Drugs mid #2

is caffeine safe in terms of therapeutic index

yes!

its therapeutic index is 1000, which is 100 cups of coffee

when was coffee first brewed?

probably around the 15th century, though some claim it may have been earlier

• Story about an Ethiopian goat herd that ate some coffee beans and were feeling energized

what 2 plants are coffee brewed from and where

Coffea arabica and C. robusta, in parts of Central and South

America, Africa, and Asia

other sources of caffeine besides coffee

There are many other sources of caffeine besides coffee, with caffeine levels varying dramatically across and within categories:

• Coffees

• Teas

• Soft Drinks

• Energy Drinks

• Chocolate

• Over-the-counter and prescription medications

  • There are other chemicals that are similar to caffeine in a lot of these common foods and drinks

How common is caffeine consumption?

Caffeine is consumed in one form or another by nearly everyone - 87% total

• About 90% of adults consume caffeine

• Children 2-5 yrs old: about 75% are consuming caffeine (probably due to soda)

the metabolism of caffine

Caffeine metabolism in the liver.

• The enzyme CYP1A2 is responsible for ~90% of caffeine metabolism:

what active caffeine metabolite is abundantly found in dark chocolate

Theobromine

“food of the gods”

what active metabolite is prevelantly found in tea

theophylline

“drink of the gods”

How is Paraxanthine different from theobromine & theophylline

is only exists as product of caffeine metabolism

how are caffine, paraxantine, theophylline and theobromine similar

they are all methylxanthines (stimulants) with similar chemical structures and therefore, similar mechanisms of action:

• paraxantine, theophylline and theobromine are metabolies that do the same thing to the brain as caffeine

what is most commonly associated with caffine use

most famously associated with its effects upon arousal, alertness and focus

How does caffeine work

• It mostly has to do with the neurotransmitter adenosine, which helps to regulate our sleep- wake cycles by promoting sleepiness. (caffeine gets in the way of this process)

• During daily activity, we use energy in the form of ATP, which eventually degrades to adenosine So, the longer we are awake and active, the more adenosine is produced....... and the sleepier we get.

• Thus, over the course of the day there is a gradual buildup of a neural signal that decreases arousal and increases sleepiness..ie. Promotes sleep:

Evidence for adenosine’s role:

its administration to rats decreases their performance on a simple vigilance task (“poke your nose here every time you see the light”)

• A peak in adenosine caused the rats to have less vigilance and less aroused

where does caffeine come in to effect adenosine

It acts as an adenosine receptor antagonist.

• Caffeine gets in the way of adenosine doing it's thing

• Our brain does not produce caffeine on it's own

• Specifically, caffeine’s blockage of adenosine receptors changes intracellular signaling (“cAMP signaling) in a way that alters regulation of our circadian clocks (sleep-wake cycles)

• caffeine blocks the effects of the sleep-promoting neurotransmitter adenosine via receptor antagonism. Adenosine may still build up, but it can’t do its thing.

indirect effects of caffeine on brain activity

it has multiple other indirect effects because adenosine often acts as modulator of other neurotransmitters, either influencing their release or their effects

Study about expresso before bedtime

A double expresso 3 hours before bedtime shifted (delayed) sleep-wake cycles by about 40 minutes

• they felt inclined to go to bed about 40mins later when they had espresso

Effects of coffee and napping on nighttime highway driving

Napping and coffee helped the participants

• When they looked at crossing over the line on the road, they found that only 20 people crossed the line who had coffee, 25 crossed for those who napped, and 73 crossed for those who had the placebo

rats and coffee

Rats with their adenosine receptors genetically knocked out (eliminated) “drink less coffee.” Good support for mechanism:

• They took the adenosine receptors out of the rats and they found that in these rats, they drank less coffee (this is because they do not need the coffee since they do not feel tired)

evidence for caffeines effect on cognitive performance

There’s substantial evidence that caffeine improves cognitive performance (and mood) in contexts with deficits, such as sleep deprivation or, Navy “hell week”

• Higher doses of caffeine lead to better cognitive performances in this study for navy hell week

• If you take these people out of this hell week situation the benefits probably would not be as dramatic as they are here

changing effects of caffeine on cognition throughout the day and when tired

Some studies find that caffeine’s effects on cognition are more substantial when subjects are tired, which fits with its proposed mechanism.

