Final Flashcards
1
Q
How are new chemicals identified and characterized for pharmacological activity? (4 EPPC)
A
- Extraction
- Purification
- Predictions
- Characterization
2
Q
What series of experiments should psychoactive chemicals pass? (3)
A
- Animal behaviour
- Physiological measures
- Biochemical assays
3
Q
In coffee Primary actives are
A
methylxanthines
4
Q
Coffee:
_ (-rgic)→base nucleus
A
purine
5
Q
Metabolism: Caffeine→ (3)
A
theophylline, theobromine and paraxanthine
6
Q
Additional chemicals and sources of coffee:
Chlorogenic acids- induce (phase II _ , like _ ) _ enzymes
* Dihydrocaffeic acid- anti- _ with vascular benefits (promotes _ production)
* Kahweol and cafestol- di_ , increase phase _ enzymes, induce anti- _ genes, but elevate _
A
(phase II transferases, like GST) liver enzymes
inflammatory, NO
terpenes, II, stress, cholesterol
7
Q
- Coffee and tea are the most common anti- _ sources
A
oxidant
8
Q
Medical indications for caffeine
Respiratory stimulation in _ infants
* 2nd most commonly prescribed NICU drug (after _ )
* PDE4 stimulation/inhibition increases [cAMP] in _ _ _
* Asthma → bronchoconstrictor/dilator
* Migraines→increase/reduces cranial blood flow
A
premature
antibiotics
inhibition, rhythmogenic preBötC complex
dilator
reduces
9
Q
t/f: Caffeine is the most commonly consumed psychoactive substance on the planet
A
t
10
Q
Caffeine distribution - 3
A
Amphipathic
* Rapid
* Widely distributed
11
Q
Caffeine absorption - 3
A
- Ingestion
- Small intestine
- 45 min to peak
12
Q
Caffeine metabolism
A
Limited or no first-pass
* CYP1A2 → demethylation
* Paraxanthine (84%) → increases blood glycerol/fatty acids via
lipolysis
* Theobromine (12%) → dilates vessels, increases urine volume
* Theophylline (4%) → inhibits PDE, increases [cAMP], relaxes
smooth muscle
13
Q
Caffeine excretion
A
Kidney
14
Q
Methyl]xanthine cellular drug actions
* Non-selective _ and _ antagonists
* Additional targets→ _ release, _ receptors
* _ and _ are ubiquitous
A
adenosine receptor (AR), phosphodiesterase (PDE)
Ca, GABA
ARs and PDE
15
Q
Adenosine receptor signaling
* _ of all 3 major types
* 4 main sub-types are
* _ and _ play primary roles in caffeine effects
* Mostly _ -synaptic receptors that limit neurotransmitter _
A
Antagonist
A1, A2a, A2b, A3
A1 and A2a
pre, release
16
Q
Adenosine Receptors form _ _
* At rest or to form a signaling complex
* 3 pair complexes
A
extensive pairs
A1-D1
* 2 A2a + 2 D2 * A1+A2a
17
Q
Acute caffeine effects:
General _ effects
* Similar, _ compared to _, _
* Increased _ mobilization,
A
stimulant
milder, cocaine, amphetamines
fat
18
Q
Caffeine physl mechanisms:
Increases _, _, _ release
* Long-term drinkers more/less likely to experience elevated heart rates/BP
* Constriction in _ vessels can treat _
* Diuretic- 300+ mg, increases _ blood flow, promotes _, prevents _ re-absorption by kidneys
A
NE, Glu, DA
less
cranial, headaches
Diuretic- 300+ mg, increases kidney blood flow, promotes micturition, prevents water/salt re-absorption by kidneys
19
Q
Caffeine heart rate, bp, endurance mech:
Heart effects are complicated by peripheral and central mechanisms *
Inhibits _ enzymes which metabolize _
producing high cAMP levels
* Results in relaxation of _ but _ vasoconstricting effect
* Increases intracellular concentration of _ by increasing activation of calcium _
* Thought to increase _ _ of muscle
A
phosphodiesterase (PDE), cAMP
smooth muscle (vasodilation), central
calcium, channels
work capacity
20
Q
Reinforcing mechanism of caffeine
* Good _ release in the _
* Likely due to blocking _
* Pre-synaptic A1 signal via _
* Also increases _ release in the NAc
A
dopamine, NAc
pre- synaptic A1 on DA-ergic VTA→NAc neurons
Gi/o
Glu
21
Q
Caffeine facilitates wakefulness by disrupting adenosine signaling
* Extracellular _ increases during waking until a point is reached that triggers sleep
* Adenosine thought to come from metabolism of _ in _
* Stimulation of _ receptors by adenosine in the _ triggers _ release
* GABA release _ arousal systems
* Caffeine prevents _ this process
* This prevents _ release, preventing _
A
adenosine,
ATP in neurons
A2a, hypothalamus, GABA, inhibits
adenosine binding to A2a receptors and interrupts
GABA, inhibition of arousal systems→wakefulness
22
Q
Coffee intake may reduce risk of _ disease
* Strong _ relationship between caffeine
A
Parkinson’s
inverse
23
Q
Caffeine + heart attack risk
_ polymorphisms confer _ and _ metabolism rates
* _ copies of *1A = fast; At least _ copy of *1F = slow
* _ metabolizers show increased _
A
CYP1A2
fast (1A) and slow (1F)
2, 1
slow, dose-dependent risk
24
Q
Caffeine chronic effects - TOLERANCE
Develops quickly/slowly
Tolerance to _, _, _, but not effects on _
A
quickly
cardiovascular, respiratory, sleep effects, mood
25
Caffeine chronic effects - withdrawal 6
THE DIF
Headache, fatigue, decreased
energy, irritability, thirst
26
Caffeine chronic effects - dependence Develops quickly/slowly
quickly
27
Long term health risks of caffeine
Osteoporosis- due to
* Increased risk of _ due to stimulant effects
* Adenosine receptor antagonists may be _ due to regulating synaptic neurotransmitter levels
Use during pregnancy
* Many women drink caffeine
during pregnancy; Effects on the fetus are _
increased calcium elimination and reduced dietary Ca absorption
panic attacks
anti- depressants
inconclusive
28
Nootropic:
cognitive enhancers
29
Does caffeine improve memory
* Acute doses increase _ _activation in the _
* _ is linked to LTP
* Remembering objects was better if learning while on caffeine
Yes, , seems to positively affect learning and memory
BDNF and TrkB , hippocampus
BDNF
30
Taurine – Monster, Red bull
* Anxiolytic→may be due to glycine receptor activation and increased IPSPs
31
What types of drugs are these
L-theanine, Herbs – TCM herbs Ginkgo biloba & Panax ginseng, Ayurvedic herb Bacopa monnieri
Nootropics
32
Nicotine, amphetamines, Ritalin, afinil family are examples of
Nootropics
33
Eg of amphetamine nootropic
Adderall
34
Afinil family drug eg
Modafinil, Adrafinil, Armodafinil
35
Forms of tobacco product - 7
* Cigarettes
* E-cigarettes
* Cigars, cigarillos
* Shisha
* Smokeless
* Patches
* Gum
36
e-cig
* Vaporize e-juice containing nicotine; usually glycerin or PG-based
* No burning of plant material, no tar
* Major marketing angle → cleaner smoke is healthier!
