Final

Question 1

Cannabis plants

Answer 1

2 distinct types, sativa and indica

Question 2

cannabis sativa

Answer 2

-slimmer leaves
medium THC content when grown in the wild
-described as producing a “cerebra energetic high”
tends to have higher cannabidiol content than indica (which is important for healthy use)

Question 3

cannabis indica

Answer 3

• tends to have higher THC content when grown wild, and lower cannabidiol content
• high described as “body stone and couch lock”
• has strong, skunky smell

Question 4

cannabinoids

Answer 4

-unique to cannabis plants
-highly lipid soluble, so are often delivered in oil form
=delta-9 THC is the only psychoactive one (linked to the high recreational users desire); others do seem to influence or modulate the high though even if they don’t produce it

Question 5

terpenes

Answer 5

another class of compounds found in cannabis

• give the distinctive skunky smell
• contribute to the overall experience of being high (may modulate, some may even have their own pharmaco properties, but not thought to directly produce high)
• ex. myrcene is implicated in muscle relaxation and sedation

Question 6

phytocannabinoids

Answer 6

(cannabinoids that occur naturally in the cannabis plant)
THC (tetrahydrocannabinol)
-responsible for some medical effects (huge collection of anecdotal reports but little clinical evidence)
-causes cognitive impairment, risk of psychiatric issues w acute and chron use
-have good understanding of how/where it acts in body
CBD (cannabidiol)
-anti-psychotic and anti-anxiolytic effects (seems to oppose some THC effects)
-no cognitive psychiatric issues
-some medically useful effects (ex. approved for seizure treatment)
-causes grogginess, sleepiness, mild impairment
-poor understanding of where/how it acts in the body

Question 7

cannabis use: recreational vs medicinal

Answer 7

recreational:
-high THC content, CBD content not a concern but typically low, and is used with the aim of getting high
medicinal:
-low THC, high CBD, no high produced

when it comes to CBD vs THC content, we typically see that as one goes up, the other goes down

• balanced content is ~10% CBD:10% THC by total weight
• health experts agree that a 20-30% by weight blend of THC will lead users down a path of high psychiatric risk

Question 8

cannabis

Answer 8

comes from the cannabis plants

• females produce a stick sap called resin; it’s meant to trap pollen from males, but also contains concentrated active ingredient
• found at highest conc in flowering tops of the plant, less in the leaves and v little in the stalks
• glandular hair-like structures all over the plant contain the resin in little bubbles, and are called trichomes
• goal in growing is to maximize the production of that sticky resin

Question 9

marijuana

Answer 9

the dried leaves and flowers of cannabis plants (also has all the bad stuff though, like seeds and stems)

• with basic cultivation methods, THC range is 2-8%, but can reach 20% with sophisticated techniques such as hydroponics
• canada is a next exporter, and production is predominantly in BC, also QC and ON
• overall potency increase from 4% in 19995 to 12% in 2014

Question 10

sinsemilla

Answer 10

• a variation on cannabis plants
• marijuana (dried leaves and flowers) from seedless, unpollinated plants
• if you stop pollination, the energy those plants would have put into making seeds instead goes to production of resin and therefore cannabinoinds
• THC conc ranges from 7-20+ %

Question 11

skunk

Answer 11

• a cannabis plant variation
• typically a hybrid with high THC conc (7-20%, same range as sinsemilla)
• has distinctive strong smell, and very potent
• linked to all kinds of psychotic episodes (in UK, strong link btw emergence of psychosis in teens and skunk use)

Question 12

hashish

Answer 12

• preparation from cannabis plants
• concentrated resin from leaves (therefore has few-if any-leaves or other plant parts if it’s high quality stuff)
• depending on purity, THC conc ranges from v low up to 70%
• packed into bricks of varying consistency (depends on moisture content) and oxidation can cause colour change

Question 13

butane hash oils

Answer 13

• if done right, you can get up to 90% TCH by extracting it from plants into a solvent such as butane
• the purity of the product changes the consistency (budder is lower quality and pasty, then crumble, the shatter, which has the texture of peanut brittle and is the highest purity/most desirable)
• once you have an oil, you heat it to drive off the butane, but it’s hella flammable and can cause a lot of damage

Question 14

dabbing

Answer 14

method of consuming butane hash oil products

• take a v small amount of the ultra conc’d product, heat to vaporize, then breathe in the blend of THC
• bc of the high conc (THC 80+%), a single inhalation can be equivalent to multiple joints
• many users feel it’s a cleaner way to use because you avoid combustion (so you’re less likely to inhale dangerous planar HCs)

Question 15

dangers of butane hash oils

Answer 15

• production uses highly flammable gas
• heating process while smoking requires butane torches
• butane contamination in poorly made batches
• reports of individuals passing out after a single use
• use linked to greater physiological dependence compared to other types of cannabis
• since high [THC] plants linked to psychosis, fear that its use will result in more cases

Question 16

THC absorption

Answer 16

• when smoked, rapidly absorbed into blood (enters brain w/in 10s, effects felt w/in 5-10 min; after 30 min most have left the brain but can still be detected in blood)
• depth of inhalation (not duration) affects speed of absorption
• peak THC content varies enormously with depth and frequency of inhalation, which makes it hard to tell ppl exactly how much they can take and still drive
• even at v low blood conc, 2.5ng/ml, reactions are compromised
• naive users have a hard time recognizing when they’re high
• v lipophil, they have trouble getting through the liquid that covers GI cells; baking in foods with added oil helps
• oral ingestion needs higher does than smoking for same effects, but lasts longer, likely because of the formation of an active metabolite 11-hydroxy THC

Question 17

THC metabolism

Answer 17

• THC has a half life of 19 hrs
• metabolites have half lives of 50+ hours
• primary metabolite is 11-hydroxy-delta-9-THC which is psychoactive and probably contributes to overall effects
• metabolism is mostly in liver, and also lungs
• also see buildup in body fat (esp in chronic users) as the high lipophilicity of the molecule and its metabolites allows fatty tissue to remain them, maybe even for weeks or months
• if taken orally, there is significant first pass metabolism, so see a higher conc of 11-OH-THC

Question 18

cannabis-psychological effects

Answer 18

• hilarity, euphoria, well-being/joyfulness, mellowness
• mundane thoughts take on great significance and unconnected events suddenly seem connected
• deficits in tasks requiring concentration, attention, vigilance (but could be just that they don’t care abt pleasing a researcher)
• cognitive effects most heightened in infrequent users (like w alcohol)
• amotivational syndrome (possibly due to decreased DA levels in chronic heavy users, esp if started young)
• short term memory effects (ex. disruption of train of though, possibly from inhib of Ach release in hippocampus)
• in some users, anxiety, panic, dysphoria-> possibly dose/experience related

Question 19

physiological effects

Answer 19

• increased heart r8 as sympa. tone increases and para tone decreases -> tolerance can lead to bardycardia (lower than normal heart r8 when not using?)
• increased BP (generally only in acute use, BP may be low in chronic users)
• reddening of eyes from dilation of small blood vessels
• sensations of intense hunger
• relaxation of muscles (may be good for treating MS, a condition characterized by uncontrolled, painful tightening of muscles, also some evidence that, at least in periph, some cannabis products may prompt re-myelination)
• decreases eye fluid pressure (maybe good to treat glaucoma, condition of high fluid pressure in eye that can damage retina and optic nerve)
• analgesia (acts at CB1 receptors in PAG (periaqueductal grey), brain region involved in pain pathways)

Question 20

endocannabinoid system

Answer 20

• the endogenous cannabinoid system modulates NT release and is involved in pain, hunger, learning and memory
• communicate by retrograde neurotransmission (endos travel from postsyn cell and bind to receptors on presyn terminals)
  examples: anadamine (AEA), 2-arachidoyl glycerol (2-AG), naturally synthesized in the brain from membrane lipids
• they decrease excitability, inhibiting NT release from presyn D1 receptors

Question 21

cannabinoid receptors

Answer 21

-coupled to G-proteins that decrease cAMP lvls by inhibing adenylate cyclase
-normally activated by endocannabinoids
two types:
CB1-primarily in CNS (one of the most common receptors), presyn, activation inhibs Ca influx, stims K efflux; net effect is inhibition of NT release
CB2-primarily outside CNS, may be immunomodulatory

Question 22

Rimonabant

Answer 22

• a CB1 receptor antagonist, or inverst agonist
• drops receptor activity below baseline, and could be used to prevent the feeling of hunger
• tried as an anti-obesity agent, but people became depressed, because endogenous cannabinoids are involved in mood

Question 23

cannabidiol binding sites

Answer 23

• either doesn’t at all or binds only weakly to CB1/CB2 receptors
• a ‘promiscuous’ ligand w low affinity at multiple receptors
• at high doses, seems to indirectly antagonize CB1
• CBD can act as an agonist at TRPV (transient receptor potential vanilloid) channels which are found in pain sensing neurons; seems to activate and then desensitize them, preventing signaling
• > may be contributing to analgesic effects
• 5HT1A agonist and 5HTs antagonist: minimize NT release and nausea respectively, may also be a potential antidepressant as it acts on serotonin receptors
• unknown how it stops seizures

Question 24

THC and DA

Answer 24

• it’s thought schizophrenia is linked to excessive DA release
• in study where patients inhales 8mg, an estimated 136% increase in DA levels in the NAc was measured 45-85 min after admin
• another showed 10 mg dose induced no measurable DA release, but it was taken orally
• increase DA release likely due to inhib of GABA release in VTA

Question 25

cannabis vaporizers

Answer 25

- analagouls to hookah, vaporize constituents off the cannabis so you can inhale w/o combustion products - THC vaporizes ~180-200C w/o burning the plant material - compared to smoking cannabis, init THC peak and levels are basically the same - users also learn to titrate their intake, so even if 2x a s much cannabis present, they adjust their breathing to get a desired peak

Question 26

cannabis: tolerance and withdrawal

Answer 26

- w chron THC exposure, the constant agonistic effect at CB1 receptors causes them to be internalized and possibly even decreases production - intensity of withdrawal symptoms depends on use, but can include hot flashes, sweating, runny nose, loose stool, irritability, anxiety, insomnia - w/drawal usually not sever though, because of the long half life and therefore slow elimination of the drug and its metabolites, giving a tapered response so the body has time to gradually adjust

