Nicotine

Galaxyshock

Nicotine is quite unique stimulant because it's a parasymphatomimetic.

I found some nicotine gum (2mg) in my closet that I bought like a year ago to experiment. It only made me anxious back then but I had high amounts of anxiety regardless.

Decided to give it a new try. Chewed one gum (2mg nicotine) a while ago with my morning coffee, feeling a bit more stimulated and "sharpened" than usual, could be placebo though. I think I'll try different doses in next few days and report back. Supposably theanine cancels out the pleasant-addictive qualities of it, I might try if black tea modifies the effects.

By binding to nicotinic acetylcholine receptors, nicotine increases the levels of several neurotransmitters – acting as a sort of "volume control". It is thought that increased levels of dopamine in the reward circuits of the brain are a major contributor to the apparent euphoria andrelaxation, and addiction caused by nicotine consumption. This release of dopamine induced by nicotine is thought to occur via a cholinergic–dopaminergic link, mediated by a neuropeptide, ghrelin, in the ventral tegmentum.[sup][30][/sup] Nicotine has a higher affinity for acetylcholine receptors in the brain than those in skeletal muscle, though at toxic doses it can induce contractions and respiratory paralysis.[sup][31][/sup] Nicotine's selectivity is thought to be due to a particular amino acid difference on these receptor subtypes.[sup][32]

Wikipedia[/sup]

Galaxyshock

Psychoactive effects

Nicotine's mood-altering effects are different by report: in particular it is both a stimulant and a relaxant.[sup][91][/sup] First causing a release of glucosefrom the liver and epinephrine (adrenaline) from the adrenal medulla, it causes stimulation. Users report feelings of relaxation, sharpness,calmness, and alertness.[sup][92][/sup] Like any stimulant, it may very rarely cause the often uncomfortable neuropsychiatric effect of akathisia. By reducing the appetite and raising the metabolism, some smokers may lose weight as a consequence.[sup][93][/sup][sup][94][/sup]When a cigarette is smoked, nicotine-rich blood passes from the lungs to the brain within seven seconds and immediately stimulates the release of many chemical messengers such as acetylcholine, norepinephrine, epinephrine, arginine vasopressin, serotonin, dopamine, andbeta-endorphin.[sup][95][/sup][sup][96][/sup] This release of neurotransmitters and hormones is responsible for most of nicotine's psychoactive effects. Nicotine appears to enhance concentration[sup][97][/sup] and memory due to the increase of acetylcholine. It also appears to enhance alertness due to the increases of acetylcholine and norepinephrine. Arousal is increased by the increase of norepinephrine. Pain is reduced by the increases ofacetylcholine and beta-endorphin. Anxiety is reduced by the increase of beta-endorphin. Nicotine also extends the duration of positive effects of dopamine[sup][98][/sup] and increases sensitivity in brain reward systems.[sup][71][/sup] Most cigarettes (in the smoke inhaled) contain 1 to 3 milligrams of nicotine.[sup][99][/sup]Research suggests that, when smokers wish to achieve a stimulating effect, they take short quick puffs, which produce a low level of blood nicotine.[sup][100][/sup] This stimulates nerve transmission. When they wish to relax, they take deep puffs, which produce a higher level of blood nicotine, which depresses the passage of nerve impulses, producing a mild sedative effect. At low doses, nicotine potently enhances the actions of norepinephrine and dopamine in the brain, causing a drug effect typical of those of psychostimulants. At higher doses, nicotine enhances the effect of serotonin and opiate activity, producing a calming, pain-killing effect. Nicotine is unique in comparison to most drugs, as its profile changes from stimulant to sedative/pain killer in increasing dosages and use, a phenomenon described by Paul Nesbitt in his doctoral dissertation[sup][101][/sup] and subsequently referred to as "Nesbitt's Paradox".[sup][102]

Wikipedia[/sup]

Neuro

Nicotine also extends the duration of positive effects of dopamine[sup][98][/sup] and increases sensitivity in brain reward systems

This makes nicotine very tempting. Increased sensitivity in the reward system could increase motivation, decrease apathy, anhedonia, and act like an antidepressant.

Nicotine is a major component of tobacco smoke contributing to the initiation and persistence of the harmful tobacco habit in human smokers. The reinforcing effects of nicotine likely arise through its ability to stimulate brain circuitry mediating the detection and experiencing of natural rewards. Nevertheless, remarkably little is known concerning the acute or long-lasting actions of nicotine on brain reward systems in vivo. Here, we investigated the effects of intravenously self-administered nicotine (0.03 mg/kg/infusion, free base) on the sensitivity of brain reward systems, reflected in alterations of intracranial self-stimulation (ICSS) thresholds in rats. Rats self-administered nicotine during 1 or 12 h daily sessions, with reward thresholds assessed 1 h before and 15 min after each self-administration session. Control rats remained nicotine naïve throughout. Nicotine self-administration increased the sensitivity of brain reward systems, detected by post-nicotine lowering of reward thresholds in 1 and 12 h rats. This nicotine-enhanced sensitivity of reward systems was reversed by the high-affinity nicotinic receptor antagonist dihydro-beta-erythroidine (DHbetaE; 3 mg/kg). Surprisingly, nicotine-induced excitation of reward systems persisted for at least 36 days after nicotine self-administration had ceased. Overall, these data demonstrate that rats can voluntarily consume quantities of nicotine sufficient to increase the sensitivity of brain reward systems, an action likely crucial in establishing and maintaining the nicotine habit. Moreover, self-administered nicotine resets the sensitivity of reward systems to a new increased level, thereby imprinting an indelible 'memory' of its effects in reward systems, an action that so far appears unique to nicotine among drugs of abuse.

http://www.ncbi.nlm.nih.gov/pubmed/16192981

Wow, does this mean nicotine permanently enhances the sensitivity of the reward system?