* Flavours and additives caused severe adverse effects:
* Diacetyl – butter flavour, obliterates lung tissue (bronchiolitis obliterans),
‘popcorn’ lung in factory workers
* Vitamin E acetate – allergic reactions
* Vapour damages immune system via ROS same as cigarettes, macrophages
infiltrate lung tissue over time
* Cause ‘throat catch’ → otherwise smooth, similar to cigarettes
* Delivers higher nicotine dose per puff
* 5-8x more than cigarette
37
Early electronic cigarette additives
caused severe adverse effects, Vitamin E
38
Hookahs are better and worse than other forms
Water cools smoke, less irritating, fewer
particulates, but much longer sessions
* Shisha is the most processed, flavoured tobacco
form
* Hot air vaporizes chemicals, produces 11x the
CO by weight compared to cigarettes
* Increased heart rate may be due to elevated CO
in blood
* Increased lung disease,
oral/lung cancer risk
39
What is smoke?
* Particulates → nicotine, water, tar, PAHs, benzo[a]pyrene, metals
* Gases → nicotine, CO, CO2
, NO, nitrosamines, ammonia, nitrites,
sulfur, alcohols, ketones, aldehydes, hydrocarbons
* Particulates + gases = aerosol
* First-hand → inhalation of smoke
directly from burning tobacco
* Second-hand → smoke that has
already been inhaled by others
* Third-hand → 1
st and 2nd
-hand fumes
from fingers, clothes, fabric, etc.
40
nicotine:
Alkaloid, causes addiction
* Competitive acetylcholine receptor (AChR) agonist
* Both Ns pick up a hydrogen at low pH
* Uncharged = free base
* Protects the plant from pests
41
Nicotine has mono- and di-protonated
forms governed by pH
42
Pharmacokinetics of nicotine
absorption 1. Inhalation
* Controlling pH in cigarettes optimizes lung absorption (free base)
* Burning generates up to 4000 new chemicals
* 1 cigarette = contains ~8 mg nicotine, delivers 0.5-2 mg, 60 mg is lethal
* Pyrolysis, filter, side-stream smoke lower bioavailability
* Art of the dose → 1-2 puffs/min, 2 sec long, 1-2 μg nicotine/kg body
weight is delivered to the brain, one pack/day is optimal for brain
stimulation
2. Oral (smokeless forms)
* 3-4x greater nicotine absorption, area under the plasma vs time curve
* Much slower rate of absorption
43
Absorption of different tobacco forms
44
Distribution of nicotine
* Blood pH is 7.4 → 70%
monoprotonated, 30%
unprotonated
* <5% is bound to plasma protein
* Liver, kidney, spleen, lung get
largest amounts
* Adipose gets least amount
45
80% of binding sites in the brain are
occupied after 1 cigarette
46
Most nicotine is converted to cotinine in
the liver
* Half life = 2 hrs
* Aldehyde oxidases CYP2A6 and CYP2B6 are main
enzymes
* Monooxygenases process small amount
* CYP2A6 mutation that slows metabolism
results in lower tobacco use
47
nic distribution summary - 2
Brain, lungs, liver,
spleen, kidney
* Crosses placenta
48
nic metabolism - 4
Liver:
* CYP2A6
* monooxygenases
* 2 hr half-life
49
nic abs summary - 2
* Inhalation (11-20%
bioavailable)
* Oral (50-80%
bioavailable)
50
nic excretion - 2
* Kidneys
* Breast milk
51
Plasma [nicotine] peaks
in the evening
* Receptors re-sensitize
over night
* First daily cigarette is
most pleasant
52
Acute effects of nicotine
Mostly
sympathomimetic
effects
53
mechanisms of tobacco and nicotine
Affects ACh, DA, GABA, Glu NTs
* Binds and depolarizes cells via nAChR
* High affinity leads to inactivation of receptor → biphasic
mechanism at high doses
* Affects heart rate, BP, GI movement, motor commands, focus
and mood
* Acetaldehyde (from burning) may inhibit
monoamine oxidases and boost NT levels,
e.g. DA
54
mechanisms of tobacco and nicotine
CNS receptors are located in:
* Cortex, hippocampus,
midbrain
* Pre-synaptic receptors cause:
* Increased glutamate release
* Increased GABA release →
quickly desensitize
* Increased DA release
55
Reinforcing mechanism of nicotine via DA, Glu,
GABA modulation in the VTA & NAc
56
Acute adverse effects
* “Safe” additives turn bad after burning
* Stimulation of the vomiting centre → common in first-time
users
* Headaches, nausea, disrupted autonomic nervous system
functioning
* Alternating tachycardia and bradycardia
* Severe intoxication → seizures, hypotension, respiratory
depression
57
Nicotinic acetylcholine receptors
(nAChRs) in the brain
* Heteropentameric receptors, alpha and beta subunits
* Conduct cation (Na+
, Ca2+) influx to
depolarize neurons
* Pre- and post-synaptic
* Trigger neuromuscular activity
58
Nicotinic acetylcholine receptors
(nAChRs) in the brain
Pre-synaptic increase NT release
* Post-synaptic will depolarize the cell
* Receptors inactivate if continuously exposed to agonist →
nicotine has high affinity
* Receptor subunit composition affects reinforcement and reward
(alpha4, alpha6, alpha7, beta2)
* α6 modulate locomotor responses
* α7 facilitate glutamate release
* β2 subunit knockout in mice prevents DA release, selfadministration stops
* α4β2 receptor antagonists block reward
59
α4β2 nAChRs are most important for DA
reinforcement
Alpha6-beta2 nAChR mainly on DA-ergic terminals in NAc
* α6β2 do not release DA after systemic nicotine administration
α4β2 are main functional nAChRs on VTA DA-ergic soma
Activating α4β2 on soma
drive DA release and
reinforcement
60
Inactivation rates depend on subunit
composition
α4β2 sub-type govern GABA
release and inactivate quickly
(after 30-60 seconds) and for a
long time (1 hour)
* α7 sub-types govern Glu release
and are not inactivated
* A single dose of nicotine injected
into NAc elevates DA levels for
80 min
61
Tolerance to nicotine
First uses are unpleasant → brain regions/circuits for dizziness, nausea, sweat
* Little or no decrease in heart effects, tremor and
peripheral vasoconstriction
* Metabolic → increased enzyme activity, first cig
is the best
* Cellular → receptor inactivation, affects reward
* Behavioural → mindset stages experience, ritual
of smoking
62
Tolerance to nicotine
nAChR expression increases, mostly α4β2 subtype
* Enhances sensitivity to nicotine effects
63
nic withdrawal
Physiological symptoms → headache,
drowsiness, insomnia, increased appetite
and weight gain, GI upset
* Psychological → Craving, mood
changes, irritability, anxiety,
restlessness, depression, difficulty
concentrating, poor judgement and
psychomotor performance
64
Nicotine dependence
If you must smoke within 30 min of
waking up, chances are you’re addicted
* Starts to occur within days of habit
* Both physical and psychological
dependence
* Quick metabolism leads to withdrawal,
seek another dose to avoid symptoms
* Intensely cue-driven habit; after eating,
while drinking, out with friends, after
sex
65
Long-term adverse effects of tobacco
Cancer → lung, liver, colorectal
* Benzo(a)pyrene initiates cancer → intercalating agent
* Nicotine enhances growth/metastasis, not initiation
* Inhibits apoptotic signaling by binding α7 nAChRs on
mitochondria → allows cells with damaged DNA to