Question 27

cannabis and cancer

Answer 27

- where cigarettes generally have a filter to help catch some tar and combustion products, joints typically don't; some sources claim marijuana smoke contains 50-70% more carcinogenic materials than cig smoke, while others say it's basically the same - cannabis itself doesn't contain overtly toxic materials, but pyrolyis generates mutagenic polycylic hydrocarbons/phenols/cresols - heavy cannabis smokers shows cells that are phenotypically different than surrounding cells, called precancerous lesions, that may go on to become cancerous cells - so far though, studies show no correlation btw cannabis smoking and the anticipated cancers (pharynx, larynx, mouth) - there is however a link to testicular cancer

Question 28

cannabis and mental illness

Answer 28

- heavy users (have used 50+ separate times in their life) shown to have increased risk of schizophrenia - UK study suggests maybe 8% of all new cases of schizophrenia are from cannabis use - 15 yr longitudinal study saw a 2x average risk increase in light users and a 6x increase in heavy users - it's definitely risk then, but the magnitude is uncertain - risk is greatest from high THC/low CBD varieties - the earlier the first use, the greater the increased risk (likely due to neuroplasticity, as the brain is still forming connections/pruning up to mid 20s) - cannabis use also linked to mutations in COMT gene (seems to code the protein that breaks down DA) and AKT (a protein that codes gene transcription and cell death in neurons); risk is greatest when both are mutated - unclear whether it "causes" schizophrenia or if people are self-medicating

Question 29

cannabis and cognitive issues

Answer 29

schizophrenia: - cannabis use precedes diagnosis by 1-5 years - use typically worsens symptoms and progression of the disease, so likely not self-medication - there's a dose-response relationship - positive (hallucinations) and negative (apathy) aspects of schizophrenia also mimicked experimentally by THC - cannabis use also linked to depression, amotivational syndrome, which are similar to -ve aspects of the disease -use of cannabis prior to 18 linked to drop of 8 IQ points by 30

Question 30

munchies

Answer 30

cannabinoids seem to stimulate food intake via a number of mechanisms, including increased olfaction, increased pleasure when eating food high, and increased activity of hunger signaling pathways

Question 31

CB1 and olfaction

Answer 31

- cannabis seems to increase sensitivity to food cues - works through presyn CB1 receptors - mitral cells in the main olfactory bulb collect and integrate information from sensory neurons - those signals are then passed to the amydgala and the PFC, which interprets the smell and what it means to us - when satiated, Glu is released onto GABA receptors, and the release of GABA inhibits mitral cells and their abilty to transmit olfactory info to the rest of the brain - when taking a cannabinoid though, or when you're hungry and the body releases its own endocannabs, they bind to presyn CB1 receptors, blocking Glu release; GABA release also halts and the mitral cells are free to send sensory info into the brain

Question 32

cannabis and pleasure/reward from food

Answer 32

- people seem to get more pleasure out of food when high on THC - experiement measure hedonic score in rats (sum of happy rat behaviours, a measure of pleasure) - a 20% sucrose solution, which is just on the threshold of being rewarding, can be made significantly more rewarding when co-administered with 1mg/kg solution of THC (no significant increase at 0.5mg/kg) - seems to indicate that food is more rewarding when you're high on THC - stereotaxic surgery on the rats also shows that while 20% sucrose alone didn't yield significant increase in DA, addition of THC to the mix did

Question 33

cannabionoids and nausea/vomiting

Answer 33

- primary signal for nausea and vomiting seems to be 5HT - 5HT1A is an autoreceptor that shuts down 5HT release if too much in the synapse - 5HTs receptors are abundant in the gut - THC prevents 5HT release by activating presyn CB1 receptors, and antagonizing both 5HT1A and 5HT3 receptors - coupled with the effect of stimulating appetite, this could be very useful in treating chemo-induced nausea and vomiting

Question 34

cannabinoid hyperemesis syndrome

Answer 34

- not everyone experiences anti-nausea and hunger effects - in a very small pop of cannabis uses, usually long term frequent users, this condition can develop - includes constant vomiting and hunger pains, and taking compulsive hot showers to relieve the symptoms (this may somehow be linked to 5HT release) - all symptoms vanish upon cessation of cannabis use - cause unknown, but body temp is controlled in the hypothalamus, where many CB1 receptors lie

Question 35

cannabis and driving

Answer 35

- risk of getting into accidents increases when under the influence of THC - from metanalysis of high quality studies (good measurements of THC method, good data on the collision, etc), we can see that there's definitely an increased risk - seems to have most severe effects on automated tasks (staying in lane) compared to concentration intensive tasks (reversing, keeping distance) - acute cannabis use nearly doubles risk of severe injury/death - other studies also show that effects of alcohol and cannabis are additive (a dose of either not considered to impair can lead to severe impairment when co-administered)

Question 36

synthetic/herbal marijuana

Answer 36

(spice, K2) - any dried plant on which a synthetic cannabinoid is sprinkled, lots of which are cast-offs from various research programs to characterize CB1/2 receptors (were never designed to get you high, but might give you a heart attack if you overdose) - JWH-018, UR-144, XLR-11 the ones that found traction on the black market - in general, subbing in a F for one H causes huge increase in potency (2-3x) and drops the EC50, sometimes up to 75% (EC50 = effective conc that caused desired response in 50% of users)

Question 37

Spiceophrenia

Answer 37

synthetics like spice induce a kind of psychosis rarely seen in standard cannabis users -see elevation of BP, heart r8, breathing, and presentations (complaints of symptoms when people come into the hospital) why? because synths tend to be full (maximal) CB1R agonists (which trigger different intracellular pathways and rapidly desensitize receptors so they can be removed more rapidly) and are generally just more potent at CB1 and CB2 receptors

Question 38

cocaine

Answer 38

- used in s. american cultures for rituals - surgical anesthetic (still used in eye surgeries, delicate operations in which you need blood vessels to constrict; stops pain transmission) - stimulant that can produce profound euphoria - Freud got everyone hooked bc he thought it would be good for treating opiod addiction - high abuse potential - major dangers form cardiovascular effects (vasoconstriction can cause clotting and stroke, also cuts off blood supply and tissues/organs die off bc of low O2) - people use inadvertently as result of transport (ex. one of the packets they swallowed bursts)

Question 39

cocaine: sources and smuggling

Answer 39

- S. america grows the plants that produce cocaine, so major sources are from Columbia (which supplies most canada), Peru, Bolivia - mostly transported in bricks of the powdered for - "mules" may swallow multiple bags to try to smuggle (either tied off condoms or the fingers of latex gloves) - increased trend in people smuggling liquid cocaine in carry-ons; frequently caught in toronto pearson

Question 40

the cocaine moelcule

Answer 40

- a natural product of the coca plant, which grows easily in S. american highlands - locals chew the leaves with chemical lime (which gives a basic pH) to extract the cocaine from the plants so it can be absorbed through the cheek membranes - chemical name is benzoylmethlecgonine

Question 41

cocaine production

Answer 41

- leaves a re dumped into makeshift trench - 1 kg of paste takes 500 kg of leaves - kerosene or gasoline is added as a solvent to extract the active ingredients, and people walk up and down to mush the leaves - this mix can be dried to get a gooey paste that's about 75% cocaine, but heavily contaminated with solvent and plant parts

Question 42

cocaine hydrochloride

Answer 42

- salt form, from refining the paste - when dissolved, gives a low pH (from the HCl)- makes it more polar and water soluble than the paste form; desirable because when snorted in can get into the mucous membranes of the nose - often cut (diluted) with other white powders to maximize profit (this could be powdered milk, baby laxative, or other anesthetics like lidocaine or benzocaine) - when rubbed on the gums, produces a brief freezing (the more freezing, the greater the purity); cutting with anesthetics can mimic that effect

Question 43

consequences of cutting cocaine

Answer 43

- most additives aren't harmful, but some are - for example, levamisole is an anti-helminthic drug given to cattle to kill off parasitic worms, and also shown to mildly increase DA release - it seems to damage the lining of blood vessels; red blood cells can't pass through as well, blood pools and forms clots, lack of O2 to peripheral tissues causes necrosis - purpura, a purple discoloration leading to necrosis of tissue dues to vasculitis (inflammation of vasculature) preferentially affects the ears and tip of the nose, where fine blood vessels are found - estimated that 70% of cocaine in the US is contaminated

Question 44

cocaine: snorting

Answer 44

- requires powdered form, so cocaine HCl usually chopped up w a razor blade - cocaine hydrochloride can be snorted (insufflation); it's easy, quicker onset than oral admin (3-5 min), effects last 30-40 min; drug is absorbed through nasal mucous membranes; 90% of usd and cad bills contam'd w trace amts - chronic snorters can lose cartilage separating the nostrils (from a mix of vasoconstriction and acidic erosion from the hydrochloric acid)

Question 45

cocaine: IV injection

Answer 45

- faster onset (15-30 sec), more profound high, but shorter effects (10-20 min) - less common route of admin, most people likely switched over due to tolerance - if the needle gets into the artery (which transports oxygenated blood to organs) instead of veins, risk of severe necorisis and vasoconstriction (due to prevention of Nora uptake (excess makes vessels constrict) and decreased nitric oxygen production (increases likelihood of of constriction)) - dull needle causes a lot of damage and continuous injection can lead to hyperpigmentation - may result in gangrene and amputation

Question 46

freebase cocaine

Answer 46

- can't smoke cocaine hydrochloride bc it will burn before producing vapors and therefore destroyed in the process of smoking - high quality freebase starts by dissolving Coc-HCl in water, adding a base (usually ammonia (which will raise the pH and get the H bonded to the Coc-N to dissociate, neutralizing the molecule)), then extracting with ether (which is highly explosive/flammable), then drive of the solvent

Question 47

crack cocaine

Answer 47

- very cheap, smokeable version of cocaine - named after the crackling sounds it makes when smoked - made by dissolving low purity cocaine in water, neutralizing with NaHCO3 (baking soda), then heating to drive off water and precipitate the freebase - the salt residue will still be left over, but theoretically there's nothing dangerous enough to kill you

Question 48

cocaine: smoking

Answer 48

- route of admin for freebase and crack cocaine - rapid onset (6-10 sec) - super intense, addictive, but brief high; leads to use patterns of repeated doses

Question 49

cocaine metabolism

Answer 49

- one major metabolite is benzoylecgonine, cocaine less a methyl group, and appears by spont hydrolysis w/in 4 hours of using cocaine (this metabolite is measured in sewage to get a picture of use) - when taken with alcohol, cocaethylene is produced; it's a potent vasoconstrictor and very toxic to heart muscle, but may enhance euphoria - methylecgonine is a pyrolysis product and indicates the cocaine was smoked - metabolites can be detected in urine up to four days after use