• Studies often show that caffeine is more beneficial later in the day

• At noon, caffeine does not have a huge benefit when compared to the placebo

• At night is when caffeine has the most benefits because you are at a higher cognitive deficit at

  this time

  • Importantly, most coffee consumption is not at night

Study: Caffeine dependent changes of sleep wake regulation: evidence for adaptation after repeated intake

They manipulated caffeine consumption of the participants - They could either have 3 placebo doses daily or 3 150mg doses of caffeine daily and for the last 3 days they are shifted to the withdrawal stage

• Measured cognition by using a vigilance task and also measured sleep

• The withdrawal group was sleepier and did worse on the PVT.

• The caffeine and placebo groups did similarly to each other.

• This means that caffeine's benefits are similar to nicotine, meaning it just pulls people back up

  to baseline

Study of long term cognitive effects of caffeine

Researchers tracked ~6500 women over 10 years, looking for an association between coffee intake and emergence of dementia / cognitive impairment.

• They found fewer cases of dementia and cognitive impairment (and higher cognitive function) among those who consumed more caffeine.

Effects of caffeine on athletic performance

The balance of research results indicate that low-moderate doses of caffeine (e.g., 200 mg) improve athletic performance, in terms of cycling and other exercises, such as running and resistance exercise

Key mechanism to caffeine

caffeine increases lipolysis – the release of fat into the blood so that it can be used for energy in place of other sources

Negative effects of caffeine

Though there are few negative side effects at low-moderate doses, higher doses can induce symptoms of caffeine intoxication or caffeinism

Caffeine intoxication - Diagnostic criteria

recent consumption of caffeine - typically in a dose well in excess of 250mg

5 or more of the following symptoms:

• restlessness

• nervousness

• excitement

• insomnia

• flushed face

• Diuresis

• Gastrointestinal disturbance

• Muscle Twitching

• Rambling flow of thought and speech

• tachycardia or cardiac arrhythmia

• periods of inexhaustibility

• Psychomotor agitation

can caffeine cause heart attacks?

CYP1A2 - enzyme influences how fast how strongly caffeine is metabolized

• A single nucleotide substitution in the CYP1A2 gene dramatically alters its activity and therefore caffeine metabolism, contributing to differences in coffee consumption (more metabolism = less circulating caffeine = more consumption)

• They found that heart attack risk went up with caffeine consumption in the slow metabolizers but not the fast metabolizers.

  • may be because caffeine sticks around longer in the slow metabolizers, having a larger stimulatory effect on cardiovascular function - The opposite is found in the fast metabolizers

  • These cardiovascular effects are due to differences in epinephrine and norepinephrine, which reach higher levels in the slow metabolizers.

caffeines overall longterm effects on health

Researchers recently examined the association between coffee drinking and mortality among ~half a million people

• They found that coffee consumption lowers overall mortality in a dose dependent manner

The best-studied benefit has been cardiovascular disease

• recent work suggests high consumption (>6 day) may increase CVD risk. Overall, there are benefits but the exact pattern is debated

effects other ingredients in coffee

Coffee contains a bunch of other beneficial ingredients, such that a lot of the good effects are similar with decaffeinated coffee

• caffeine: reduces liver fibrosis + May counter Parkinsons, Alzheimer’s + depression

• Diterpenes :fights certain carcinogens + antioxidant + anti-inflammatory + prevents blood cells needed for cancer to grow & spread

• Polyphenols: Reduces liver fibrosis + boosts DNA repair + reduce formation of red blood cells + boosts metabolic efficiency + lowers blood pressure + prevent cancer antioxidant

• Trigonelline: antioxidant + lowers blood sugar

Addiction potential of caffeine

Caffeine’s addiction potential is low… there is no “Caffeine Use Disorder” in the DSM.