replicate
66
Nicotine promotes cancer growth and
metastasis
* Nicotine enhances
cancer cell growth in
vitro
* Nicotine
injections/patches on
mice injected with
cancerous cells
display enhanced
cancer growth
* Does NOT initiate cancer formation
67
Nicotine promotes cancer growth and
metastasis
* Experimental design:
* Mice given cancer
* Treated with nicotine or saline for
two weeks
* Tumours were removed
* Treatment continued
* Re-examined lungs after two weeks
* Nicotine treated mice re-grew
tumours and developed new tumours
68
Long-term adverse effects of tobacco
Accelerate skin aging due
to peripheral
vasoconstriction
* Sexual dysfunction →
impaired NO signaling
prevents erections
* Type 2 diabetes → stressed
vasculature is insensitive to
insulin
69
Long-term adverse effects of tobacco
* Cataracts, macular degeneration
* Tooth decay, periodontitis, IBS, Crohn’s
* Infection
* Rheumatoid arthritis, osteoporosis
* Cardiovascular disease, like coronary heart disease
(CHD), MI, ischemic stroke
* COPD includes chronic bronchitis and emphysema2
* Caused by inflammation of airways covered in tar
and ash deposits
* Cilia function is impaired by PAH and ketones in
smoke
* ‘Smokers cough’ when quitting indicates
recovery of cilial function
70
Long-term adverse effects of tobacco
* Second-hand smoke, nonsmokers that live with
smokers have higher rates
of lung cancer, heart
disease
71
Pregnancy and smoking
Constriction of umbilical arteries, reduced oxygen
May affect reward system leading to increased addiction
risk
Higher risk of stillbirth, premature
or miscarriage, low birth weight
* Cleft palate and lip risk goes up
72
Smoking cessation
* Like safe injection sites, the goal is to provide safe nicotine to ease
withdrawal and cravings
* Very difficult; 74% of American smokers want to quit and 78% make
a serious attempt → success rate is 6%
* 3 day hump correlates with nicotine clearance
* Is it harder to quit smoking or smokeless forms? Smokeless, higher
doses
73
Smoking cessation
* Earlier the better: at 30 years old reduce risk by 90%, at 45 years old
reduce risk by 87%, at 50 years old reduce risk by 50%
* Within 8 hours, blood [CO] normalizes
* Within a week, heart, BP, circulation, breathing improve
* Within 9 months, respiratory cilia recover
* Within 1 year, CHD risk drops 50%
* Within 5-10 years, risk of stroke matches non-smokers
* Within 15 years, CHD risk matches non-smokers while lung cancer
risk is 50% lower than smokers
74
Smoking cessation is big business
Nicotine withdrawal must be overcome so cessation therapies offer nicotine without the
hazards of smoking
* Several forms include patches, gum, nasal spray, inhalers, lozenges and e-cigarettes
* Gum can cause bad taste, irritate throat, induce nausea
* Patches/spray can cause irritation
* E-cigarettes might be effective, risk of reverting might by high
75
Pharmacological cessation aids
Bupropion → antidepressant
* nAChR antagonist, blocks the channel
even when nicotine is present
* DAT and NET inhibition
* Helps reduce cravings
* Varenicline → partial nAChR agonist,
reduces reward and cravings
* Methoxsalen and NicVAX are in
development
76
Behavioural and psychosocial cessation
aids
* Counseling, stress management
* Behaviour modification → identify and avoid
risky situations
* Combine with pharmacological treatments
Large-scale awareness campaigns in N. America
have lead to increased attempts to quit
77
difference between a sedative and a hypnotic?
Sedatives
* Relieve anxiety, cause relaxation,
mild CNS depressants
* Hypnotics
* Cause drowsiness and sleep
* Z-drugs (Ambien), orexin antagonists,
melatonin agonists, anti-histamines
78
difference between sedative and hypnotic
Anxiety
* benzos → ‘aze’-pams (Valium diazepam, Klonopin clonazepam)
* Anti-convulsants
* Longer-acting drugs treat seizure disorder → Phenobarbital
* Anesthesia
* Short-acting drugs → Thiopental, midazolam, triazolam
* Sedatives for calming
* Hypnotics for sleeping e.g. zopiclone (Lunesta), zolpidem
(Ambien)
79
Sedatives in the clinic
* Progressively greater depression of electrical activity
80
Categorization based on duration of action
In general, sedatives are a more
lipophilic class of drug → faster onset
due to rapid distribution
* Within the sedative class, barbiturates
and benzos are categorized based on
their duration of action
* Longer-acting are typically used as
anticonvulsants, muscle relaxants,
and anxiolytics
* Shorter-acting are used as preanesthetic sedatives or to treat
insomnia
81
Predicting chemical categorizations; long or
short acting
82
Summary of common benzos and barbees
83
Absorption and distribution of sedatives
* Routes of administration
* Oral, rectal, injection
* Absorption and distribution
* Benzos
* Less lipid soluble than
barbiturates, absorbed more
slowly, slower onset of action
* Barbiturates and benzos are highly
bound to plasma proteins
* Cross placenta
84
Pharmacokinetics of sedatives - metabolism
* In the liver by CYP450 system
* Some produce active metabolites prolonging duration of
action, e.g. chlordiazepoxide, diazepam
* Midazolam t1/2 = 2 hours
* Diazepam t1/2 = 100 hours
* Takes 4-5 half-lives for elimination
* Metabolism decreased in infants, pregnant women, those
with liver disease, the elderly
* Reduced muscle tone in infants causes inability to nurse
that can last for months = floppy infant syndrome
85
GABAa r binding mechanism
The receptor has five
subunits arranged
around a chlorideconducting pore
* GABA binds between
alpha and beta subunits
* Benzos bind between
alpha and gamma
subunits in those
receptors that contain
these subunits
86
GABAa r binding mechanism
Benzos
* Bind to a site on the GABAA
receptor,
which increases the frequency of chloride
channel openings
* GABA receptors with benzo binding sites
located in limbic system, reticular
activating system, cortex
* GABA receptors that control
respiration don’t have many benzo
sites
Barbiturates
* Have a more general effect on GABA
receptors
* When they bind, they enhance the affinity
of the receptor for GABA, which
increases the duration of time that the
chloride channel is open, leading to
neuronal inhibition
* Can do this even when GABA is not
present
87
Benzos are allosteric modulators, barbees are activators
88
Acute effects of sedatives
Reduce muscle tone, impair coordination, and increase sedation and sleep
* Total sleep time is increased
* REM sleep and restorative deep sleep are reduced
* Reduce anxiety, learning, memory, and can cause bizarre, uninhibited
behaviors
* Common side effects
* Drowsiness, lethargy, dizziness, confusion, reduced libido, diminished concentration,
incoordination, and impairment of driving skills
* Prevent consolidation of short-term memories, especially alpha subunit-containing
receptors; can last for months
* Combined with alcohol to facilitate assault, e.g. GHB, rohypnol