Question 50

cocaine: psychological effects

Answer 50

- intense, extreme euphoria from super high DA levels, results in high energy - hyperactivity, hypersexuality (some ppl use exclusively for this effect) - increases confidence (larger-than-life persona), sense of invincibility - makes the mundane more pleasurable - high dosage/chronic use can cause psychosis to develop

Question 51

cocaine: physiological effects

Answer 51

- blocks sodium channels so sensory nerves can't conduct pain signals - > in heart tissue, this inhibs depolarization and can lead to dsyrhythmia (in which heart ventricles can't adequately fill with blood) - sympathetic NS is stim'd due to excess release of NTs (DA, 5HT, NA, adrenaline) in synapses - > increases heart 8, which increases BP (effect also heightened by vasoconstriction) - can also lead to anorexia, insomnia, agitation

Question 52

mechanism of cocaine action

Answer 52

- the N and the phenyl in the structure allow it to mimic DA quite well, as well as 5HT, NA and adrenaline - it blocks action of transporter proteins that normally remove NTs, leading to prolonged and greater stim of postsyn receptors - results in large accumulation of DA at NAc

Question 53

cocaine: transporter binding

Answer 53

- cocaine binds to the same DA binding site on presyn DA autoreceptors, but gives the protein a slightly diff shape, locking it so that it can't release contents back to the inside of the cell - it no longer cycles through open and closed shapes, rending it non-functional - background/tonic DA release will then induce a massive DA buildup - since the presyn neuron can no longer recycle and you eventually run out of DA to dump into the cleft, it will diffuse out (binging cocaine might eventually stop the high then)

Question 54

cocaine transporter effects

Answer 54

although most research focuses on DAT, see similar effects with nora and 5HT transport - studies using drugs that exclusively block DAT don't perfectly mimic the effects of cocaine, meaning it's not just DA that's responsible - also know from cardiovasc effects that nora (hypertension) and adrenaline (tachycardia) levels are significantly increased via blockade of their transporters

Question 55

chronic cocaine use and increases DAT activity

Answer 55

- expose animals to cocaine for several days, then isolate nerve endings from specific brain regions, add radioactive DA, and measure how much gets transported into the endings - when compared to uptake in animals exposed to saline for the same time, see huge increase in DT activity in NAc (mild increase in caudate-putamen) - shows that since drug inhibs transporter activity, the brain compensates by increasing their number or activity - in absence of DA, this elevated DAT activity sucks so much of your normal/baseline DA from the cleft; thought to cause the depressed state of users between doses

Question 56

cocaine related damage

Answer 56

- increases coagulation and impairs thrombosis (the breakdown of clots), leading to increased risk of stroke - high acute dose can lead to medullar effects such as respiratory and circulatory failure - hyperactivity combined with vasoconstriction can lead to hyperthermia (which can in turn lead to rhabdomyolysis (breakdown of muscle tissue) and then myoglobinuria (myoglobin in urine, which can lead to kidney failure) - risk of psychosis in chronic users of high doses

Question 57

COCAINE AND CARDIAC EFFECTS

Answer 57

I don't have time rn to puzzle through this diagram rn tbh, so please come back :) (cocaine, slide 37)

Question 58

cocaine: withdrawal

Answer 58

- symptoms are usually fairly mild when compared to alcohol and sedative (probably because its time in the brain/action is so short-lived) - depression the most common characteristic; acutely observed as a "let down" w/in 30 mins of use whose severity is related to dose and duration of use

Question 59

cocaine: acute treatment of symptoms

Answer 59

- benzos play central role in controlling agitation from acute intoxication; decrease CNS effects but also treat cardiovasc issues by decreasing NT release (which decreases BP and reduced heart r8) - antipsychotics can also be used - both decrease mortality (52% reduction for benzos, 29% for antipsychotics) - for myocardial infarction, first line treatment is nitroglycerine; it produces nitric oxide, a vasodilator, which increases oxygen supply to heart by dilating blood vessels and reduces workload and O2 consumption of heart muscle cells - cooling w ice water can help with hyperthermia

Question 60

amphetamine

Answer 60

- is itself a particular kind of drug and a catch-all term for a family of structurally similar derivatives - amphetamine was found when searching for an asthma treatment - stimulants - meth is a derivative that enters the brain more quickly, giving a bigger peak conc - crystal meth is they hydrochloride smokable form; the bigger the crystals, the more pure it is

Question 61

amphetamines and narcolepsy

Answer 61

amphetamines are a powerful stimulant, and can be used during the day to treat sleep/wakefulness disorders such as narcolepsy

Question 62

amphetamines: psychological effects

Answer 62

-same as cocaine; euphoria, energy, alertness, wakefulness -at high doses, the huge DA levels in basal ganglia can cause punding (repetitive meaningless behaviours), which is seen in PD patients if their medication drastically increases DA levels (note also that the basal ganglia is involved in voluntary motor control and action selection (which of several behaviours to engage)) -tied to unprovoked aggression and increased criminal and violent behaviours, esp in the intoxication stage (study says 43% of users engaged in violent behaviour and 27% attempted suicide) -grandiosity (ruler of the world/laws don't apply to me) -intense hallucinations and paranoia -delusions of parasitosis (bugs under skin) -symptoms worsen with prolonged use and may also include homicidal/suicidal thoughts coupled w violence + extreme anxiety

Question 63

amphetamines: physiological effects

Answer 63

- unlike coke, doesn't block Na channels so no local anesthesia - same type of sympathetic stim though; increase heart r8, insomnia, BP (which can lead to headache) - tremors, profuse sweating - meth mouth (profound tooth decay), scabs/meth mites (skin disorders from picking bc of parasitosis and general itching) - hyperthermia, renal and hepatic failure (renal and kidney failure as muscles breakdown/dissolve) - strokes, seizures

Question 64

amphetamines: source

Answer 64

-purely synthetic (not from plants) originally synthesized to expand airways (which they do) for asthma treatment, but had adverse side effects and stimulant properties -used for weight loss, depression, asthma, narcolepsy, ADHD (adderall is an amphetamine), even used to give to soldiers so they could fight 24 hrs straight

Question 65

Amphetamines: structure

Answer 65

- fairly similar to DA and NA, so they interact with those receptors - methamphetamine has an additional N-methyl group instead of an H, which makes it much more lipid soluble, so it can get into the brain faster

Question 66

why is meth the amphetamine of choice?

Answer 66

- the extra N-methyl group gets it into the brain faster, and makes it more difficult to metabolize, leading to a more profound euphoria - users perceive less peripheral effects and more CNS affects when compared to amphetamines - it has a crystalline hydrochloride form which is smokable; you would need to use amphetamine IV to get the same rush, which comes with its own problems (needles, disease, etc)

Question 67

methamphetamine synthesis

Answer 67

- maj entering canada comes from mexico - smaller labs use pseudoephedrine, a vasoconstrictor from cold remedies, as a starting point (it's an OH group away from meth, which is relatively easy to remove) - 1 kg product typically produces 5-7 kg dangerous waste (lithium from batteries, sodium, phosphorus from match heads, ammonia) - some amphetamines have a red tint from the match heads - new shake-n-bake method requires less starting material (in 2L pop bottle, shake then vent pressure); remaining waste is discarded and is a huge money drain bc they end up on highways and have to be disposed of, since they can cause explosions or flash fire of oxygen enters the bottle too quickly

Question 68

amphetamine use

Answer 68

- oral (pills), snorting powder, some users even inject - pattern of use similar to cocaine, but has longer lasting effects, so not administered quite as frequently - high doses produce rapid tolerant which seems to be due to rapid NT depletion

Question 69

meth vs cocaine

Answer 69

- in IV admin, [coke] in brain peaks in ~5 min and is essentially gone in 0.5 hours - meth peaks in 15-20, and is still present around 90 min - user reported high peaks around the same time (~5 min mark), but cocaine's drop off is much quicker

Question 70

amphetamine metabolism

Answer 70

-some of the metabolites produced in the liver are pharmocologically active CYP2D6 can: -add an OH to the ring (to make 4-hydroxyamphetamine) or the backbone (to make norephedrine) to make it more water soluble and easily excreted -remove meth's CH3 group to give amphetamine, or add an OH to get 4-hydroxymethamphetamie 4-HMA, 4-HA and NE are all stimulants in their own rights (NE mimics effects of adrenaline at adrenergic receptors, 4-HA (and 4-HMA?) stimulate NA release, inhibit MAO (which breaks down NA) and activate TAAR (trace amine associated receptor)) -10% of caucasians are CYP2D6 efficient; the lowered function of their enzymes increases the half life of the drug

Question 71

amphetamines: mechanism of action

Answer 71

- like coke, targets NT transporters to increase synaptic levels by blocking uptake of DA, NA, 5HT - unlike coke though, amphetamines don't have to rely on depolarization for NT release, and can induce it themselves; they're substrates for the transporter, which brings them into presyn nerve ending, and can then interact w VMAT (vesicular monoamine transporter) to enter NT storage vesicles, causing all of their contents to be released - this is bc amph molecules are smaller and more structurally similar to DA - they can also diffuse into the presyn terminal

Question 72

amphetamine in the synapse

Answer 72

- at high enough conc, amph will diffuse passively into the presyn terminal, and is also pumped in by mimicking DA at DAT - from there, it binds to VMAT on vesicles, inducing a state where NT starts to leak out and the presyn nerve ending fills with DA - amph also inhibs MAO (which breaks down DA), so the NT continues to accumulate - finally, the VMAT binding also sets off a pathway that phosphorylates DAT, which then begins to push DA out of the cell, and at a high enough conc, the DA will start passively leaking out too - the same effect is observed in NA and 5HT nerve endings - overall effect is that NT release is increased beyond basal/tonic levels

Question 73

TAAR (trace amine associated receptor)

Answer 73

- a G-coupled intracellular receptor that results in the activation of other enzymes (kinases) that add phosphate groups to various proteins - can be activated by amphetamines (and not coke) to result in the reversal of DAT action (via phosphorylation of the protein)

Question 74

amphetamines: tolerance

Answer 74

- tyrosine hydroxylase, an enzyme in the DA/NA synthesis pathway, is inhibited (nerve endings interpret the massive NT release induced by amph as a signal of too much production, so it shuts down their synthesis pathways) - this in turn leads to a decrease of the NT transporter, bc the presyn cell is so full already that it doesn't want to pick up anymore NT - acutely, a single high dose of amph results in decrease of DAT function - chronically, less cell-surface expression of DAT (transporters are internalized) - transporter effects have been linked to TAAR activation