• Yet over half of regular coffee drinkers experience withdrawal symptoms with abstinence, which peak after a day or two and typically last about a week (with lots of variation)

Dependence on caffeine: effect on dopamine activity

There is little if any effect on dopamine activity in the brain reward pathway

what kind of drug is alcohol

depressant

History of alcohol consumption

• Temperance movement: 1840s

• Prohibition: 1916-1919+

• 2023: new guidelines that recognize and treat high-risk drinking

• There has been a decline in years of Canadas alcohol consumption

how is alcohol made?

Yeast + Glucose = Ethanol

• Yeast converts sugars from fruits and other sources into ethanol.

  • Similar thing happens in nature when fruit rots

    • bears don’t get drunk off rotten fruit

• Note that this only works up to a percentage of about 15% alcohol,

  • after this the yeast dies, making distillation necessary for production of “hard liquors”

Alcohols proof

Alcohol’s proof is typically 2x its percent alcohol, originally because gunpowder burned in rum that was more than ~50% alcohol, but not less, which once provided “100 proof” with regard to alcohol taxation.

Route of administration of alcohol

• By far the most common route of administration is of course oral ingestion…but it’s not the only possibility

  • Butt chugging

  • Vaping of alcohol

  • Intravenous.

• With oral ingestion, alcohol is subject to first-pass metabolism in the liver

Alcohol absorption

• alcohol absorption occurs primarily within the small intestine.

  • Speed of absorption is roughly proportional to % alcohol.

  • Carbonation in drinks and an empty stomach each increase absorption, ultimately getting you drunker.

breakdown of Alcohol (metabolism) - main pathway

Ethanol - ADH - Acetaldehyde - ALDH - Acetate

• Acetaldehyde is toxic and associated with alcohol’s negative effects, likely including hangovers!

• The vast majority of alcohol metabolism occurs via this two-step pathway catalyzed by the enzymes alcohol dehydrogenase  and aldehyde dehydrogenase, which stays pretty consistent

  • Associated with African heritage: ADH that is really good at its job

breakdown of Alcohol (metabolism) - less used pathway

Ethanol - CYP2E1 - Acetaldehyde - NAD/NADH - Acetate

• This less used alternate pathway, catalyzed by CYP2E1, is called the microsomal ethanol oxidizing system (MEOS)

  • named after the cellular organelle where it happens, and becomes  increasingly prominent with chronic consumption

• Unlike the main metabolic pathway,  this does change in chronic drinkers, with more CYP2E1 leading to higher alcohol metabolism

  • Metabolic tolerance - think homeostasis

Comparison of the 2 alcohol metabolism pathways

Both of the variations lead to a relative build-up of acetaldehyde, associated with  negative/hangover effects

Genetic differences in ALDH and ADH

Can cause some well-known cultural differences in alcohol effects / experiences.

• ALDH: Associated with east Asian heritage: ALDH that doesn’t work very well

  • Japanese subjects with a less effective version of ALDH experience hangover symptoms with less alcohol leading to less alcohol use and less alcoholism in these groups

• African-American subjects with the efficient version of ADH, producing more acetaldehyde, were less likely to have family history of alcoholism

Blood Alcohol Content (BAC)

BAC varies with body weight (volume of blood) and % body fat

Distribution of alcohol

Distribution into the brain is easy: ethanol readily crosses the blood brain barrier because it is small and lipophilic.

Elimination:

occurs partly via sweat and breath, but mainly via urination

Does alcohol really have specific effects on urinary function

Yes! Makes you have to urinate more often

• In typical functioning, the pituitary gland  releases the hormone vasopressin, AKA anti-diuretic hormone (ADH), that regulates kidney function.

  • More vasopressin à more water re-absorption in the kidney à less urination.

• Alcohol decreases vasopressin release, leading to less re-absorption and more urination!

  • Also explains dehydration and decreased  urination, a withdrawal symptom.

Effects of alcohol

Alcohol has what is sometimes called a biphasic effect, with initial stimulant-like effects eventually giving way to dramatic depressant effects

• have a multitude of physical and mental effects that worsens BAC

How does ethanol act in brain to cause such a large array of effects

Mainly by affecting activity related to two different neurotransmitters

• GABA

• Glutamate

It likely has to do with how these lower doses affect activity in the prefrontal cortex, vitally important to inhibition, impulse control,  regulation of other systems, and much more.

