symptoms

(2) Low-dose bupropion (antidepressant)—MOA unknown

(3) Varenicline:
- most effective at improving cessation (44% quit rate)
- a partial nicotinic receptor agonist—activates nAChRs, stimulating a moderate dopamine release, reducing withdrawal symptoms

Question 22

Serotonic Hallucinogen Facts

Answer 22

• Serotonic hallucinogens are also called “entheogens” — from Greek “Entheo” meaning “God” due to the religious/spiritual experience they induce
• Hallucinogens are far less addictive, as they don’t tap into the dopaminergic system (DA)
• Hallucinations occur when the brain attempts to make sense of corrupted sensory input
• Salvia (salvinorin A) is highly selective, activating only one receptor (kappa opioid receptor)

Question 23

Serotonic Hallucinogens

Answer 23

Natural hallucinogens:
- psilocybin (mushrooms)
- dried mushrooms are ingested or brewed into tea
- converted to psilocin by the body
- currently being investigated as a treatment for GAD, OCD, PTSD

• mescaline (peyote)
  
  • dried tops of cacti are ingested
  • used for religious/shamanic rituals
  • mainly induces visual hallucinations
• DMT (ayhausca)
  
  • consumed as a tea (P. viridis shrub; B. caapi vine)
  • DMT inP. viridis is quickly metabolized by monoamine oxidase; effects last for roughly 15 minutes
  • B. caapi contains harmine, a MOA inhibitor, extending effects of DMT to 2-3 hours
• salvinorin A (salvia divinorum)
  
  • member of the mint family
  • induces brief but intense (often unpleasant) hallucinations
  • reduces the firing rate of dopamine neurons
  • very selective of kappa opioid receptors; can be analgesic

Semisynthetic hallucinogens:
- lysergic acid diethylamide (LSD)
- derived from Ergot fungus
- tasteless, odorless white powder/clear liquid
- ingested or held under tongue (tincture)

Synthetic hallucinogens:
- MDMA (ecstasy)
- similar to amphetamines, but acts more selectively on the serotonin transporter (SERT)
- reverse transporter of serotonin; stimulates all serotonin receptors to release 5HT and then blocks reuptake

Question 24

Hallucinogens: Common Effects

Answer 24

Common effects of hallucinogens:
State-dependent effects
- effects depend on the environmental setting and the user’s state of mind
- pleasant: feelings of peace, serenity, well-being, connectedness to others or to nature
- adverse: fear, paranoia

Lucid thought and contemplation
- without the influence of emotions or ego
- altered state of consciousness

Ego dissociation (“ego death”)
- separation from body and dissolving of self/non-self boundaries

Enhanced sensations
- visual, tactile, auditory, etc.
- vivid hallucinations

Synesthesia
- experiencing one sense through another
- eg: seeing colours with music

Time distortion
- altered sense of time

Question 25

Hallucinogens: Adverse Effects

Answer 25

Adverse effects:
- serotonin syndrome: caused by excessive activation of serotonin receptors
- nausea; vomiting: common
- bruxism: clenched teeth
- hyperthermia; sweating: hyperthermia can be lethal
- dry mouth
- increased blood pressure
- muscle twitching and convulsions
- acidosis: accumulation of acid in bloodstream
- injuries: eg: falling

Question 26

Natural Hallucinogens:
Target, Mechanism of Action, Drug Class

Answer 26

Natural hallucinogens
Target: 5HT2A receptor (psilocybin, mescaline, DMT); kappa opioid receptor (salvanorin A)
Mechanism of Action: agonists of 5HT2A (serotonin) receptor/kappa opioid receptor
Drug Class: hallucinogens/psychedelics

Question 27

Cocaine Facts

Answer 27

• cocaine (extracted from coca leaves) was a key ingredient in coca-cola from the 1890’s to the early 1900’s
• in addition to being a stimulant, cocaine is an analgesic (pain reliever) and played a large role in the development of lidocaine
• cocaine was used in dentistry as a local anesthetic
• in the Andes, cocaine leaves are brewed as a tea to relieve headaches

Question 28

Cocaine:
Target, Mechanism of Action, Drug Class

Answer 28

Cocaine as a stimulant
Target: dopamine transporter
Mechanism of Action: indirect agonist of dopamine neurons (blocks DA transporter so that DA accumulates in the synapse)
Drug Class: stimulant

Cocaine as an analgesic
Target: sodium channels on peripheral nerves
Mechanism of Action: binds to and inactivates sodium channels, preventing action potentials; inhibits nociceptor signaling (stops pain signals)
Drug Class: local anaesthetic

Question 29

Cocaine Acute Effects

Answer 29

Acute effects:
- increased wakefulness/alertness (psychostimulant)
- increased motor activity (psychomotor stimulant)
- euphoria
- grandiose thoughts
- appetite suppression
- hallucinations
- delusions
- increased heart rate and blood pressure
- addiction

^ Effects are result of blocking the transporters that clear dopamine, serotonin and norepinephrine

Question 30

Cocaine Chronic Effects

Answer 30

Chronic effects:
- headaches
- muscle convulsions, seizures
- high risk of heart disease, heart attack and stroke
- mood dysregulation
- sexual issues
- addiction (and high relapse rates)

if smoked:
- lung damage

if snorted:
- loss of smell
- nosebleeds
- runny nose
- trouble swallowing

if injested:
- bowel decay

if injected:
- HIV
- hepatitis

Question 31

Cocaine Withdrawal Symptoms

Answer 31

Withdrawal symptoms:
- depression
- anxiety
- fatigue
- trouble concentrating
- increased hunger
- cravings for drug
- nightmares
- chills, nerve pain, muscle aches