Question 75

amphetamines and brain damage

Answer 75

- studies show it causes profound changes in brain structure, esp with meth - meth itself is directly toxic to neurons (kills them outright) - decrease in NT terminals, likely permanent, if not long lasting - damage seems to be due to production of ROS (there's just enough uninhibited MAO left to metabolize free DA, which produces so many ROS that the brain is overwhelmed) - this leads to damage of cell membranes, proteins, mitochondria - excessive Gle release causes a toxic environment that leads to neuronal cell death (excitotoxicity) - may also inhibit neurogenesis, as chronic meth use results in neuronal loss (esp in limbic system and cingulate cortex)

Question 76

amphetamine and PD

Answer 76

- chronic users start to show symptoms of PD such as die off of dopaminergic neurons and similarly reduced DA levels in some brain structures - seems that DA related structures are preferentially damaged - meth users show 76% increased risk of developing parkinsonism, while cocaine users show no change

Question 77

amphetamines and nicotinic receptors

Answer 77

- brain damage may be mediated by ampt binding to nicotinic Ach receptors - when bound w amph, receptors allow Ca to pass into the neuron - increased Ca levels may trigger a cascade of events that lead to increased ROS levels - nicotinc receptor blockers have also been shows to prevent ROS increase and prevents some neuronal damage in vitro

Question 78

amphetamines: withdrawal

Answer 78

- tyrosine hydroxylase in inhibited, so we've already used up a bunch of NT and have difficulty producing more - this reduced signaling can lead to anhedonia (inability to feel pleasure), extreme fatigue, mood volatility, vegetative state, intense craving - w/drawal symptoms usually v long lasting, often 12+ months, which links to the degree of brain damage/dysfunction caused by use - if the dopaminergic neurons were destroyed, it unlikely to see complete recovery

Question 79

meth mouth

Answer 79

- profound dental decay; teeth are literally rolling in someone's mouth, and usually requires complete extraction - may be from contaminants in meth, esp stuff coming from basement labs, which can be highly corrosive and eat away at enamel, letting bacteria get in there - lack of saliva may contribute - may also be due to vasoconstriction in gums caused by excess NA floating around in the vasculature; this leads to unhealthy gums as they just don't get enough O2

Question 80

ecstasy

Answer 80

- an amphetamine, even though it's often classed as a hallucinogen - also known as MDMA (3,4-methylenedioxymethamphetamine) - differs from meth by presence of methylenedioxy ring - modification of the aromatic ring in meth tends to reduce stimulant effects and produce more serotonergic effects - comes in a variety of shapes and colours specific to a manufacturer, which is often helpful for warning about dangerous batches - for most people, it's perfectly safe, but some can react very badly and die; there's no way to tell which beforehand

Question 81

MDMA precursor

Answer 81

- safrole: an aromatic oil obtained from distillation of root bark of sassafras trees, which grow across the US and in parts of east asia (fun fact: root beer and sarsaparillas originally made from this root) - due to its scarcity, some manufacturers use a different but similar, safrole-like molecule from another plant as a starting material, but this increased the risk of contamination with PMA, a much more toxic molecule found ubiquitously in bad batches that injure or kill dozens

Question 82

ecstasy: administration

Answer 82

- almost always taken in pill form, though sometimes snorted (molly is a powdered form) - this means the onset is typically slow, and blood plasma conc tends to peaks in 2-2.5 hours - depending on source, the actual MDMA content of a tablet may be 10-150 mg; most people feel effects between 75-125 mg and may stack (take multiple doses simultaneously) to get the desired effect (this is dangerous though, because you never know exactly how much you're putting in your system) - most users are occasional, although a small percentage (10% or less) use once per week-they may have trouble reducing use, but dependence seems to be more psychological than physical - often used alongside alcohol, cannabis, amphetamines, which may cause synergistic effects

Question 83

ecstasy: psychological effects

Answer 83

-high lasts 2-3 hours gives positive mood change, drop in defense mechanisms (you stop blaming others for your woes), increased empathy for others, openness, oneness with others (drugs that elicit these feelings are called entactogens) -increased self esteem -overall stimulant effects (still get DA and NA effects, tho less so than traditional amphs) -trialed for use in PTSD, to decrease anxiety and suffering, but unclear whether it was any better than therapy alone

Question 84

octopuses and MDMA

Answer 84

- octopuses are extremely asocial creatures - they have 5HT transporters than contain an MDMA binding site, v similar to what's seen in humans - MDMA exposure increases social interactions in normally solitary, asocial octopuses (the animal that received the drug spent more time interacting with another octopus as opposed to some cool new object)

Question 85

MDMA: mechanism of action

Answer 85

- high 5HT levels may lead to release of oxytocin, a hormone related to feelings of empathy and bonding; in both men and women using MDMA, we do see peaks in oxytocin levels, but they don't correlate with the peak of empathetic behaviours - also evidence that it boosts cortisol (a stress hormone and glucocorticoid, which released sugar to give a quick burst of energy, which may lead to temporary feeling of excitement or even happiness) - in fact, studies see 800% increase, and the timing of the peak correlated with peak of feelings of excitement and happiness - this also contributes to lack of fatigue and increased energy (via induced glucose release)

Question 86

MDMA: physiological effects

Answer 86

- as with other stimulants, rise in BP, heart r8 - hyperactivity - hyperthermia - jaw clenching and grinding of teeth (bruxism) due to excessive 5HT release, which we don't see in most other stimulants

Question 87

MDMA: mechanism of action

Answer 87

- blockade and reversal (competitive inhibition) of NT transporters (primarily 5HT, potency of block goes 5HT>NA>DA ; affinity of MDMA for 5HT transporter is 10x high than for NA) - also seems to bind TAAR, similar to amphetamines, to induce reversal of transporter action - hallucinogenic action comes from agonist interaction with 5HT2A receptor, which is where hallucinogens act (probably binds here at higher concs, but this isn't the primary binding site) - causes leak of 5HT from vesicles into nerve ending cytoplasm, as well as partial inhibition of MAO

Question 88

ecstasy targets

Answer 88

- animal models show modest DA increase (200-300%) in NAc, and huge increase in 5HT (1400%), esp in PFC and other areas of reward pathway - suggests ecstasy isn't as rewarding or therefore addictive; also see that while animals will self-administer, they won't work nearly as hard as they would for cocaine - at recreational doses, also bind adrenergic receptors (which may cause some cardiovascular effects, hyperthermia), histamine type 1 receptors (whose stimulation can lead to Ach release that results in excitation), and a7 containing nicotinic Ach receptors (where it acts as a partial agonist and may lead to increased NT release)

Question 89

ecstasy metabolism

Answer 89

- occurs mainly in the liver, by CYP2D6 (which also metabs amph); 80% is metabolized and the other 20% excreted unchanged - much more complicated than amph metab tho, and as many as 9 MDMA metabolites have been found to induce apoptosis (programmed cell death) in neurons (which may explain neuronal damage/death) - the conc of each of these metabolites will depend on an individual's CYP activity; some may therefore be more susceptible to production of harmful metabolites than others, which might explain the random pattern of toxicity

Question 90

MDMA tolerance

Answer 90

- just as with amphetamines, ecstasy results in decreased transporter activity via an internalization of the transporters at the neuronal membranes - this effect is primarily seen at the 5HT transporter, but to a lesser extent at DAT/NAT also

Question 91

MDMA damage

Answer 91

- adverse effects following ingestion can include depression (run out of 5HT for normal signaling), anxiety and hallucinations (via interactions at 5HT2AR), paranoia - also see lethargy, irritability, memory loss, panic - use can cause severe mini-withdrawal/rebound, likely due to the exhaustion of NT supply - can be lethal to a small percentage of the population

Question 92

serotonin syndrome

Answer 92

- most commonly seen in people who OD on antidepressants, and is brought about by high levels of 5HT - rapid onset of increased heart rate and BP, muscle rigidity (from overstimulation, esp in lower limbs), severe perspiration, delirium, diarrhea (so many 5HT receptors in the GI), hyperthermia, rhabdomyolysis (muscle breakdown; essentially the cardiovascular system goes into overdrive - the muscle breakdown releases myoglobin into the kidneys, where the Fe causes kidney damage and potentially failure - can also lead to convulsions, shock, death - super dangerous to take ecstasy alongside psychiatric drugs tat increase 5HT levels (ex. Prozac a SSRI)

Question 93

bath salts

Answer 93

family of designer stimulants, pop alternatives to traditional drugs like coke and MDMA - have rep for being dangerous drugs that can harm or kill the user, but as people get used to the potency of one type, accidental deaths decrease - they undergo no clinical testing, and are often used for years before people figure out their mechanism of action

Question 94

synthetic cathinones

Answer 94

- cathinone is a naturally occurring drug found in the plant khat, which is used in some parts of the world to make a stimulant tea; it was made illegal in several countries due to hospitalization of many users, but people got around it by slightly modifying it into a derivative - first drugs readily available online - mephedrone (a cathinone with two extra methyl groups (4-methylmethcathinone) was one of the first to gain traction and be sold legally - come as nondescript, white, crystalline substances of varying granularity, which were also easier to transport than rolled up khat leaves

Question 95

bath salts: structure

Answer 95

- cathinone and derivative are beta ketonated amphetamines; this means we can also make a methamph version, mephedrone, a 4 methylated methcathinone - we can also add a b-carbonyl to MDMA to give methylone, an MDMA analog whose effects are somewhere btw MDMA and amphetamines - turning the a-Me to an Et and switching the amine for a pyrrolidine ring give MDPV - ketone group makes it more polar and slower than amphetamine to cross the BBB

Question 96

the 3Ms

Answer 96

mephedrone, methylone, MDPV - all stimulants that produce excitation by increasing DA/NA lvls via transporter effects - lead to violence, homicidal combative behaviour, self-mutilation, excited delirium syndrome (ExDS; agitation and violent combativity, hyperthermia, tachypnea (rapid breathing), tachycardia (rapid heart beat), a period of not struggling followed by bradycradia, cardiac arrest and death; seems to be caused by increased NA lvls via blockade of its transporter) - stimulants similar to meth at low doses, but produce bizarre behaviours at high doses, possibly due to interaction with different receptors

Question 97

bath salts: routes of administration

Answer 97

- most common are snorting and ingestion - keying (dipping keys into powder and snorting) - parachuting/bombing (wrapping powder in cigarette paper and swallowing - often both methods are combined to obtain a quick onset with prolonged effects - MDPV is highly lipophylic and can produce effects with doses as low as 5mg, but tends to be short lived (it exits just as quickly as it enters)