Ethanols effect of GABA neurotransmitter

Ethanol acts as an indirect agonist at receptors for GABA, the brain’s most important and widespread inhibitory neurotransmitter.

• ethanol doesn’t bind and have its effect where the neurotransmitter  binds, but elsewhere on the receptor.

• Ethanol enhances the inhibitory effects of GABA (i.e., increases the typical effect), which is why it is an agonist here

• when ethanol is bound, GABA binding to its receptor has a larger inhibitory effect than it normally would!

• Indirect agonist effect

Ethanols effect of glutamate neurotransmitters

Ethanol acts as an indirect antagonist at receptors for glutamate, the brain’s most important and widespread excitatory neurotransmitter

• Ethanol makes glutamate signalling less efficient, leading to an overall  decrease in its excitatory effects in the brain.

• That is, ethanol lessens  glutamates excitatory effects.

The effects of ethanol on GABA & Glutamate together

1. enhances inhibitory GABA’s effect (inhibition up!)

2. lessens excitatory glutamate’s effect (excitation down!)

   • Both lead to overall inhibition of brain function this is why alcohol is a powerful depressant

effects of alcohol on prefrontal cortex

lower doses affect activity in the  prefrontal cortex, vitally important to inhibition, impulse control,  regulation of other systems, and much more.

• Different parts of the prefrontal cortex change in different ways and to different  degrees, but overall PFC activity is decreased by alcohol

  • What seems like a stimulatory effect of alcohol likely results from inhibition of PFC activity, in turn causing the loss of inhibitory control, impulse control, etc.

Brain effects of alcohol as dose increases

As ethanol amounts increase, the more obvious brain-wide depressive effects kick in

• Alcohol-induced memory blackout

Alcohol-induced memory blackout

“a transient amnesic event during which the  individual remains conscious in the environment but loses the capacity to form  long term episodic memories (i.e., memories for lived events and experiences)” 

• linked with overall amount consumed… as well as negative reports of the drinking experience.

• This is due to depression of activity in the hippocampus and other areas  involved in long-term memory… but also specifically affects the very neural mechanism by which long-term  memories are formed, long-term potentiation.

• Lower activity in the cerebellum to poor coordination and slurred speech

ethanols effects on long term potentiation

• LTP hinges on / start with activation of NMDA receptors, a type of glutamate receptor… and the exact type influenced by ethanol.

Study: The acute effect of alcohol on decision making in social drinkers 

all participants picked the experimental gamble more frequently when the probability of winning was high vs low, when the gains were large vs small and when the loses were small vs large

• alcohol group had impaired ability to factor in the magnitude of gains and the likelihood of winning when the losses were large

• deliberation time did not differ between the groups

• alcohol given acutely impairs risky decision making

Study: prolonged neurophysiological effects of cumulative wine drinking

In this study, researchers tested cognitive functioning  over a 7-hour period of wine consumption, with glasses  of wine at the start and at hours 2, 3, and 4.

• Found that the prefrontal cortex is centrally important to both  cognition and decision making.

Beer goggles:

Idea that when drunk people are more attractive

Beer goggles study about attractiveness: the effect of facial symmetry - does alcohol effect how attractive people are

• Intoxicated people were worse at distinguishing symmetrical from  asymmetrical faces, but didn’t rate faces as more attractive

• No evidence for the beer goggles here.

Study: Beer goggles or liquid courage?

