Drinking alcohol after meals will reduce the peak blood values of ethanol regardless of nutrient composition, the delay is due to gastric absorption of alcohol being slower than duodenal absorption rates, and food delaying gastric emptying.
The difference between the fasted and the fed state, quantitatively, varies between person to person but is typically in the range of complete absorption in the fasted state and around 65-70% bioavailability in the fed state.
Ethanol reliably induces dopamine release in the nuclear accumbens (nAc) of animals including humans, an area of the brain associated with drugs of abuse when dopamine is spiked; serum ethanol levels correlate with nuclear accumbens ethanol level and restore dopamine deficits seen in alcohol withdrawal in rats.
This release of dopamine in the nAc appears to be dependent on an increase in extracellular taurine levels (which ethanol does itself and reducing taurine levels 40% in vivo using beta-alanine fails to abolish the dopamine spike) with both taurine and ethanol acting vicariously through glycine receptors. Actions of alcohol in increasing nAc dopamine is actually not localized either, and mediated in the Ventral Striatum (VTA) where ethanol acts as a co-agonist of nicotinic acetylcholine receptors (nAChRs) where it fails to act on these receptors in isolation but enhances other agonists, which plays a role in ethanol augmenting nicotine addiction (prototypical nAChR agonist). This is further evidenced by the nAc increase in dopamine being blocked by the nAChR antagonist mecamylamine. Futher studies noted that this effect is more localized to the anterior VTA rather than posterior and that ethanol in this area may cause an increase in acetylcholine which then induces activation of nAChR alongside ethanol acting as co-agonist, as depletion of acetylcholine also abolishes the nAc increase in dopamine and the increase in acetylcholine has been observed in vivo.
Ethanol can increase dopamine release in the Nuclear Accumbens (nAc) which is most likely due to acetylcholine acting on nAChR (its receptors) in the Ventral Striatum, where ethanol enhances signalling here and said signalling enhances dopamine release in the nAc
In humans, an increase in dopamine has also been observed in the Ventral Striatal (VTA) which correlates with subjective estimates of euphoria and stimulation.
There is a strong correlation between chronic ethanol consumption and cancers of the intestinal tract, although ethanol itself is not carcinogenic; causation may lie with the metabolite acetaldehyde. This includes oral cancers and has been hypothesized to be related to 25-68% of Upper gastrointesinal tract cancers. The risk appears to be dose dependent in both smokers and non-smokers
The link between stomach cancer is slightly more controversial as the risk ratios are much smaller. That being said, there seems to be a stronger correlation in those with genetically less active alcohol dehydrogenase activities (Asian populations). Colon cancer shares much of the same pathology, with there being a positive but minor increase in cancer rates that become more significant in those with less active alcohol dehydrogenase enzymes.
Alcohol appears to work synergistically with tobacco smoke in increasing the risk of various oral and oesophageal cancers/ Individuals who both drink (greater than 1.5 bottles of wine) and smoke (greater than 10 cigarettes daily) have approximately a 150-fold increased risk of oesophageal cancers. More moderate consumption of either parameter has negligible risk, but the combination increases risk by 12-19 fold, with women at higher risk.
In regards to cancers that may be furthered by mTOR and Phospholipase D signalling, alcohol has been hypothesized to reduce these cancer risks via suppression of phospholipase D induced mTOR activation and this mechanism has been demonstrated via Rapamycin (a selective mTOR antagonist).
Alcohol consumption may suppress protein synthesis slightly via inhibition of exercise-induced mTOR, which is partially dependent on phosphatidic acid (PA) from the cell membrane for complex stabilization. Ethanol is used as preferential substrate by the enzyme Phospholipase D and phosphatidylethanol is produced in lieu of phosphatidic acid, which causes an indirect suppression of mTOR. It appears to act more on the mTORc1 subcomponent, as higher concentrations are needed to inhibit the mTORc2 component. This mechanism of action has been demonstrated acutely with mouse myocytes and chronic alcoholism adversely affects mTOR and S6K1 phosphorylation.
In studies measuring liver protein kinetics, one study in humans pairing a meal of 632kcal with alcohol (71g) alcohol reduced the protein synthesis rate (assessed by fibrinogen and albumin) by about 30% over the 4 hours measured afterwards; this study also noted that leucine oxidation (a marker of muscle protein breakdown) was reduced by 24%; and later it was found that lower doses of alcohol (28g) found smaller hindering of protein synthesis (albumin) but not fibrinogen and also noted a blunting of leucine oxidation. A later study confirmed that alcohol, relative to saline, was able to suppress leucine oxidation at two varying doses and was more effective this apparent anti-catabolic action when no circulating nutrients were present.