89
Other dangers associated with sedatives
* Effects on the Fetus
* Rapid entry, increased half life due to under-developed liver
* Potential increased risk of cleft palate, floppy infant syndrome,
withdrawal
* No risk of major malformations
* Must weigh risks to fetus against risks of the mother going off the
drug
* Drug interactions
* Synergistic with other depressants such as alcohol, opioids
* Interact with other drugs metabolized by CYP450 system
* Overdose, treated with flumazenil
* Relatively rare for benzos by themselves
* Alprazolam TI = 662-4342
* Barbiturates very low therapeutic index
90
Tolerance and chronic effects of sedatives
Tolerance develops at different rates → receptor subunits shift
* Tolerance develops for sedative, hypnotic effects (days to
weeks)
* Slowly to anxiolytic effects (3-4 months)
* Does not develop for respiratory depression
* Users can require 40x original dose
* Barbees
* Cellular and metabolic mechanisms
* Benzos are well-known for producing tolerance
* Chronic effects
* Associated with daytime fatigue, accidents, depression,
violence and increased overall mortality
91
Withdrawal and dependence
Withdrawal is worse with short-acting drugs
* Should be medically supervised due to
hyperexcitability
* Insomnia, anxiety, tremor, headache, confusion,
and difficulty concentrating
* Dependence and addiction
* Both physical and psychological dependence
* Benzos are not as strongly addictive as
barbiturates
92
sedative Abuse potential is much lower than
other drugs
* In progressive
schedules, animals
exert less effort for
sedatives compared to
cocaine, opioid
93
Disinhibition of VTA DA-ergic neurons
increases DA release in NAc
GABA receptors are also present on DA-ergic neurons
* Benzos cannot potentiate inhibition without GABA-mediated activation
94
In vivo recordings of benzo-evoked
reinforcement
Single unit recordings
from neurons in mice
* Midazolam (MDZ)
increases VTA DA-ergic
firing (left)
* MDZ decreases VTA
GABA-ergic interneuron
firing (right)
* Flu = flumazenil
95
Gamma-hydroxybutyric acid (GHB)
Pro-drugs gamma-butyrylactone and 1,4-butanediol are uncontrolled
* GABAB
receptor agonist → Gi/o-linked, inhibits Ca channels, activates GIRK
* Both a neurotransmitter and an illegal drug
* Precursor of GABA, Glu and Gly
* Dose-dependent effects
* Also affects dopamine, acetylcholine, serotonin, opioids
* Sensation of GHB is similar to alcohol inebriation
* High doses can lead to suppressed respiration, convulsions, coma, and death
96
Dose-dependent effects of GHB
Low doses of GHB have
a stimulatory effect
At higher doses, GHB binds
to GABA receptors and can
cause sedation
97
Sources – cannabis plant species
Emergent view: only one lineage,
produces cannabis
phytocannabinoid chemotypes e.g.
THC and CBD (+others) →
experience is chemical-dependent
98
When to harvest? Observe the trichomes
Phytocannabinoids, terpenes,
etc. are synthesized in heads
99
Cannabis extraction produces resin for
second generation cannabis products
Solvent or solvent-less
extraction
* Super-critical extraction
* Goal: high purity or a
single isolated
compound
100
Legally produced and sold cannabis must
pass quality testing and be labeled
How to calculate THC% based on labeling:
* % is mg per g (1/1000)
* So 15% = 150 mg / 1 g = 150/1000 mg = 0.15
* THC vs. total THC (THC + THCA) per unit
101
Cannabinoids and other chemicals
Most are in their acid forms in the plant
* THC acid
* Psychoactive
* CBD acid
* Anti-oxidant, anti-convulsant, anti-inflammatory,
anti-anxiety, anti-psychotic, and neuro-protective
102
CBD has medical uses
* Personalized cultivar selection, tailor the therapeutic effect to the disease and individual
103
cannnabis administration
To optimize absorption, THCA →
THC by heat or pressure
* Inhalation, ingestion, oral-sublingual, topical
104
Comparing cannabis and cigarette smoke
* Smoke is solid/liquid particulates and gases created during combustion
* Similar levels of tar, CO, acetaldehyde, acetone, benzene, toluene, benzopyrene,
HCN
* Poorer filtration of cannabis smoked, more irritation
* Toking and choking
* Cannabis
* → linked to increased risk of chronic cough, bronchitis
* → no link to lung cancer, COPD
* Water bongs, dabs may reduce harmful components
and reduce irritation
105
Cannabinoid ADME
Terpene profiling, vape temp
* Routes of administration
* Smoked
* Joints, pipes, bongs, vaporizers
* Ingested
* Slower onset of effect, less predictability of action,
but more user control
* Absorption, distribution, metabolism
* THC is very fat-soluble and easily crosses the
blood brain barrier
* Metabolized by CYP450 system
* Metabolites can stay in body for days
or even weeks
106
pharmacokinetic summary of cannabinoids
adme
107
Endocannabinoid receptor biology
Endogenous CBR ligands are arachidonoyl ethanolamide
(AEA) and 2-arachidonoylglycerol (2-AG) discovered in
1992 and 1995, respectively
CB1 expressed in the CNS (basal ganglia, cerebellum,
hippocampus, cortex, amygdala), eye, pancreas, liver, skin,
uterus and testes
* CB2 expressed in immune cells, spleen, tonsils
108
acute effects of intoxication
109
Physiological mechanisms cannabis
Pleasure, reward, giggles, enhanced perceptions
(time is longer)
* High CB1 expression in the hippocampus,
cerebellum, basal ganglia, hypothalamus and
cortex
* Analgesia via CB1-mediated blockage of pain
neurotransmission
* Stimulant- Dose-dependent heart rate increase,
skin vessels dilate flushing warmth core temp
decreases, salivary gland vessels constrict drying
mouth, eye vessels dilate leading to red, bloodshot
eyes
Energy metabolism, increased appetite and thirst via
CB1 in hypothalamus, pancreas, liver
* Reduced gastric secretions and GI inflammation →
low endocannabinoids are linked to irritable bowel
disease
* CB1 in hypothalamus may influence sex drive,
sperm production, fertilization, implantation, fetal
development and suckling in newborns; also
modulates DA and 5-HT release
110
cannabis Cellular mechanisms of action
* Retrograde signaling
* Cannabinoids modulate the release
of other NTs
111
cannabis cellular targets of action
Binds several receptors including:
* CB1/2,
* transient receptor potential cation
channels (e.g. TRPV1/2), and
* 5HT2 sub-type
* CB1/2 linked to Gi/o
* TRPV1/2 are Na+
/Ca2+ channels
* Pleiotropic signaling → multiple
downstream targets and
effects
112
cannabis Tolerance
* Regular use of marijuana will cause metabolic, cellular and
behavioural tolerance
* Faster metabolism, reduced CB1 receptor expression
* Reduced high, hypothermic, cardiovascular, analgesic, locomotor and
immune effects Withdrawal
* Mild burn-out (i.e. lethargy, apathy), perhaps to certain cultivars
* If withdrawal symptoms occur, they are usually not severe
* Chronic users will retain higher levels of residual metabolites, eases withdrawal
with elimination over months?