Alcohol attractiveness perceptions and partner selection among men

alcohol did not effect traditional perception of physical attractiveness but did significantly enhance the likelihood that participants would choose to interact with most attractive targets

alcohol and adolescence

As with many drugs, adolescent use can interfere with brain development, especially with one of the last regions to mature, the prefrontal cortex.

study: brain development in heavy drinking adolescents

In controls, PFC volume stayed the same over adolescence, but in drinkers it decreased in volume

Study: association of heavy drinking with deviant fiber tract development in frontal brain systems in adolescents

Deficit in functional connectivity

Study: long term risk preference and suboptimal decision making following adolescent alcohol use

researchers exposed their “teenage” rats to alcohol (or none, as a control),  then tested adult behaviour using a task that let each rat choose between between large but uncertain rewards or small but certain rewards…

• The adult rats that had been teen drinkers chose the risky  option way more than the control rats, demonstrating long-  term effects of alcohol use.

Effects of chronic drinking

• “wet brain” - Wernicke-Korsakoff syndrome

• Chronic alcohol use is hard on the liver, with damage  progressing gradually towards cirrhosis.

• Characteristic shrinkage of the mammillary bodies of the hypothalamus largely contributes to memory problems - large-scale brain atrophy.

Wet brain

Wernicke-Korsakoff Syndrome - results from a malnourishment-associated  deficit in thiamine, a vitamin critical to glucose metabolism

• Its early form is Wernicke’s encephalopathy, which is somewhat reversible and characterized by bouts of  confusion, vision problems, and altered stance/gait

  • if unchecked, progresses to Korsakoff syndrome, much less reversible and characterized by anterograde amnesia,  hallucinations, and confabulation (someone pretends to know what's going on in a story)

effects of chronic drinking on liver

• Liver dysfunction influences how well it  metabolizes drugs

• Decline in metabolic activity associated with various CYP450 enzymes

are hangovers well understood

no

factors of hangover symptoms

Acetaldehyde, cause of acute toxic effects associated with alcohol, contributes to hangovers, but that isn’t the only contributor.

• Some research suggests oxidative stress and inflammation to be important drivers of hangover symptoms.

• Circulating levels of some immune factors are higher in hungover subjects compared to controls.

  • Inflammation an immune response, is known to cause things like nausea, vomiting and headache

how the effects of alcohol type change hangover severity

Hangover severity differs with alcohol type, based mainly on the presence of congeners, which are ingredients besides the ethanol itself.

• Congeners are highest in dark liquors

• Methanol, the most common congener, is metabolized to formaldehyde and formic acid, both of which are toxic.

  • Similar idea as acetaldehyde

why does Advil help decrease hangover

 it decreases inflammation

how to fix a hangover

research is mixed regarding  the importance of dehydration/electrolyte imbalances

Survival curve

•  represents time to next drink after hangover

  • Somewhat but not much, overall they concluded there to be a "Modest or inconsistent influence on the timing of subsequent alcohol use” after one experiences a hangover

Are low levels of alcohol consumption actually beneficial for us?

• Hormesis

• There has been evidence in support of beneficial effects of low-moderate alcohol  consumption mostly related to cardiovascular disease, diabetes, and similar

  • Recent evidence suggests otherwise

  • Results suggest the most beneficial number of drinks to have is 0

  • Minor benefits for heart disease - for 1 drink/day but outweighed by everything else

what is hormesis

The idea that a substance can be beneficial in small doses but toxic at larger doses.

• It’s been shown with many different  chemicals and, with ethanol, in some animal species

Alcohol use disorder - aspects of addiction

• alcohol is often taken in larger amounts or over a longer period of time then intended

• there is persistent desire or unsuccessful efforts to cut down or control alcohol use

• a great deal of time is spent in activities necessary to obtain alcohol, use alcohol or recover from its effects

• recurrent alcohol use resulting in a failure to fulfill major role obligations at work, school or home

• continued alcohol use despite having persistent or recurrent social or interpersonal problems caused or exacerbated by the effects of alcohol

• important social, occupational, or recreational activities are given up or reduced because of alcohol us

• recurrent alcohol use is continued despite knowledge of having persistence or recurrent physical or psychological problem them is likely to have been caused or exacerbated by alcohol

alcohol use disorder - aspects of dependence

• craving or string urge to use alcohol

• tolerance as defined by either of the following

  • a need for markedly increased amounts of alcohol to achieve intoxication or desired effect

  • a markedly diminished effect with continued use of the same amount of alcohol

• withdrawal as manifested by either of the following

  • the characteristic withdrawal syndrome for alcohol

  • alcohol is taken to relieve or avoid withdrawal symptoms

psychological dependence of alcohol

moderate

physical dependence of alcohol

intense

dependence study: alcohol promotes dopamine release in human nucleus accumbens

alcohol administration moderately increases dopamine release in areas of the reward pathway.