Question 98

flakka

Answer 98

(also A-PVP, for a-pyrrolidinovalerophone) - derived from MDPV after it was made illegal; they just took of the methylene dioxy ring, but the tertiary N of pyrrolidine offsets the ketone, keeping them lipid soluble - super cheap (could get u fucked up for just $5) - if you take out one Me in the tail, you get A-PBP, and if you take out another, A-PPP - the shorter the hydrocarbon tail, the more potent it becomes at DAT and SERT

Question 99

bath salts: mechanism of action

Answer 99

- those w/o pyrrolidine ring more similarly mimic amph (bind to DA/5HT/NA transporters, are brought into the neuron by SERT (and possibly others) where they interact with TAAR to cause release of cytoplasmic stores of NT via reversal of transporters and inhibition of VMAT-dependent NT uptake into vesicles) - MDPV and pyrrolidine ring derivatives more closely mimic coke (they give potent transporter block, but are too bulky to be brought into the nerve ending, so there's no reversal of transporters

Question 100

cathinone medical issues

Answer 100

symptoms related to surge of DA, NA and 5HT in the periphery, and include: - hyperthermia (indicated as primary problem in several deaths and may prompt users to take off clothes, explaining the streaking behaviour) - this can lead to rhabdomyolysis (muscles breakdown and the Fe in myoglobin gets to the kidneys and causes all kinds of trouble) - tachycardia (elevated heart rate, sometimes followed by bradychardia, hypertension, chest pain - psychological effects like panic attacks, paranoia, suicidal thoughts, confusion, psychosis - hyponatremia (water intoxication to try to deal w extreme thirst triggered by hyperthermia causes water to flood cells, they swell and press against the skull and brainstem)

Question 101

dextromethorphan (DXM)

Answer 101

- called the poor person's PCP (keeping in mind PCP causes extreme violence, and also anesthetizes) - recreational use called robotripping (robitussin abuse) - at doses higher than therapeutic recommendations, see similar effects to ethanol or cannabis, but with more impairment of cognition, motor function, perception - ExDS (excited delirium) occurs at high doses and is often linked to deaths from use of DXM

Question 102

DXM: mechanism of action

Answer 102

- both DXM and its metabolites block NMDAR, the same sites blocked by PCP and ket, and is linked to psychosis and violence - CYP2D6 metabs DXM to dextorphan, whic as a higher affinity for NMDAR; psychoactive effects and dependence are linked to indv differences in CYP2D6 genes, with a decreased metabolism seeming to reduce the euphoric effect - chlorpheniramine, an antihistamine (decongestant) also found in the cough syrup, will interact with anything at a high dose, including muscarinic Ach-R on cardiac tissue, blocking their function and leading to tachycardia (elevated heart rate) and delirium

Question 103

DXM and the brain

Answer 103

- primary user group is teens, giving rise to concern abt brain development, as significant neuronal pruning takes place during adolescents, and interference can lead to greater than normal volumes and brain dysfunction, such as increased impulsivity - DXM users are more impulsive, and have increased volume in certain brain areas such as PFC and areas that integrate signals from the reward pathway (pallidum) - earlier onset showed increased thickness of some regions

Question 104

codeine, promethazine cough syrups

Answer 104

- choice drug of abuse in some american centres, heavily associated w some musicians/genres, athletes - heavy duty, prescription cough syrup - codeine: a painkiller converted to morphine in the brain/liver, used to treat aches and pains and inhibit coughing - promethazine: antihistamine used to inhibit vomiting and induce sleep - often mixed w soft drinks and jolly ranchers - often used in combination with drugs that may inhibit breathing, such as cannabis or xanax (a benzo), which may lead to synergy - becomes addictive and potentially lethal at high doses

Question 105

codeine cough syrups: mechanism of action

Answer 105

- unlike DXM cough syrups, overall sedative effect (bc codeine gets converted to morphine, which acts on mu-opiod receptors to cause sedation and lack of worry (not only does it block the pain signal, you don't even worry about it), but also inhibits respiration at high doses) - promethazine causes sedation by blocking central histamine type 1 receptors, but can also inhibit respiration at high doses, and has cardiovascular effects via the muscarinic Ach receptors that can cause sudden death

Question 106

opiod

Answer 106

- catch all term to describe natural and synthetic compounds that have properties similar to opium or morphine - opiate is a sub category referring to naturally occurring compounds such as opium from poppies - powerful analgesics that both interrupt pain signaling pathways and address the psychological aspects (anxiety, worry, unease) - referred to as narcotics, substances that cause sleep - can is one of the top 5 overprescribed countries, and top users per capita

Question 107

basic types of opioids

Answer 107

- natural opiates (opium from poppies, morphine, codeine) - semisynthetics (modified versions of naturally occurring chemicals found in poppies; heroin, oxycodone) - synthetics (entirely artificial chemicals that bind to opioid receptors; fentanyl)

Question 108

general effects of opioid abuse

Answer 108

- even at low doses, see some euphoria - at high doses, intense euphoria, drowsiness, mental clouding, sleepy sensation, "nodding" - IV admin give a rush as a large amt enters the brain rapidly ("body orgasm" followed by ~1 hr sedation) - analgesia may last 3-5 hours, and users don't feel any pain

Question 109

opioids: physiological effects

Answer 109

- constriction of pupils (except meperidine/Demerol) due to agonist effects on mu and kappa receptors in oculomotor nucleus; important diagnosis tool as most other causes of come (ex head trauma) produce pupillary dilation - nausea and vomiting via chemoreceptor trigger zone in the medulla; the body's way of trying to rid itself of something dangerous, but tolerance to this develops - lowering of BP via medulla and histamine effect (histamine dilates blood vessels, which drops BP, this vasodilation may lead to profuse seating) - the histamine release also constricts muscles in airways (bronchoconstriction) and causes itching by activating skin's sensory receptors

Question 110

opioids and respiratory depression

Answer 110

- the body's breathing reflex is triggered as it senses differences in the blood concentration of O2 and CO2 - even at therapeutic doses, opioids activate mu receptors that are associated with decrease in sensitivity to arterial pH, CO2 and O2 and inhibition of respiratory rhythm generation in the medulla - this causes the autonomic drive to breathe to be lost, which is problematic if the user in unconscious - most opioid deaths are due to asphyxiation

Question 111

opioids: physiological effects

Answer 111

- the GI had the 2nd highest conc of neurons in the body, and lots are acted on by opioids - this disrupts the coordination of the digestive system so food passes slowly (anti-diarrheal property, causing constipation that few people develop tolerance to) by activating those mu opioid receptors in the GI tract and CNS - this results in increased muscular tone but less motility - codeine suppresses the cough centre, though that mechanism is unclear

Question 112

harvesting opium

Answer 112

the main source is a particular strain of poppy, Papaver somniferum - when the petals fall out, you're left with the seed head; when scored, sap called opium oozes out - the seed head is only good for 10 days, so the process is traditionally labour intensive - workers scratch the seed pods in the evening so that white sap (called latex) oozes out overnight; it oxidizes into a brown gummy substance that is scraped off by hand and compressed into opiod

Question 113

what is opium?

Answer 113

- a mixture of narcotic and non-narcotic alkaloids - major narcotic components are morphine (10%-from greek god of sleep Morpheus) and codeine (0.5%-from greek for poppy head) - also contains other similar compounds that are inactive but used as starting points for semisynths - morphine is 10x as potent as raw opium - codeine is metab'd to morphine by CYP2D6; in the enzyme-deficient (~10% of caucasians), codeine produces no effect; ~2% of the population have multiple copies of the gene and their overactive metabolism means they can get morphine intoxication from codeine use - because this isn't normally known, it's why you don't give codeine cough syrup to kids, bc if they're overactive metabolizers, their small bodies can be easily overwhelmed

Question 114

heroin

Answer 114

- a semisynth; morphine with two acetyl groups - was designed with the goal of making a safer morphine, but instead they made an ultra-efficient delivery system, bc those acetyl groups make it 10x more lipid soluble than morphine so it can get into the brain faster and in higher concentrations - there, the acetyl groups are metabolically removed, converting it back into morphine, which can bind opioid receptors

Question 115

heroin: incomplete acetylation / deacetylation

Answer 115

- in the brain, one acetyl group at a time is quickly removed; sometimes you're left with intermediates - 6MAM binds to mu receptors and is psychoactive; it can only be produced from heroin and is used in legal cases to prove use - 3MAM is inactive - black tar heroin gets its dark colour from heroin mixed in with 3MAM and 6MAM formed in incomplete acetylation reaction - some people actually swear that 6MAM adds a different level to the high

Question 116

krokodil

Answer 116

semisynth opioid - found in countries where you can't buy inexpensive street drugs - requires codeine, red phosphorus (from match heads), gasoline, iodine and HCl to generate desomorphine (which is more potent that morphine because of increased lipophilicity (it's less one OH group) - the final product is an unfiltered suspension and is injected directly; the extra junk eats away at the user, leading to immediate damage to blood vessels, muscle, bones, and eventually abscesses, gangrene, large-scale necrosis (which gives crocodile-like skin texture) - "the drug that eats junkies"

Question 117

oxycodone

Answer 117

semisyth opioid - one of the most abused prescription analgesics - called percocet if mixed with acetaminophen and percodan if mixed with aspirin - oxycontin, a tablet that contained many times the amount of oxycodone in a regular tablet, was designed to address chronic pain by slowly releasing the active ingredient - instead, people would crush it up then snort it or dissolve and inject it - because of the abuse potential, it was reformulated to oxyneo; this pill contained polyethylene oxide, a hydrophilic polymer that formed a gummy gel when exposed to fluid

Question 118

synthetic opioids

Answer 118

eg. fentanyl - was developed to be a clinical surgical anesthetic - some abuse is from prescription patches and lollipops, but lots is accidental as it's popping up in cocaine, heroine, tablets sold as oxycodone or ecstasy - causes much greater respiratory depression than other opioids - highly lipophilic (100x more potent than morphine, 40-50x more than heroin)

Question 119

fentanyl derivatives

Answer 119

- modifications change lipophilicity, leading to increased affinity for mu receptors, increased ability to enter the brain and higher potency - carfentanil (change an H for ester group) is used as an elephant tranquilizer and is 100x more potent than fentanyl (just 20 micrograms can be fatal; 1kg contains 50 million fatal doses) - 3-methylfentanyl is 10-15 times more potent than fentanyl