dependence
* Limited, slight psychological
* Less addictive than other drugs of abuse, but can be addictive in some
* Treatment for cannabis dependence typically involves psychological approaches
113
cannabis acute adverse effects
Green-out – vomiting, nausea, complicated 5-HT signaling
Anti-5-HT effects account for anti-emetic activity vs. chemo
* Higher THC impairs learning, memory, concentration via
hippocampal effects, also inhibits LTP
* Psychosis- hallucinations, delusions of control, grandiosity
Anxious, paranoid
* Heart rhythm
complications
* Pesticide contamination
114
cannabis overdosing
No, not fatally
* Not a single case of fatal overdose directly caused by cannabis
* Comparative risk assessment relative to alcohol or tobacco is very low14
* Based on toxicity studies, 4 g of orally administered THC is lethal in a
70 kg human15
* 4 g-oral x 0.2-bioav-oral = 0.8 g-plasma / 0.3 bioav-smoking
= 2.67 g-smoked
* The average 0.5 g pre-roll at 15% total THC contains 0.5 g-preroll x
150 mg-THC / g-preroll = 75 mg THC (75/2667 = 1/35th of 2.67 g)
* An individual would have to:
1. Ingest 400 10 mg THC capsules in < 4 hours,
2. Spray 133 mL of 30 mg/mL THC oil in
their mouth in < 3 hours, or
3. Smoke 35 0.5 g 15% total THC
flower in < 2 hours
Lachenmeier & Rehm (2015); WHO Expert Report on THC Toxicology (2018)
115
Acute adverse effects cannabis
* Decreased attention, reaction
time, hand-eye coordination and
concentration can affect driving
ability, but stoned drivers may
be defensive drivers
116
Long-term health risks cannabis
* Increased risk of chronic cough, bronchitis
* Reduced ability for egg implantation, increased miscarriage rates
* Supressed LH release, impaired ovulation, low birth weight
* Lowered testosterone, sperm count, more abnormal sperm, increased
side-swimming in sperm
* Most effects appear to be reversible
Gateway drug hypothesis → the younger
teens are when they first use alcohol,
tobacco and/or cannabis, the more often
they use these drugs, the more likely they
are to use other drugs and possibly become
dependent
117
Volcanoes and vapes
Increased long-term cough and bronchitis
incidence
Combustion/pyrolysis generates carcinogens
* Oxygen + high temperature
* Vaping delivers de-carbed chemicals without burning
* THC (and THCA) vaporizes at 157°C
* Select the chemical composition of vape smoke
by controlling temperature
118
Vaping is well-tolerated and contains
fewer combustion products
Volcano administration results in similar THC delivery while
reducing CO delivery
119
Vaping allows users to ‘select’ chemicals
in smoke
Known as the ‘entourage effect’
* Chemical interactions with receptors enhance each
others effects
120
Mechanism of reinforcement
* Increases DA levels in rats by 100% (5 mg/kg i.v. dose)
* 8 mg of THC inhaled in humans raises DA levels 136%
45-85 min post-administration (Bossong et al. 2009)
* However, 10 mg delivered orally induced no measurable
DA increase
* Likely through CB1-mediated inhibition of GABA release
in the VTA, i.e. disinhibition of DA-ergic VTA→NAc
neurons
* Striatal DA release by THC may underlie link to
schizophrenia
121
Does cannabis cause bloodshot eyes?
Noradrenaline (NA) causes narrowing
of blood vessels
* Anandamide (AEA) relaxes those
blood vessels
* AEA is dependent on CB1 receptor
and nitric oxide (NO)
* CBD induces relaxation of arteries
122
Acute effects of intoxication
* Munchies
* Result from hunger signaling
* Increased smell, olfaction
sensitivity
* Increased pleasure when
eating → induces DA release
123
Hunger signaling
* Olfactory afferent information coming
in via bi-polar mitral neurons
* Inhibitory GABA-ergic interneurons
project to mitral neuron soma
* Glu-ergic neuron expressing CB1 presynaptic receptors triggers inhibitory
GABA-ergic interneurons in the main
olfactory bulb (MOB)
124
Mechanism of enhanced olfactory
sensitivity
Glu-ergic inputs
trigger GABAergic firing
* This sets
baseline mitral
afferent firing to
the brain
125
Augmented olfaction by cannabinoids
* Endocannabinoids naturally
reduce GABA-ergic interneuron
firing leading to increased
transmission through mitral cells
* Disinhibition of mitral neurons
and increased afferent inputs to
the brain hypersensitizes smell →
animals feed
126
How to study a physiological (in vivo)
process?
Gene/protein knock-outs
127
Physiological mechanism linked to the
munchies behaviour
* Anterior olfactory nucleus +
piriform cortex = centrifugal Gluergic input to the MOB
* Cortical feedback projections to
the MOB regulate food intake
via CB1 signaling
128
Summary of pro-appetite effects
* Increased olfactory
sensitivity triggers
feeding
* Users report greater
pleasure from food
* Appetite-related
hormones are modulated
by cannabinoids
129
Anti-emetic activity of cannabinoids
Nausea and vomiting
* Primary signal is 5HT3R-mediated in the medulla by afferent
input from the gut
* THC inhibits 5HT release in medulla via pre-synaptic CB1
* THC binds and decreases activity of 5HT3
receptors
* CBD is an agonist at 5HT1A auto-receptors,
prevents 5HT release; also antagonizes 5HT3R
130
cannabis Acute adverse effects
Bad driving
* Mostly affects automated tasks (staying in lane)
relative to attention tasks (reversing, distancing)
* Doubles risk of severe injury/death
* Synergistic effect when combined with alcohol,
sub-effective doses create impairment
Spice, K2 synthetic cannabis
* Contamination with toxins, e.g. rat poison (brodifacoum), causes severe
bleeding
131
cannabis long term health risks
Cancer
Cannabinoids may protect cells from oxidative stress
132
cannabinoid detection and testing
Colorimetric- ELISA or dipsticks
* Immunoassays, lateral flow
* Gas chromatography mass spectrometry (GC-MS)
* Roadside screening tests are lateral flow assays,
typically
133
Sources of hallucinogens
Fungi:
* Claviceps purpurea fungus
→ lysergic acid (LA)
* ~200 Psilocybe, Panaeolus,
Conocybe spp. → psilocybin
* Amanita muscaria (fly
agaric) → ibotenic acid and
muscimol
* Animal:
* Colorado river toad →
bufotenin
134
souorces ofo hallucinogens
Plants:
* Ipomoea nil (Morning glory) seeds → LA amide (LAA;
ergine)
Lophophora williamsii (peyote) → mescaline
* Ayahuasca (made from Psychotria viridis and
Banisteriopsis caapi vines) → N,N-dimethyltryptamine,
(DMT), harmine, harmaline
* Anadenanthera peregrine and Virola trees → DMT and
bufotenin
* Atropa belladonna, Datura, Henbane, Mandrake →
atropine, scopolamine and hyoscyamine
* Tabernanthe iboga roots → ibogaine
* Myristica fragrans (nutmeg
and mace) → myristicin,
elemicin
135
Chemical forms of hallucinogens
* Indoleamine nucleus
Phenethylamine nucleus
* Catechol nucleus
Dissociatives and deliriants
136