• Ethanol doesn’t directly affect dopamine activity, but does so second-hand by affecting neurotransmitters that regulate dopamine neurons.

Study: alcohol craving in heavy & occasional alcohol drinkers after cue exposure in virtual environment: the role of the sense of presence

• need notes

Study does acute bout of moderate exercise reduce alcohol cravings in university students

• need notes

study: preliminary findings in ablating the nucleus accumbens using stereotactic surgery for alleviating

• This study outlines an extreme treatment for alcoholism that demonstrates the importance of the brain’s reward pathway.

• need notes

The nucleus accumbens and alcoholism: a target for deep brain stimulation

• need notes

intense physical dependence of alcohol

Physical dependence is driven by particularly severe withdrawal symptoms… which can be fatal

• delirium tremens symptoms

delirium tremens symptoms

• tremors in hands

• chest pain

• rapid heartbeat

• high blood pressure

• fainting or passing out

• confusion, anxiety'

• hallucinations

• heavy sweating, pale skin

• fever

• nausea and vomiting

• sleepiness or fatigue

• sensitivity to light or sound

• severe dehydration

• hyperactivity or excitability

• seizures

Study: Analysis of factors determining survival of alcoholic withdrawal syndrome patients in general hospital

the factors determining survival after admission to general hospital for alcoholic withdrawal syndrome depends on the intensity of clinical manifestation

Unity, service, and recover triangle

alcoholics anonymous symbol

study: AA and 12 step facilitation treatments for AUD: a distillation of a 2020 Cochrane review for clinicians and policy makers

portion of findings: in most cases significantly better (or close to it) than other clinical approaches

pharmaceutical treatments for alcoholism - naltrexone

an opioid receptor antagonist that reduces cravings

pharmaceutical treatments for alcoholism - acamprosate (Campral)

has similar effects as ethanol in the brain and therefore serves to lessen withdrawal symptoms.

pharmaceutical treatments for alcoholism - Antabuse

Less prevalent than it once was– but interesting – is disulfiram

• changes metabolism in order to make drinking less pleasant to increase abstinence

what type of drug is an opioid

narcotic

raw opium

harvested from the seed pods of Papaver somniferum during a very specific seasonal time window.

earliest history of opium

Sumerians (modern day Iraq) allegedly called opium the “plant of joy” as early as 4000 BCE.

The Ebers Papyrus (~1500 BC), an Egyptian medical papyrus outlining herbal knowledge, also mentions opium.

history of opium - 16th century

the Swiss doctor Paracelsus created laudanum, a “tincture” consisting of opium extract dissolved in ethanol, which was soon promoted for a variety of different medical conditions.

• Laudanum is still available via prescription, typically for diarrhea or withdrawal symptoms in babies, though it’s tightly regulated and probably “on the way out”.

history of opium - 18th century

Smoking opium in opium dens rose to popularity, inspired partly by tobacco smoking’s popularity.

history of opium and China

it was introduced to China, leading to lots of opium addiction in China and money for England. So China banned opium.

• This lead to opium wars, which China lost.

  • By the end of this period roughly half of all Chinese men were addicted to opium.

Canadian opium act of 1908

an act of xenophobia?

2 naturally occurring opioid drugs that can be extracted via chemical processes:

Morphine (~10x stronger than opium itself) Named after Morpheus, the god of dreams

• First isolated from opium in 1803.

Codeine: Named after the Greek word for “poppy head”;

• first isolated in 1832

events influencing the rise of morphine

Invention of the Hypodermic syringe (1853)

Assorted wars (mid-1800s) (Dysentery/diarrhea and pain relief)

• Opium and morphine were used to treat nearly everything during this period, from tuberculosis and pneumonia to malaria, bedwetting, and nymphomania.