Question 120

opioids: administration

Answer 120

- heroin and morphine are weak bases that become ionized in stomach acid and are therefore not well absorbed from GI; oral route has significant first pass metabolism so people are more likely to inject - some opioids such as oxyneo and methadone are designed to be taken orally and absorbed from the GI (in fact, methadone was actually designed to treat opioid abuse) - chasing the dragon (heat on tinfoil and inhale the fumes, or smoke with pipe) - this method specifically shows destruction of white matter (leukoencephalopathy), esp in the cerebellum; the spongiform destruction progresses from ataxia to apathy to akathisia (need to move) to a complete inability to speak/move - may be due to inhaling tin from the foil or a contaminant in the batch - for injection, heroin is mixed with water in a spoon, sometimes with lemon juice or smth else acidic to dissolve it, then you heat to dissolve and warm to body temp, "filter impurities and bacteria" through a cotton ball - heroin can also be snorted

Question 121

opioid injection sites

Answer 121

- "track marks" are scars and hyperpigmentation left by frequent injections, esp with dull reused needles - multiple injections result in collapse veins due to scarring (by the 6th use, you're just punching a hole in vessel and it has a much harder time repairing itself and untrained users can actually punch through to the other side; the scar tissue can cause it to pinch off, forcing blood to be rerouted through deeper, smaller veins) - fillers make crushed pills esp dangerous to vein health - frequent users eventually need to find new veins in which to inject which can be risky

Question 122

opioids: mechanism

Answer 122

- we have four distinc families of endogenous opioid-like substances that bind to specific receptors; enkephalins (delta), endorphines (mu), endomorphins (mu) and dynorphins (kappa) - each family is derived from different precursor proteins, and they all contain a tyrosine at the N-terminus - some parts of morphine mimic that tyrosine Ian amine group separated from a phenol ring by two carbons) in our endogenous opioids - all may function as neurotransmitters, neurohormones, or neuromodulators - involved in pain, placebo responses, acute stress responses and social attachment

Question 123

opioid receptors

Answer 123

-G protein coupled with 7 transmembrane domains; the opioid sits in the middle or the receptor at a binding pocket really accessible to the exterior space -presence of certain subunits changes the effects caused by binding mu subunit: responsible for euphoria, respiratory depression, analgesia, dependence; is relatively large, so the open binding pocket may allow for exchange of ligands delta: some analgesic effects kappa: dysphoria, some analgesic effects -when activated, they all inhibit adenylate cyclase, reducing cAMP levels, inhibit N-type voltage gated Ca channels (the decrease in Ca influx inhibs NT release), stimulate specific K channels to induce hyperpolarization as K flows out -overall, opioids tend to decrease neuronal excitability at the cellular level, which is why they're so good a interrupting pain signals -in the reward pathway, they increase DA release in NAc by inhibing GABA-induced inhibition

Question 124

opioids and DA release

Answer 124

- opioids give rise to surprisingly small changes in DA lvls in animal NAc, perhaps only 2-4x baseline, and some human scanning studies in addicts failed to detect any changes - many of these studies were performed on dependent individuals using methadone, an opioid agonist - more recent study suggests approx 400% increase in DA for opioid-naive humans in response to morphine

Question 125

opioids: physiological tolerance

Answer 125

- develops to analgesia, vomiting, euphoria, and respiratory depression, but see little change in constipation or pupil constriction - long term addicts can take 50x the normal analgesic dose of morphine w little respiratory depression; this is dangerous because they can lose that tolerance if they stop using for a period of time, and resuming at the same dose can be fatal

Question 126

biased agonism

Answer 126

- one agonist will preferentially active certain signaling pathways while another agonist for the same receptor will preferentially activate different pathways - this is because different agonists stabilize different receptor conformations, allowing them to interact with different proteins - activated receptors are phophorylated by kinases, which attracts b-arrestins to inhibit G-protein signaling and prevent prolonged activation of pathways; receptors bound to b-arrestins can be removed from the membrane or participate in other signaling pathways

Question 127

biased agonism at opioid receptors

Answer 127

- some opioids are biased towards g-protein effects, which is our traditional understanding of how opioids work and is related to a low degree of receptor phosphorylation; morphine favours this pathway - others are biased towards b-arrestin effects, which are more strongly associated with down-regulation, leading to side effects, tolerance, and dependence, and is related to a high degree of phosphorylation; fentanyl favours this pathway

Question 128

opioids: biased agonism and tolerance

Answer 128

- there are different forms of subtypes of b-arrestin that each trigger slightly different pathways - it can inhibit the G protein coupled pathway via GRK, a group of g-protein related kinases that add phosphate groups to agonist-bound receptors - b-arrestin is kinda the bad pathway; if you knock it out, see less tolerance and fewer side effects - also see that experimental drugs that favour g-protein path have fewer side effects and produce less tolerance in humans

Question 129

opioids: short vs long term exposure

Answer 129

GRK adds phosphates to the inside of the receptor, which attracts b-arrestins and causes the receptors to be removed from the membrane - with short term exposure, internalized receptors are recycled to the surface in minutes or hours - with long term exposure though, internalized receptors are destroyed; we also see an increase in adenylate cyclase because of chronic inhibition of existing adenylate cyclase, leading to an increase in cAMP and NMDA - this can lead to hyperalgesia, a hypersensitivity to pain - degree of degradation depends on the agonist; morphine doesn't cause much but fentanyl does

Question 130

opioid overdose

Answer 130

- triad of classic symptoms are coma, depressed respiration and pinpoint pupils - overdose death is most often from respiratory depression - synergist effect when combined with other drugs; one study showed that 85% of OD deaths also involved a depressant, 45% a benzo, and 36% alcohol

Question 131

treating opioid overdose

Answer 131

- use naloxone, a fast acting opioid antagonist; bind the receptor and inactivates it, but only lasts 20-40 minutes - can reverse opioid-induced respiratory depression, coma, and miosis, and prevent death if given w/in minutes of the OD - they do precipitate withdrawal symptoms if given to someone abusing opioids, and if other substances are present, the person will begin to exhibit symptoms of those drugs (ex. of co-admin with meth, will see meth symptoms) - has no significant effects on undrugged subjects

Question 132

opioids: withdrawal

Answer 132

- pretty unpleasant, but not lethal - drugs that are less potent (ex. methadone) will give milder but prolonged withdrawal symptoms; while heroin withdrawal is intense but short - symptoms can begin 4 or less hours after previous use, and start to feel quite ill 6-8 hours after a dose (users therefore need at least 3-4 injections per day just to stop feeling ill) - many symptoms caused by massive NA release; chronic opioid use suppresses firing of adrenergic neurons in locus coeruleus (LC), resulting in decreased NA release - tolerance develops in presence of chronic opiate exposure and firing rate/NA release normalize, but when opiate removed, LC becomes hyperactive, giving massive NA release and w/drawal symptoms (chills, sweating, cramps, emesis, diarrhea, muscle pain, runny nose/eyes)

Question 133

symptoms of opioid withdrawal

Answer 133

include craving, anxiety, yawning, perspiration, runny nose, tearing eyes, pupil dilation, goose bumps (which give rise to term quitting cold turkey), tremors, hot/cold flashes, aching bones/muscle, loss of appetite, insomnia, raised BP/temp/pulse/respiration, restlessness, nausea, fetal position, vomiting, diarrhea, weight loss, spont ejaculation and increased blood sugar

Question 134

how to combat NA effects of opioids (treating withdrawal)

Answer 134

- use clonidine and lofexidine to drastically decrease withdrawal symptoms in the detoxification stage - these are both non-opioid a-2-adrenoreceptor agonists that bind to the presyn receptors to prevent NA release in and from locus coeruleus (LC) - addressed many physical symptoms of withdrawal but not psychological issues or craving, and can lead to low BP; can be combined with methadone or buprenorphine

Question 135

opioid maintenance treatment: methadone

Answer 135

- methadone is a synthetic opiod meant to substitute for the opioid that was being used, as it has a relatively long half-life compared to heroin and is clean, pure and often free to the addict - has some mood-elevating effects but euphoria is minimal compared to heroin, and still causes constipation - taken orally to prevent needle-related health issues - also an NMDA Glu antagonist, so may eventually play a role in treating addiction

Question 136

opioid maintenance treatment: buprenorphrine

Answer 136

semisynth partial agonist with higher mu-affinity than morphine; blocks the effects of heroin but only produces mild effects itself - take orally 1-3 time per week (has half life of 37 hrs) - less activation so less risk of respiratory depression compared to methadone - causes constipation in some people - overall better safety profile than methadone (lower OD risk, lower rec use, better tolerability)

Question 137

opioid agonist/antagonist therapy

Answer 137

- treat with a 4:1 ratio of buprenorphine and naloxone (suboxone) - when taken sublingually (under the tongue), naloxone has no effect and partial agonist effects of buprenorphine are felt, but if the patient tries to inject, the naloxone will cause fairly immediate withdrawal effects, which prevents abuse - patient needs to be in active withdrawal, or the partial agonist can precipitate rapid withdrawal symptoms

Question 138

hallucinogen types

Answer 138

- indole hallucinogens (ex. LSD) - catechol hallucinogens (which include amphetamine derivatives, ex 2C drugs) - anticholinergics (ex. Mandrake) - deliriants (which are quite different as they remove you completely from reality, ex. PCP) - indoles and catechols are lumped under the umbrella term phastastica, for they psychoactive effects; they're capable of altering perceptions such that the person remains in communication with the present world and is therefore aware of both fantasy and reality simultaneously - >little physiological toxicity (mostly psychol effects), but some new synthetics can be deadly

Question 139

indole hallucinogens

Answer 139

LSD (a synthetic) psylocybin (from mushrooms) lysergic acid amide (LSAA, like a weaker LSD; from morning glory) bufotenin (from toads) -all have indole backbones, as does 5HT; due to structural similarity, they interact at the same 5HT receptors

Question 140

catechol hallucinogens

Answer 140

mescaline (peyote cactus) MDMA (ecstasy) 2C drugs -like DA and NA, have catechol backbone, but actually bind to 5HT receptors like indoles

Question 141

egot and ergot alkaloids

Answer 141

- ergot is a fungus that affects rye, and contains lysergic acid as well as other complex ergot alkaloids, some of which (such as ergotamine, which is used to treat migraines) are potent vasoconstrictors (cause cerebral blood vessels to constrict) - in the middle ages, outbreaks of ergotism arose from consuming these infected grains; one form produced severely constricted blood flow in limbs which made them feel like they were burning and led to gangrene and amputation, other forms lead to convulsions, delirium, hallucination

Question 142

LSD

Answer 142

- albert hoffman wanted to harness the vasconstrictive properties of ergot w/o all the other nasty side effects; used ergot alkaloids as starting point to synth new respiratory and circulatory stimulant and came up with LSD (lysergic acid diethylamide) - he deliberately administered 0.25 mg, which he though was a small dose but turned out to be 7x the normal dose, and had the first recorded LSD trip - was used to develop psychoses in animal models (to study things like schizophrenia), in general therapy to access the subconscious, potential therapy adjunct for alcoholics, may be useful in treating cluster (suicide/migraine) headaches and end-of-life anxiety

Question 143

are hallucinogens rewarding?