Medical uses are gaining traction - hallucinogen
* Set and setting are foundational to accessing subconscious and avoid bad trips
* Not all hallucinogens are safe
Cluster headaches may be due to dilated vessels, cause intense pain on one side of head
Elevated 5HT-induced vasoconstriction
137
Classifying hallucinogens by acute effect
* Psychedelic (a.k.a. phantastica) - vivid sensations, altered perceptions
and reality
* Users are still responsive, communicative
* Deliriant – vivid, maybe confusing, fantasy
* Dissociative – analgesia, amnesia, catalepsy, detached reality
Rosenthal (2019)
* Big 3 effects:
* Hallucination – an experience involving the perception of something that may
not actually be present
* Illusion – altered and distorted perceptions, thoughts, feelings, insights,
awareness
* Delusion – fixed belief, unchanged by conflicting evidence
138
Hallucinogens vary in their EC50
Trips are dependent on mindset
(expectation, experience and
personality) & setting
Potency (high→low): LSD→mescaline
139
hallucinogen adme
Focus on prototypical psychedelic LSD &
5HT2A receptor biology which affects frontal
cortex thought and perception plus locus
coeruleus & thalamus
140
Administration of LSD
*Ingested, injected, transdermal
* 10-300 μg
*Blotting paper, sugar cube, gel caps,
pressed tablets/microdots
Microdosing- sub-psychedelic amounts
141
Pharmacokinetic summary of LSD
142
Stages of LSD trips
* Generally, trips occur in stages after initial onset:
* 1 (0-30 min)- physiological changes outside the brain,
sympathomimetic, dizziness, nausea, muscle tremors,
numbness
* 2 (30-120 min)- alteration of perceptions, familiar objects
take on new appearances, time is lengthened, intense colors,
patterns/textured illusions, movement in stable objects,
intense sounds, smells, tastes, synesthesia
* 3 (3-5 hr)- illusions continue, perception of self as
mind/body disconnect, distorted body appearance, deeper
sense of self
143
Acute effects of LSD intoxication
* Psychological:
* Visual hallucinations and illusions
* Synesthesia → overlapping senses, altered thalamic routing
* Time and physical distortions
* Intense emotion
* Mystical, spiritual encounters
* Introspection, ego dissolution
* Cognitive → inability to concentrate/focus, preoccupation with
trivial thoughts, impaired judgement, communicating with God or
telepathy with other animals
144
Behaviour and physiological mechanisms of LSD
* Animals will not self-administer
* Animals actually evoke effort to STOP administrations
* Activates D2-like signaling in NAc, striatum
* Not rewarding
* May drive hallucinations
* Sympathomimetic:
* Increase BP
* Vasoconstriction
* Sweating
* Dilated pupils
145
Physiological mechanisms of LSD
* LC fear centre, 5HT2A in other
regions (e.g. mPFC) projects to
LC, augments LC responses to
regular events into extremely
novel, seemingly new encounters
* Thalamus- routing hub for
sensations, mixing of inputs and
outputs
* Cortex- conscious perceptions
146
Cellular mechanisms of LSD action
* LSD is an agonist at 5-HT1A/B, 2A/B/C, 6 and 7; primarily 2A, likely others too
* 5-HT receptors → GPCRs, several sub-types, signaling modes, biased agonism
* 2A:
* High pre-synaptic expression in cortex → perception and information processing
centres
*Controls transcriptional programming even after a single use
* Presynaptic in mPFC,
* Governs neuroplastic changes via glutamate signaling
*Complementary actions by other 5-HT receptors and DA receptors
* High affinity agonist at D2-like receptors, coupled to Gi/o
* Likely underlies aversive conditioning,
lack of self-administration
147
receptor structure function
Drug-receptor conformation explains high occupation
time → 221 min, depends on L229
148
Drug-receptor interactions
* Note the conformational
differences
* This allows selection of
signaling capabilities
* Biased agonism via 5-
HT2A
149
Receptor conformations bias signaling
Gαq → PKC and Ca2+ pathways are activated by non-hallucinogenic
chemicals
* Prolonged receptor occupation shifts activation away from Gαq
* Hallucinogens activate β-arrestin → desensitization/internalization,
MAPK pathways
150
Most hallucinogens do not evoke positive reinforcement
LSD is very low on abuse potential scale
* One exception is deliriants (i.e. muscarinics)
* M2/4 are Gi/o-linked
* M5 is Gq
-linked, elevates intracellular Ca2+
* Why do users use? Reasons often different than
other drugs of abuse, recreationally/socially
151
Psilocybin (from Psilocybe, Panaeolus,
Conocybe spp.)
Ingested, 3-6 hour duration
* Milder version of LSD
* No flashbacks, no lethal cases
* Metabolized to psilocin in gut and liver
* 5HT2A agonist
* Sympathomimetic, altered time and perceptions, hallucinations,
heightened emotions
* Not addictive, rapid tolerance
152
DMT (from P. viridis, A. peregrine,
Virola)
Snort, smoke, inject
Destroyed in the gut – might treat worms, parasites
5-HT2A/C and 1A agonist, many other receptors
* No tolerance
* Physiological effects similar to LSD, psilocybin
* Psychological effects- intense, vivid hallucinations, emotions, introspection,
connection to surroundings
153
Harmine & harmaline (from B. caapi
β-carboline chemicals
* Selective and reversible monoamine
oxidase-A inhibitors
* Acetylcholinesterase inhibitors → may be
useful in Alzheimer’s disease
* Stimulate striatal DA release at
high doses → used to treat
Parkinson’s patients
154
Ayahuasca (DMT + β-carbolines)
MAO inhibitors protect DMT from degradation
→ enhanced distribution to the brain
* Activates vision and memory brain regions
* Powerful visions, intense emotion, profound
introspection
Adverse effects: vomiting, diarrhea
155
Bufotenin
Close chemical similarity to 5-HT
* Common effects include drooling, heart palpitations, elevated BP,
oxygen depletion, cramped muscles, blurred vision, headache, toad
breath
Hallucinations likely caused by decreased oxygen to
optic nerve
Toads produce toxic
glycosides too →
dysrhythmias
156
Nutmeg and mace
Ingested, inhaled, insufflated
* Lower doses (5 g) cause very mild
hallucinations, disorientation, confusion,
feelings of unreality, euphoria
* Higher doses (5-30 g) cause hallucinations,
facial flushing, dizziness, apprehension,
nausea, vomiting; unreality can persist for days
157
Psychedelic microdosing
* Sub-hallucinogenic doses, 1 day-on/2 days-off, for a few weeks =
microdosing, may still get physiological effects outside of the brain
* Primarily LSD (5-20 μg) and psilocybin (1-2 mg)
* Emerging studies support beneficial effects on mood, creativity, outlook
* Not random sampling, self-reported benefits, detrimental effects reported too
* 5-HT underlies ‘complex’ cognitive and emotional functions in humans, e.g.