Although these studies measuring liver protein synthesis may not be too valid for talking about muscle protein synthesis, the apparent reduction in leucine oxidation suggests that alcohol may have an anti-catabolic effect
In rats, injections of ethanol suppress muscle protein synthesis rates and this is mediated by both ethanol itself as well as acetylaldehyde.
When measured acutely, moderate doses of alcohol (0.83g/kg) in resistance trained men when consumed immediately after exercise (where nothing was eaten 3.5 hours before, food given during drinking ab libitum) failed to note any significant differences in testosterone levels for up to 300 minutes after exercise and another sports related study using 1g/kg after a simulated rugby match failed to note a decrease in testosterone despite noting a reduction in power output. A third study using that did not pair ethanol with exercise but used a low dose of 0.45g/kg on three separate pulses 90 minutes apart noted that although there was a trend (via the circadian rhythm) for testosterone to increase in this study that it did not differ between ethanol and water intake.
Conversely, a slightly lesser intake (0.5g/kg) has been shown to actually increase circulating testosterone from 13.6nmol/L to 16nmol/L (+17%) 2 hours after ingestion (which normalized by 4 hours), and inhibiting ethanol metabolism with 4-methylpyrazole (alcohol dehydrogenase inhibitor) by 37+/-3% and thus increasing the time ethanol could act abolished the increase in testosterone. This increase in testosterone after 0.5g/kg has also been noted in premenopausal women, and suggested to be act vicariously through the increased NADH/NAD+ ratio in the liver after these doses. Steroid metabolism and REDOX couplets interact in the liver, where an increased rate of 17β-HSD type 2 enzyme and its conversion of androstenedione to testosterone is observed due to the increased NADH relative to NAD+ observed after ethanol intake, and this also explains the reduction in androstenedione observed in studies where testosterone is increased and may help explain the increased levels of androstenedione in studies where testosterone is suppressed, where androstenedione may be increased by up to 54% (and dehydroepiandrosterone by 174%) 12 hours after large intakes of alcohol.
That being said, another study using 0.675g/kg noted that testosterone increased and was more sensitive to being increased by gonadotropin releasing hormone, suggesting multiple pathways may be at play. Red Wine may also confer additional benefits through its phenolic content, as Quercetin appears to be glucuronidated by the enzyme UGT2B17 in place of testosterone (sacrificial substrate) and may indirectly increase testosterone. This study was in vitro, however, and Quercetin has low bioavailability.
Low to moderate doses timed around exercise have twice failed to demonstrate an increase or decrease in testosterone levels, with the increase being from a favorable change in the testosterone:androstenedione ratio in the liver (mimicking the NADH:NAD+ ratio, which is increased during alcohol consumption). Not all studies not this increase though, and some just note no significant changes at all
One study lasting 3 weeks with daily consumption of 30-40g alcohol in non-smoking and social drinkers noted a 6.8% decrease in circulating testosterone levels in men (n=10), with no significant effect in women. At the end of the study, control had circulating testosterone measured at 16.4nmol/L while the alcohol group was measured at 15.3nmol/L.
These low doses, when taken over a prolonged period of time, might decrease testosterone; the degree of suppression is not likely to be practically relevant, however
Higher doses of alcohol, 1.5g/kg (average dose of 120g), have been demonstrated to suppress testosterone by 23% when measured between 10-16 hours after acute ingestion with no statistically significant difference between 3 and 9 hours of measurement. It appeared, in this study, that alcohol suppressed a rise of testosterone that occurred in the control group which may have been based on the circadian rhythm. Anothers study using an even higher dose (1.75g/kg over 3 hours) noted that over the next 48 hours that a small short-lived dip occurred at 4 hours, but a more statistically significant drop was seen at 12 hours which was mostly corrected by 24 hours (still significantly less than control) and completely normalized at 36 hours. By 12 hours, the overall reduction in testosterone was measured at 27% while the overall decrease in testosterone at 24 hours was 16%. Finally, a third study using 100-proof vodka at a dose of 2.4ml/kg bodyweight in 15 minutes (to spike blood alcohol concentration (BAC) up to 109+/-4.5mg/100mL, similar to the aforementioned 1.75g/kg study) noted suppressed testosterone levels correlating with the peak BAC, observed 84 minutes after ingestion. This time delay seen in some studies, when put in social context, correlate with the observed lower serum testosterone levels seen with hangovers. This study also noted that the changes in hormones were further from baseline in persons self-reporting a hangover, and less significant in persons without hangovers.