Answer 143

- animals generally cannot be trained to self-administer LSD or other hallucinogens - some may enjoy it, but more often, they will work harder to actually stop the administrations - aside from deliriants, there's no evidence that they're reinforcing, so reasons for taking are often very different than with other drugs of abuse

Question 144

hallucinogens: administration

Answer 144

mostly oral - LSD doses range from 10-300 micrograms - "hits" are made by dotting solution onto perforated blotting paper (you tear off a tab and let it extract onto your tongue) - also see gel tabs (LSD in gelatin windowpanes), microdots on candies or small pulls - often take at a dose that doesn't induce full blown hallucinations - also see microdosing: taking sub-threshold doses is supposed to increase creativity (studies show that parts of the brain that don't normally communicate with each other do under the influence of LSD< which may explain that)

Question 145

LSD: patterns of use

Answer 145

- doesn't seem to be habit forming and is v low on the abuse potential scale - generally no compulsive drive to take it; people just take it when they feel like taking it, when the opportunity arises, or in certain situations (ex. concerts) - experience depends on the environment (setting, which should be safe), and user's expectations or psychological mindset (set) - microdosers do take regularly, a number of times per week, but shows no measurable clinical effects (likely bc they don't induce 5HT release but just interact directly with a few specific 5HT receptors)

Question 146

LSD metabolism

Answer 146

- effects begin 30-90 min after ingestion, and only ~1% actually makes it to the brain due to extensive first pass metabolism in the liver - the drug's half life in the blood plasma is ~110 min, but effects can last much longer, 5-12 hours, because once bound to 5HT2AR, it sticks hard

Question 147

LSD (phantastica??) psychological effects

Answer 147

- visual hallucination - synesthesia (a mingling of senses, possibly due to communication btw parts of the brain that don't usually talk) - intense emotions, sometimes including aggression/violence - time distortion (seems to pass slowly) - distortion of sense of body and objects - mystical experience

Question 148

LSD: physiological effects

Answer 148

because it is sympathomimetric, it causes autonomic responses (increased BP, vasoconstriction, sweating, dilated pupils)

Question 149

LSD: mechanism of action

Answer 149

- LSD is weak partial agonist at central 5HT2A/B/C receptors; it's thought that the 2A is the primary target - 2A is found in high levels in the cortex, and their activation changes gene expression; even acutely, see changes in expression of genes linked to neuroplasticity and Glu signaling