language, altruism, empathy
* 5HT2A expression in sub-cortical nuclei may alter functional connectivity →
support perception, memory, attention
* Cortico-striato-thalamo-cortical feedback loops, gating theory
158
Plant-derived anti-cholinergics
Plant-derived anti-cholinergics
Low doses relieve anxiety, induce sleep
* High doses cause hallucinations, amnesia, muscular paralysis
Atropa belladonna (nightshade)
Datura stramonium (datura
Hyoscyamus niger (henbane)
159
Plant-derived anti-cholinergics
* 3 primary tropane alkaloids atropine, scopolamine, hyoscyamine
* High (near toxic) doses required for hallucinations
* Block muscarinic AChRs- dilate pupils, increase heart rate, dry
secretions
160
Anti-cholinergics
* Produce hallucinations, but don’t remember it
* Physiological effects: elevates heart rate, dry mouth, lack of
perspiration, constipation, difficulty urinating
* Can be fatal – rapid heart rate, hyperthermia, asphyxia
* Usually no euphoria
* Prevent ACh-mediated activation
161
Dissociatives
Phencyclidine (PCP) and ketamine anaesthetics
* Amanita muscaria, Salvia divinorum
* Completely removed from reality, detached
Produce reinforcement in animal models, unique
amongst hallucinogens but not due to augmented DA
release in the NAc
162
Phencyclidine (PCP)
Inhaled, dip a cigarette in free-base and smoke it
* Ingested, insufflated, or injected (hardcore users)
* Duration 4-8 hours, TI 10-15
* Diverse effects dependent on dose
* 5mg: Anaesthetic, analgesic, stimulant, depressant, convulsant, hallucinogen
* 10 mg any combination of: muscle rigidity, loss of pain sensitivity, agitation, mood
swings, combative, sympathomimetic, visual/auditory hallucinations, detachment
* Blocks NMDARs in cortex and hippocampus
* Increased synthesis and release of DA causing agitation, stimulation, locomotor activity
* Delirium, confusion, paranoia, impaired memory may last for days or weeks
* Toxic doses (>20 mg) can cause convulsions, respiratory failure, coma, death, but most
deaths are due to behaviours while tripping
163
Ketamine
Rosenthal (2019)
* Ingested, inhaled, insufflated, injected
* 15-20 min onset, 35-60 min duration
* Same effects as PCP, shorter acting
* Blocks NMDARs in cortex and hippocampus
* Increase synthesis and release of DA causing agitation,
stimulation, locomotor activity
164
Cellular mechanisms of PCP, vit. K
* Block the NMDAR ion channel
* Affect Glu, NE, DA, ACh, 5-HT neurotransmitters
Dependence on PCP, vit. K
* Moderate risk, mildly reinforcing but no DA increases in the NAc
* PCP self-administration in animal models
* Mostly psychological, very slight physical dependence in humans
* Vit. K dependence is linked to access, not neurochemistry
165
Adverse effects of PCP, vit. K
ref
* Psychosis and analgesia lead to
damaging behaviours
* Attempting ‘superhuman’ feats
* Ketamine cystitis
* Arrest bladder cell growth, cause cell
death
* Causes bloody urine, pain,
incontinence
* Long-term users experience memory
loss, speech problems, delusional
thinking
166
amanita muscaria
* Ingested, onset 30-90 min, duration up to 12 hrs
* Withdrawal headaches, amnesia, sleepiness can last for days
* Active chemical is excreted unchanged in urine
* Alter body perception, euphoria, dizziness, vivid hallucinations
* Muscle twitches, sweat, salivation, constricted pupils, lowered BP
* Muscimol is GABAAR agonist responsible for most effects
* Ibotenic acid binds NMDARs
* Fatal dose is around 15 mushroom caps
167
Salvia divinorum
Inhaled, chewed; 15-120 min duration
* Mild alteration of consciousness to full psychedelic trip
* Vivid visuals, sensory and time disturbances, detachment and floating through
time
* Nausea, slurred speech, chills
* Very high dose can cause brain lesions
* Salvinorin A – 1 of 3 non-alkaloid hallucinogens
* Potent kappa opioid receptor agonist
* Causes dysphoric effects, anxiety, fear,
confusion in most cases
168
New psychoactive substances (NPSes)
Chemical alteration of existing hallucinogens
169
2-C drugs
5HT receptor agonists, likely other receptors/transporters too
* Produce hallucinations, stimulant effects
* Adverse effects: seizure, extremity rigidity, lethal
170
Bromo
-dragonFLY
* Benzodifuran * Duration 1-3 days! * Binds 5-HT1 and 2A receptors * Severe vasoconstriction via alpha adrenergic
receptors
* Similar effects to LSD * Narrow therapeutic window, several overdose
deaths have been reported
171
N-benzyl-oxy-methyl (NBOM) drugs
Several ‘N-bomb’ derivatives (list), 2C-I-NBOM is most common
* Potent 5HT2A agonists
172
bath salts history
Designer drugs, include several evolving classes of stimulants
* Resemble amphetamine + methylene ring feature of MDMA
Cathinones, ‘-lones’ and ‘-drones
173
bath salts sources and forms
Khat plant
* Bath salts, resemble
Epsom salt crystals
174
bath salt Chemical structure resembles
amphetamine
* Beta-ketonated amphetamines
* Ketone reduces lipophilicity,
reduces transport across BBB
* 4-methylmethcathinone =
mephedrone, most common
* Compare amphetamine,
cathinone, meth, methcathinone,
mephedrone
175
Chemical evolution of bath salts
* Synthetic and highly modified:
* Addition of methylenedioxy ring
* Addition of pyrrolidine
* Extended chains
* Pyrrolidine makes it more lipophilic,
more easily crosses BBB, tend to be
more potent
* 3rd generation flakka (αpyrrolidinovalerophone)
176
Recreational effects of 3Ms
* Sympathomimetic effects, high energy
* Euphoria
* Arousal
* MDPV is stimulant at low
doses, induces bizarre
behaviours at higher doses
177
Physiological mechanisms of 3Ms
* Sympathomimetic (via DA, NA + 5HT increases):
* Agitation, hyperthermia, tachypnea (rapid
breathing), tachycardia (rapid heart rate),
hypertension, cardiac arrest
* Hyperthermia leads to rhabdomyolysis, kidney
failure
* Euphoria via elevated NAc DA
* Increased DA and 5HT in NAc of rats
* Striatal DA elevations cause locomotor activity
increases in mice and rats
* Hyperthermia, hypertension, cardiac arrest, and
serotonin syndrome are most common adverse
effects
178
Cellular mechanisms of action
Without pyrrolidine ring: similar to
* Bind DAT, SERT, NET
* Enter terminals via SERT
* Interact with TAAR
* Leak cytoplasmic neurotransmitter stores, reverse transporter, inhibit
VMAT
* Mephedrone and methylone stimulate non-exocytotic release of DA, 5HT,
NE
methylone
MDPV
mephedrone
* With pyrrolidine ring: similar to
* Blocks transporters, does not reverse
transporters
* MDPV is a potent DAT/NET blocker, weaker
SERT activity
amphetamine
179
Potency of bath salts on DAT/SERT
* IC50 represents the concentration of drug required to block 50% of uptake
* Lower IC50 = more potent
Most of these bath salts are as or more potent than cocaine, amphetamine
DAT/SERT of 806 means that MDPV is 806x more potent at DATs compared to SERTS
* If you synthesized a new drug, what
type of test could you perform and
what ratio would you want?