Finally, an intervention in which alcohol was supplied intravenously (via catheter) to keep a breath alcohol level of 50mg% noted that free testosterone was suppressed at this level of intake in young (23+/-1) men only, with young women experiencing an increase in testosterone and older (59+/-1) men and women having no significant influences. This correlates to a moderate dose of oral ethanol.
The mechanism of alcohol suppressing testosterone levels sub-chronically is via its actions as a testicular toxin, where it can reduce testosterone synthesis rates with no negative influence on the hypothalamus signals to the testes (if anything, a stimulatory effect occurs on the hypothalamus).
Around the 1.5g/kg or higher ethanol intake, it appears that a subsequent dose-dependent decreasing of testosterone occurs and appears to occur with some degree of time delay up to 10 hours after consumption. One study using shots of vodka did note this suppression of testosterone occurring within 90 minutes though
In alcohol abusers, the chronic high intake of alcohol appears to be negatively correlated with circulating testosterone at rest; with longer duration and higher intakes of alcohol leading to less testosterone.
Overall, alcohol can increase testosterone acutely through increasing a REDOX ratio in the liver (NADH:NAD+) but this spike is short lived; a reverse trend is seen at a later point when alcohol probably reaches the testicles to suppress testosterone synthesis, this is also short-lived for the most part. Chronic alcohol consumption at low doses is associated with a decrease in testosterone, but to a degree where it may not be practically relevant; alcoholism is associated with a larger and significant reduction in testosterone levels
A three week intervention in middle aged men and post-menopausal women drinking 30-40g of alcohol daily noted that in both genders there was no significant influence of this dose of alcohol on circulating estrogen levels.
Another study measuring serum levels during hangover (induced by 1.5g/kg ethanol the night prior) noted less circulating estrogen levels associated with hangover yet another study using similarily high levels of 1.75g/kg ethanol noted no significant influence of ethanol on estrogens for the next 48 hours measured, if anything a slight trend to decrease estrogens was noted.
Luteinizing Hormone, as well as follicle-stimulating hormone (FSH), do not appear to have neither their wave amplitude nor frequency affected when healthy male subjects ingest a large dose (1.5g/kg) of alcohol and are measured for the subsequent 20 hours, although one study using a slightly higher dose (1.75g/kg over 3 hours) noted that, at 24 hours post-ingestion, that a small but statistically significant increase occurred and somewhat normalized over the next 24 hours (was no longer significant, but still trended to being higher).
One hard-drinking study (2.4mL/kg 100-proof vodka in 15 minutes) noted that at peak BAC that the suppression of testosterone also existed alongside an increase in luteinizing hormone above baseline.
Growth hormone does not appear to have its pulse amplitude influenced by alcohol for up to 20 hours after ingestion of a large dose (1.5g/kg) of alcohol acutely in otherwise healthy men. However, pulse frequency during these 20 hours was slightly but significantly reduced (from 4.7+/-0.2 to 3.8+/-0.3).
After consumption of 1.75g/kg ethanol, a spike in cortisol is seen at 4 hours and persists for up to 24 hours after consumption, normalizing at 36 hours. At 4 hours, the largest spike of cortisol seen, it was measured to be 152% higher than control and this increaes in cortisol does not appear to correlate to the decrease in testosterone.
After administration of a large bolus of ethanol (1.75g/kg) a significant spike in prolactin to 412% of control value (586+/-185mU/l relative to 142+/-40mU/l) is seen by 4 hours, which according to this study is abolished by 12 hours and a slight suppression may occur at 24 hours (not seen at 36 nor 48 hours).
In a study where 14 healthy persons were given multiple pulses of 0.45g/kg ethanol (low dose, but numerous) either in the morning (7:30am, measured for 6 hours) or evening (5:30, measured for 14 hours) was able to decrease circulating leptin to variable degrees (measured at both 11.7% and 25.7% on different days)
Alcohol can adversely interact with acetaminophen (paracetamol) and potentially cause acute liver failure, although only high doses of acetaminophen have been associated with acute failure, any dose can theoretically cause a degree of damage.