Question 150

hallucinogen receptors interactions

Answer 150

``` why do some drugs that bind 5HT2A cause hallucinations while others don't? -the b-arrestin pathway is really important for drugs to have hallucinogenic effects, and no other class of drugs causes significant activation of the pathway the diethlyamide group of LSD is just the right size (egotamine is way too big, and lysergic acid is too small) to lock the receptor into a specific shape that results in activation of the b-arrestin pathway; which promotes internalization of g-protein coupled receptors and desensitizes those on the cell surface -normally tho, the g-protein in 5HT2A would activate phopholipase C which results in increased intracell. Ca lvls and activation of protein kinase C (PKC) -LSD also bind in such a way that a lid closes over it, decreasing its ability to leave the site and increasing binding time, which seems to contribute further to b-arrestin signaling ```

Question 151

LSD and 5HT2 receptors

Answer 151

- LSD increased release of Glu from glutamatergic neurons in cortex - 5HT2 recpetors may be presyn in this region, and their activation leads to increased Glu release, esp in the medial prefrontal cortex, which is important for perception and information processing, and is thought to be the interface btw cog and emo systems where emotions and meanings of things are experienced - Glu effects in the cortex thought to be a major contributor to hallucinogenic effects - in chronic animals studies, also see dramatic increase in GABA-AR lvls

Question 152

LSD: other targets

Answer 152

- 5HT2A receptors increase input into the locus coeruleus, which is part of the fear center and detects novelty in the environment; LSD enhances the novelty response and makes the ordinary seem novel; also why some user report "truly" seeing or hearing for the first time when using - LSD is also a high affinity d2 agonist in the striatum (which contains the NAc); it's known that over-stim of DA receptors can lead to hallucinations

Question 153

LSD harms

Answer 153

- no true reported deaths from LSD OD, and actually physiologically safe, but may cause users to do unsafe things under the influence - flashbacks called Hallucinogen Persisting Perception Disorder (sudden and unexpected return to the drugged state; usually only short lasting and visual) eventually lead to illegalization - may be that the drug is stored and slowly released from body fat, or that it occurs when taking other drugs or under stress; either way, it can occur for years after last taking the drug

Question 154

LSD tolerance

Answer 154

- develops quickly; if take repeatedly can see complete tolerance in 2-3 days as the 5HT2 receptors rapidly disappear - when use discontinued, receptors make their way back to the surface within a week and the sensitivity returns - induces cross-tolerance to mescaline and psylocybin - no withdrawal symptoms have ever been reported and there's no evidence to suggest it causes addiction

Question 155

psilocybin

Answer 155

- an indole hallucinogen and the active ingredient in magic mushroom - psychological and physical effects seem to be milder version of LSD - no case of lethal OD reported - psilocybin itself is naturally occurring and has some effects, but in gut/liver metabolism, the phosphate group is removed to give psilocin, which is also active - both are 5HT2AR agonists - non addictive and tolerance develops rapidly; also imparts cross tolerance to LSD - some people might have bad experiences or engage in dangerous behaviours, but there's no physiological risk - used as part of religious ceremonies in mexico

Question 156

DMT

Answer 156

dimethyltryptamine - an indole that is usually snorted, smoked, or injected, because gut MAO enzymes destroy it - regardless of route, effects are short lasting, usually less than 30 min - has a 5HT like backbone, and is an agonist at 5HT2A/C and 5HT1A receptors - hallucinogens usually steer 5HT2A towards the b-arrestin pathway, but no tolerance to DMT develops, so all receptors must stay at the surface - mammals naturally produce small amounts in the brain and levels seem to increase with stress - physiologically, the same effects as LSD or psilocybin (increased BP, vasoconstriction, sweating, but nothing dangerous) - psychological effects are intense, vivid hallucinations with some twists ("self-transforming machine elves", meeting beings of energy from other universes, ripping sound as you pass into the alt dimension)

Question 157

ayahuasca

Answer 157

- originally a concoction of plants brewed as tea by indigenous people of the Amazon (vine of the soul); uses two types of plants, those that contain DMT and those that contain MAO inhibitors called b-carbolines (this prevents DMT from being degraded by MAO in the gut so it can reach the brain) - brain scanning shows it activates parts of the brain involved in vision and memory, and that recalled images produce the same level of activation in those regions as natural images (suggesting your brain really thinks what it's seeing is real) - potential for use in treating withdrawal and other psychiatric issues as it allows you to work through/revisit/sort out troubling memories

Question 158

bufotenin

Answer 158

- indole found in the skin of specific toads and hallucinogenic plants, and also seems to be produced naturally by mammals; known as 5-hydroxy-DMT, and the addition of the OH group likely makes it less potent than DMT - schizophrenics have increased levels of its endogenous version in their urine - also marketed as an aphrodisiac - most users just get nausea, headache, or some adverse cardiovascular effects (toad toxins contain cardiac glycoside which can cause fatal heart rhythm to develop), though some report profound experience

Question 159

new psychoactive substances (NPS)

Answer 159

- Alexander Shulgin was interested in psychedelics and synthesized and test various batches of MDMA before synthesizing and testing dozens of other compounds (over 200 in fact, whose detailed synthesis instructions were published in PiKHAL, phenethylamines i have known and loved) - most famous is the 2C series of drugs, which saw a rise in use after publication of the book

Question 160

2C drugs

Answer 160

- all have a catechol-like backbone and are phenethylamines, also share some characteristics with amphetamines - 2C refers to the two carbons separating the amino group from the benzene ring - 4 position of the phenyl ring usually had a halogen, which increases hallucinogenic effects - act primarily at 5HT2 receptors, but probably with other types and transporters as well - produce a combination of hallucinogenic and stimulant effects - unlike may psychedelics, these can kill

Question 161

bromo-dragonFLY (benzodifuran)

Answer 161

- called dragonFLY because of its structural resemblance to the insect; can see it's actually a 2C drug with the oxygens closed into a ring structure - effects in humans can last 1-3 days - interacts primarily with 5HT2A receptors, but also 5HT1 - produces severe vasoconstriction via activation of a-adrenergic receptors (this can prevent blood flow to extremities and result in gangrene) - effects mimic LSD, but tend to be more intense and long lasting - several death related to taking this drugs, sometimes in conjunction with ket, and it has a very narrow window of safety for dose (symptoms presented by individuals who died include severe agitation, violence, seizures and hyperthermia (all of which are consistent with ExDS)

Question 162

NBOMe series

Answer 162

- other NPS - highly potent (more so than the 2C series) 5HT2A full agonists (as opposed to LSD, which is only partial); synthesized to characterize the receptor - psychoactive dose is the size of a grain of salt - derived from 2C series; a 2-methoxybenzyl group is added to the N of the 2C backbone, which gives them a high affinity for the receptor - can also be deadly with the same symptoms seen in @Cs (ExDS, etc)

Question 163

anticholinergics

Answer 163

- deliriants that give complete disconnect from reality; hallucinogenic effects but that people don't often remember - stops Ach from binding to muscarinic Ach receptors, dispurting a system that needs to be intact for parasympathetic NS functioning (rest and digest); leads to a general inhibition of secretory glands, lack of secretions and excretion - increase heart rate, dry mouth, lack of perspiration, constipation, difficulty urinating, rapid heartbeat and overheating (worsened by lack of perspiration), asphyxia - plus you're hallucinating madly the whole time - no euphoria and generally unpleasant

Question 164

plants containing anticholinergics

Answer 164

- three major subtypes are atropine, scopolamine, hyoscyamine - deadly nightshade/belladonna: when you drink it, your pupils dilate (which was considered a mark of beauty) due to the atropine; optometrists actually use atropine drops to dilate pupils - mandrake (which supposedly would only grow in the drippings of a hanged man) - hensbane (a weed, hens would pick at it and die) - Jimsonweed or Datural

Question 165

PCP (phenylcyclidine) and ketamine

Answer 165

- PCP and ket are both dissociative (instead of just knocking you out, you stay semi-conscious but unaware of the pain) anesthetics classified as synthetic deliriants - ket still used in animal and sometimes human surgeries - very different experience from true hallucinogenics because it completely removes you from reality - used by a small minority, but considered one of the most dangerous drugs of abuse - reliably linked to accidental deaths like drowning, suicides from severe depression, self-inflicted wounds and violence to yourself and anyone in your surroundings

Question 166

PCP and ket: administration

Answer 166

PCP -common to see people dip cigarettes in the freebase form and then smoking; you pay based on how much of the cig is dipped -some hard core users may snort or inject, but oral route not common -relatively long lasting effects (4-8 hours) Ket: -usually snorted or injected, but can also be smoked and swallowed -fairly short lasting effects (35-40 min)

Question 167

PCP and ket: behavioural effects

Answer 167

- very different than other hallucinogens because they're anesthetics - most people use ket at low doses to capture that anesthetic effect - low doses also produce relaxation, warmth, numbness, euphoria, distorted body image, feeling of floating, profound analgesia, near death experiences (and increased locomotion in animals) - seems to be somewhat rewarding, which is likely a DA-mediated effect - most PCP use is at high doses which produces psychosis (which may require several weeks of hospitalization), violent paranoia, sudden and extreme mood changes, stereotypical movements (repeated non-productive movements, indicative of excess DA), rigid body posture (catalepsy)

Question 168

PCP and ket: mechanism of action

Answer 168

- both affect a wide variety of NT systems, including Glu, NA, DA, Ach, 5HT - both block the ion channels that are part of NMDA Glu receptors (positive ions can't flow in and they become non-functional) - the only hallucinogens show to be reinforcing in animals (they'll work a bit for them, but not nearly as hard as for coke or heroin), but little evidence to show if it's via DA release at the NAc

Question 169

PCP and ket: damage

Answer 169

- most problems occur with PCP of a user enters a psychotic state; because of the anesthetic properties, they may not feel pain and can therefore perform "superhuman" feats (break their thumbs to get out of handcuffs, of break their teeth trying to bite through the metal) - ket is known to cause severe bladder damage called ketamine cystitis; it stops the cells that line the bladder from growing and they die, sloughing off until the bladder becomes completely necrotic and non-function and may need to be removed (symptoms are bloody urine, pain, incontinence)

Question 170

salvia divinorum

Answer 170

-a unique deliriant type of hallucinogen that comes from a plant -seems to be destroyed of swallowed but can be absorbed through the buccal membranes between the cheek and gum if chewed, or can also be powdered and smoked the active ingredient is salvinorin A, the only known non-alkaloid hallucinogen (doesn't contain nitrogen) and the only non-alkaloid to bind to opioid receptors -binds potently an selectively to kappa opioid receptors, which are known to induce dysphoria, and NOT 5HT2A receptors as other hallucinogens do -most report unpleasant effects (anxiety, fear, confusion)

Question 171

anabolic steroids

Answer 171

- the major performance-enhancing drugs, but historically used to help ppl with muscle wasting or malnourishment gain weight - based on testosterone, and includes this but mostly synthetic derivatives altered to improve muscle building - first used by soviet athletes and quickly spread to be prevalent in olympics, but now also considered a lifestyle drug (it rearranges fat distribution so you can more closely resemble societal ideals without working)

Question 172

steroids

Answer 172

- naturally occurring steroids are substances involved in the growth and maintenance of the body; testosterone, the male sex hormone, is good at stimulating muscle growth - have both androgenic effects (promotion of male sex characteristics (adam's apple, facial hair, deep voice)) and anabolic effects (underlying physiological effects that increase muscle mass, protein synthesis, Ca deposits in bone, redistribution of body fat) - users only want the anabolic effects, which are nearly impossible to isolate

Question 173

classes of anabolic steroids

Answer 173

type I: testosterone esters build on cholesterol backbones -slow down metabolism for longer effect; they're hydrolyzed in the body to free testosterone, which can also be aromatized into estrogens -easy to detect ex. is testosterone cypionate type II: 19-nor-testosterone derivatives -removal of the C19 methyl extends the half life and reduces some androgenic activity (only ~20% is converted to estrogen) ex. is nandrolone decanoate type III: 17a-alkyl derivatives -addition of Me group to carbon 17 (same as the OH) greatly reduces metabolism so the drug can be taken orally -also poorly converted to estrogen form, which made it desirable -addition of an extra ring can also increase the anabolic effect ex. is stanozolol

Question 174

steroid detection

Answer 174

- many steroids have been or are being used clinically, which makes them easily detected, but they've also been tested for safety - plain testosterone was abandoned early on, and as detection methods for type I/II/III steroids were developed, those too were abandoned in favour of designer steroids - these are modifications of existing steroids produced by illicit drug labs; they're hard to detect because their MW and structure will be unknown to testers, but humans start using them when they've undergone zero safety testing

Question 175

steroid mechanisms

Answer 175

- lipid soluble steroids cross the membrane and bind to the cytosolic androgen receptor (at high conc of androgens, they may bind to other receptors as well, eg estrogen receptors, to trigger other pathways) - the receptor-steroid complex enters the nucleus and binds specifically to DNA, altering transcription of genes - steroids also steer undifferentiated, developing stem cells towards becoming muscle cells as opposed to fat cells - unfortunately, the proteins made aren't just the ones involved in muscle, and there's a huge uncertainty in what unwanted/dangerous side effects may be precipitated by gene activation

Question 176

steroids: effects

Answer 176

- esp in bodybuilding, users may take 100-1000x times therapeutic lvls - females see masculinization (facial hair, balding, reduced breasts, loss of period) - hypogonadism (testicles stop making their own testosterone and basically atrophy; they shrivel up, their sperm count is decreased, and some men may become irreversibly infertile) - colateral damage from IV injection (HIV and other infections, etc) - gynecomastia (fat accumulates in the pecs so male breasts enlarge because of estrogen; countered with aromatase enzymes, which block conversion to estrogen) - severe acne

Question 177

steroids and acne

Answer 177

enlarged sebacious glands produce more sebum and increase ceel growth in hair follicles leading to increased increased population of Propionibacterium acnes (a bacteria) - acne fulminans is a severe type of acne which can even lead to arthritis and bone lesion; this might be the body participating in an immune inflammatory reaction to rid itself of the P. acne baterium - can leave permanent residueal scarring

Question 178

steroids and the liver

Answer 178

- the liver metabolizes steroids, leading to increased risk of liver tumours - see formation of benign cysts that fill with blood and other proteins; they grow and grow and if they rupture, the liver can fail or the abdomen will fill with blood because it's so heavily vascularized, and you can bleed out - unclear why the cysts form (maybe a gene transcription thing or a defense to combat the drug?)

Question 179

steroids: cardiovascular effects

Answer 179

- good evidence that they increase blood pressure, cholesterol, and heart abnormalities; overall cardiovascular age increases - many steroid abusers die from cardiac issues such as heart attack and stroke - typically want low LDL to high HDL ratio but steroids reverse this, leading to more fatty deposits in the blood vessels and liver - see increased aggregation of platelets and therefore formation of blood clots - even in absence of true inflammatory signals, immune cells with stick to vessel walls and invade surrounding tissue, initiating the inflammation - inhibition of NO synthesis (it's a vasodilator, so when lacking, vessels constrict and blood pressure increases) - steroids also increase the muscle mass of the heart, but not blood vessels needed to deliver it O2

Question 180

steroids and aggression

Answer 180

- "roid rage" proven in several studies - also see drug-induced psychosis (which looks like schizophrenia) and depression, and increased suicides in users (all of which are far more common effects in dependent users) - our naturally produced steroids bind to and modulate the activity of GABA-A, NMDA and 5HT receptors, which may be the link between steroids and mood issues - anterior hypothalamus seems to be the centre of aggression; stim of D2 receptors here results in violence/aggression in animal models, and mod doses of anabolic steroids in adolescence increase expression of those d2 receptors - exposure to steroids increases AVP effects (arginine vasopressin, which is excitatory and potentiates aggression) and decreases 5HT effects (inhibitory, decrease aggression)

Question 181

steroids and serotonin

Answer 181

- chronic exposure to nandrolone (a type II steroid) increases chronic aggression in mice - some seem to decrease the expression of receptors, some of which are selectively targeted - this is displayed as a decrease in the levels of 5HT receptor mRNA in several brain regions (PFC, hypothal, hippo, amyg)

Question 182

steroids and depression

Answer 182

- in study of steroid abusers, depression was one of the most commonly reported effects - seems to be linked to BNDF lvls, which we already know are decreased in those diagnosed with depression, and which is important for regeneration of hippocampal neurons - in rats, application of two different steroids led to a decrease in BDNF and correlated with depressed behaviour, both of which could be reversed with chlorimipramine (and antidepressant)

Question 183

do steroids actually increase muscle mass?

Answer 183

- depends on the dose, but even small changes give an advantage when you consider sports that are won or lost by seconds - when you overload muscles (give them some work to do), the leads to an increase in the number of myonuclei and of muscle fibre cross-sectional area - when steroids administered though, see those changes immediately, and they only go up with muscle overload

Question 184

should athletes who stop doping be allowed a second chance?

Answer 184

- evidence suggests acute anabolic steroid exposure can lead to long lasting increases in myonuclei that help muscles grow even in the absence of the drug - steroid mice start with more myonuclei and greater cross-sectional area of muscle fibre; after 3 weeks, the cross sectional areas match the sham rats', but the number of myonuclei stay essentially the same; when you introduce a program to make the muscles work, both show an increase in myonuclei, but the steroid mice had a significantly greater increase in cross-sectional area

Question 185

steroids and dependance

Answer 185

- meta-analysis indicates that 30% of steroid users are dependent; many report experiencing euphoria, which may come from increased b-endorphin levels that decrease GABA release to dopaminergic neurons in the VTA (less inhibition of DA firing) - also see increased firing rate of dopaminergic neurons in the mesolimbic pathway when steroids modulate GABA-A receptors