Structure-activity relationship → larger carbon tail + pyrrolidine
= highest activity at DAT
180
Mechanisms of 3M reinforcement
3M bath salts bind DAT
* Mephedrone and methylone enter terminals, displace DA into
synapse and reverse the DAT
* MDPV does not enter terminal
181
Adverse effects off bath salts on
behaviour at high doses
* Violence, homicidal combative behaviour,
self-mutilation, excited delirium syndrome
(ExDS)
* Panic attacks, paranoia, suicidal thoughts,
confusion, psychosis
182
Cathinone case reports- fatal
DA+NA+5HT levels
Symptoms are related to surge in levels of dopamine,
noradrenaline and serotonin in the periphery and
include:
* Hyperthermia (indicated as primary problem in
several deaths – many users take off clothes)
* Leads to rhabdomyolysis, kidney failure
* Tachycardia (elevated heart rate, sometimes
followed by bradychardia), hypertension, chest pain
* Panic attacks, paranoia, suicidal thoughts,
confusion, psychosis
183
Adverse effects of 3Ms
* Water intoxication → hyponatremia
* 5HT causes secretion of anti-diuretic
hormone, water re-absorption in kidneys
* Polydipsia (thirst), evoked by
hyperthermia/high metabolism, an
attempt to cool down
* Excessive sweating causes loss of Na+
* Increased cranial pressure caused tonsillar
herniation of cerebellum
* Pressure on medulla lead to respiratory
depression, cardiac arrest
* Patient died of mephedrone overdose
184
Tolerance, withdrawal and dependence
Rhesus monkeys show higher self-administration for
longer with MDPV and α-PVP compared to cocaine
and meth
* Rats display escalating drug-taking behaviour when
given free access to MDPV
* Mephedrone causes CPP in mice and rats
* Altogether, bath salts appear to have a very high abuse
potential
185
Categories of PEDs
Anabolic/androgenic
steroids (AAS) & hormones
186
Forms of AAS
Major PEDs
* Based off testosterone
steroid nucleus
* Altered to enhance
muscle building
type 1
Esters
* Prolonged half-lives
* Hydrolyzed to testosterone
* Aromatized to estrogens by
aromatase
type 2
19-nor-testosterone (nandrolone)
derivatives
* Prolonged half-lives
* Reduced androgenic effects
* 80% less aromatization
compared to type 1
type 3
17α-alkyl derivatives
* Greatly reduced liver
metabolism
* Not converted to estrogen
* Increased anabolic effect
187
administration
Pyramiding – increasing doses
followed by decreasing dose
* Stacking – Using multiple
steroids
* Cycling – alternating periods
of use, co-ordinated with
training or testing schedules
* Certain users (e.g.
bodybuilders) may take 100-
1000x therapeutic doses
188
pharmacokinetics summary of AAS
189
Steroid physiology, critical tissues and enzymes
Fundamental male and female
differences are determined by sex
steroids
* Testosterone converted to
DHT by 5α-reductase
* Aromatase is rate-limiting step for estrogen
production
* Direct transcriptional
regulation and signaling
* Muscle mass,
tendon/joint/bone health
* Levels are cyclical,
negative feedback
* Production in reproductive
tissues (e.g. ovaries/adrenal
glands, testes stimulated by
FSH/LH from anterior pituitary
* Influence physiological effects
via cellular mechanisms
190
Mechanisms of AAS action
* Anabolic steroids bind androgen receptor
* Higher concentrations cause additional receptor binding, e.g. estrogen receptors
* Drug-receptor complexes translocate to nucleus, bind specific DNA sequences
* Activates gene transcription mRNA production, make new protein e.g. to build
muscle
* Steroids shift stem cells towards muscle cell differentiation, as opposed to
adipose cell
191
Mechanism(s) of reinforcement
* Many users report euphoria
* May come from increased
beta-endorphin levels which
decrease GABA release onto
VTA DA-ergic neurons
* When steroids modulate
GABAA
receptors, DA-ergic
mesolimbic neurons increase
firing rate
192
AAS produce massive weight gains,
virtually all muscle
* When treated with AAS
animals showed:
* Increased number of
myonuclei (blue)
* Increased muscle fibre
cross-sectional area (CSA;
green)
193
Cellular ‘memory’ allows rapid muscle
building after period of inactivity
More pronounced CSA response after 11
week break in steroid-treated animals
194
cellular mechanisms of action
Trenbolone:
* 19-nor derivative of testosterone
* Higher affinity for androgen receptors
* Not a substrate for 5α-reductase nor aromatase
* Induces myotrophic effects without unwanted effects
* Reverses expression of atrophic genes (e.g. MuRF1)
* Increases expression of anabolic genes (e.g. IGF-1)
195
Tolerance
* Even after a single dose
* Presence of steroids inhibits their own production – negative feedback
Withdrawal
* Depression, mood swings, fatigue, headache, insomnia, lack of energy, no
appetite, body dissatisfaction
dependence
* 30% of users become dependent
* More likely at higher doses
* Mostly psychological due to cycle length
* Want to avoid negative affect
196
long term health risks of steroids
Steroid receptors are present in multiple tissues, e.g. muscle and
brain
* Lack of knowledge of how many and which genes are turned on
* Activation of other genes leads to unwanted, dangerous side effects
Increased blood pressure, cholesterol and
heart abnormalities
“’Roid” rage
* Increased aggression, anger, rage
especially in dependent users
* Psychosis and depression also
occur more frequently
* GABAA
, NMDA and 5HT
receptors can bind endogenous
neurosteroids
Anterior hypothalamus (AH) is the
aggression centre
* Activation of D2 in AH results in
aggression and violence in animal
models
* Moderate doses in adolescence
increases D2 expression in AH
* Arginine vasopressin is excitatory
and potentiates aggression, while
5HT is inhibitory and decreases
aggression
* Steroid exposure enhances vasopressin,
reduces 5-HT effects
* Chronic nandrolone increases
aggression in mice
Reduces 5-HT receptor mRNA in
PFC, hypothalamus, hippocampus
and amygdala
Depression is a common effect
reported by steroid abusers
* Abuse is linked to reduced brainderived neurotrophic factor
(BDNF) levels and correlates
with depressed behaviours
* BDNF stimulates neuronal
growth in hippocampus
197
Testing
* Clinical steroids are safe and easily
detected
* Designer steroids:
* Modified by clandestine labs
* Undetectable
* No one knows the mechanisms, longterm effects
* How are samples tested?
* Usually urine, tested for known
metabolites
* Can run HPLC, ELISA, GC-MS
198
Technologies and assays, innovating
* Chemical and immunoassays are most
common
* Improved technology allows detection of
unique metabolites, lower thresholds for
detection
Chemical haptenation – a small molecule that binds a
macromolecule (e.g. protein) to produce an immune reaction