The mechanism of action if via the enzyme CYP2E1, one of the two enzymes responsible for degradation of ethanol. After consumption of ethanol, CYP2E1 levels rise in order to accommodate more ethanol metabolism. When this occurs, acetaminophen can diverge from normal routes of metabolism and be metabolized through CYP2E1 to a greater extent. Only via CYP2E1 will acetaminophen form the metabolite NAPQI, which is highly hepatotoxic. Although acetominophen will always metabolize into some amount of NAPQI, the overall percentage of orally ingested acetominophen devoted to this pathway increases after CYP2E1 induction.
Taking Acetominophen (Tylenol) after heavy drinking is an absolutely horrible decision for your liver
Another inducer of CYP2E1 include the ketone body acetone whereas the other two ketone bodies (Acetoacetate and Beta-hydroxybutyrate) induce translation of CYP2E1 mRNA. This potentially means that alcohol in the state of ketosis or otherwise during starvation may be more hepatotoxic than during a fed state.
Taking Acetominophen after a night of drinking while on a ketosis diet (little to no dietary carbohydrates) or after spurious vomiting (can increase ketone bodies) is even worse than just taking acetominophen after drinking. Ketosis, ethanol, and acetominophen may be the trifecta of cirrhosis
Note that the enhanced liver damage from alcohol under ketosis may be related to 'getting smashed faster' than is commonly reported with ketosis, and the combination of keto and alcohol may not be as problematic if alcohol consumption is limited
Aspirin, when taken alongside alcohol, can increase blood alcohol levels by inhibiting gastric alcohol dehydrogenase. It does not seem to do this to hepatic alcohol dehydrogenase. These results, however, have been contested. Aspirin may also delay gastric emptying which would increase the time that ethanol is exposed to the remaining alcohol dehydrogenase enzymes and thus make partial inhibition a less critical point.
Conversely, ethanol can benefit Aspirin by increasing intestinal uptake of aspirin. This would result in more circulating levels of Aspirin at the same oral dose.
N-Acetylcysteine is a compound that is able to increase levels of the endogenous anti-oxidant Glutathione. Co-ingestion of NAC with alcohol can reduce some of the unwanted oxidant-mediated side-effects of alcohol and alcohol-potentiated acetaminophen toxicity can be attenuated with N-AcetylCysteine, although not completely.
There are a class of herbs that can accelerate regeneration of liver cells and reduce fatty liver deposits induced by a night of drinking, but have a critical catch to their benefits. These compounds must be consumed after drinking, either the next morning or prior to sleep; pre-loading these 'Night After' herbs can exacerbate (increase) damage from alcohol.
It is critical to consume these herbs after drinking, as consuming them before drinking confers the opposite effect and can be damaging
Withania Somnifera, more commonly known as Ashwagandha, appears to be able to be more effective at decreasing social anxiety when paired with alcohol; doses too low of either to be seen as effective appear to be highly effective when combined.
The anxiolytic (anxiety reducing) effects of Ashwagandha have also been shown to, in rats, reduce spikes in anxiety that are a result of cessation of chronic alcohol consumption; basically, possibly able to prevent anxiety from increasing as a result of quitting alcohol.
Agmatine is a neurotransmitter derived from L-Arginine that is currently thought to be highly involved in helping neuropathic pain and drug addiction, and appears to interact with a wide variety of drugs. It has both positive and negative interactions with alcohol dependent on context.
Alcohol's reduction of anxiety (anxiolysis) is prevented by inhibition of the arginine decarboxylase enzyme, suggesting that it works via agmatine. The increase in anxiety seen during alcohol withdrawal is also normalized with agmatine.
Additionally, the analgesic (pain killing) effects of alcohol appear to be augmented with agmatine injections in rats thought to be due to imidazoline receptor signalling and agmatine has been noted to block the alcohol induced hyperactivity seen in rats (male only) at 5-20mg/kg without affecting locomotion inherently. There does not appear to be any interaction between agmatine and conditioned place preference (CPP), thought to be indicative of no alterations on motivation/addiction.
On a negative side, agmatine is known to be a gastroprotective agent (aids in protecting parietal cells from stomach acid) but has counterintuitively enhanced ulcer formation from alcohol consumption in rats.
At this moment in time, agmatine appears to be useful for alcohol withdrawal. The usage of agmatine alongside alcohol might not be prudent as one study noted an enhancement of stomach ulceration, so timing of agmatine and alcohol consumption would be prudent