Galaxyshock

Yes it's interesting, in theory that should even reverse anhedonia to some extent but I'm not sure if it quite works like that. This needs further investigation.

Chewing three gums now (6mg nicotine), feeling a stimulation buzz, but also a bit uncomfortable and dizzy. I think it's the release of epinephrine. Kinda fun though. The gum tastes pretty bad, it's mint flavor but doesn't really cover it.

edit: the effect was short-lived, not really finding much of a nootropic benefit from nicotine so far.

Neuro

That's disappointing to hear that it was short-lived. Are you still taking it or have you dropped it completely?

Galaxyshock

I had only like 6 nicotine gums so my experiments were short. I think I will try it again at some point, maybe with patches or something. The stimulant effect was interesting but short, I'd like to make it more subtle but long lasting, I think a nicotine patch could work for that. When the stimulation hit me I actually felt like chasing rewards for a moment, so I think it really does something for the reward system. But I'm not sure if in a healthy way.

Neuro

I wonder if drugs that block and upregulate the nicotinic receptors also alter the reward system in a way similar to nicotine? Only drugs I know of are Bupropion and Memantine.

Galaxyshock

Hmm I think the nicotine receptor was a bit odd so that it actually upregulates in response to agonism, not sure of this though, better check. Agmatine I think is an antagonist.

Neuro

Oh, I've heard of that, but didn't realize it was a nictonic antagonist. It syngersies with a lot of antidepressants, including bupropion:

Agmatine has been found to work synergistically with numerous antidepressants such as bupropion (at 10-20mg/kg agmatine injections, dependent on imidazoline receptors), imipramine (0.01-50mg/kg, although a failure noted elsewhere, SSRIs (5-10mg/kg agmatine injections, dependent on imidazoline receptors), and oddly putrescine (a polyamine) is synergistic with agmatine on depressive symptoms (0.001mg/kg agmatine injection).

http://examine.com/supplements/Agmatine/#summary3-13

It's also supposed to be good for bodybuilding. Have you ever tried it?

Galaxyshock

I started experimenting with nicotine again. I find half a 2 mg gum, so 1 mg, to produce somewhat pleasant effect that is both stimulating and calming. 2 mg seemed too much as it caused some dizziness, sweating and nausea. Probably because I have no tolerance - those side effects are supposed to disappear in continuous use.

I find nicotine improves mood and focus, and decreases anhedonia a bit or at least I find things more interesting. Perhaps some decrease in inhibitions too. It's definitely effective stuff and works rapidly. The fruitmint flavored gum actually tastes fine.

Not sure how healthy it is to take though?

Neuro

Galaxyshock

I also experienced similar side effects when taking too much nicotine. Personally, I've only experimented with it maybe 2 times. I couldn't stand the icy hot burning in the throat. As for benefits, I did get some positive effects on mood, focus, and a bit on anhedonia.

I'm not sure if this is true, but I vaguely remember reading that both agonism and antagonism of the nicotinic acetylcholine receptors upregulates them. However, I don't think people report more benefits from chronic dosing so it's odd in this regard. Perhaps some downstream mechanism gets desensitized?

Regarding safety, it's difficult finding literature that only takes into account pure nicotine and is not confounded with smoking or even vaping. Apparently it has negative health effects according to this review:

Nicotine poses several health hazards. There is an increased risk of cardiovascular, respiratory, gastrointestinal disorders. There is decreased immune response and it also poses ill impacts on the reproductive health. It affects the cell proliferation, oxidative stress, apoptosis, DNA mutation by various mechanisms which leads to cancer. It also affects the tumor proliferation and metastasis and causes resistance to chemo and radio therapeutic agents.
https://www.ncbi.nlm.nih.gov/labs/pmc/articles/PMC4363846/

Honestly, I have no idea if it's safe or not. But the harmful effects listed in that article seem, I don't know, exaggerated? Like what is the mechanism of action behind the increased cardiovascular disorders? Is it the drug itself or is it through a downstream mechanism? If it's the latter, wouldn't simply increasing acetylcholine levels also have those negative effects?

Pretty much all those harmful effects come from smoking and I find it hard to believe nicotine alone can cause them.

Also, is nicotine gum expensive in your area? I got mine for free from a stop smoking sample even though I don't smoke lol. It's the brand name Nicorette and very expensive to take on a regular basis. It also tastes rather bad.

Galaxyshock

Some say nicotine isn't any more dangerous than caffeine. Some say it's dangerous and can cause cancer. The truth is probably somewhere in between?

Nicorette fruitmint xylitol costs about 9 euros for 30 gums. It's that flavor which actually tastes good.

Neuro

Galaxyshock Huh, 9 euros is about $13 CDN and I just saw that the price of 30 gums is around $14. So not too bad. But doesn't nicotine have a short duration of action? So you'll need to chew more than 1 piece of gum a day and it can get expensive this way.

Oh, I just saw that mine is 4 mg per piece. No wonder I was having dizziness and a burning throat lol. I haven't tried 1 mg yet. So maybe it isn't as expensive as I thought?

Anyway, the problem with the negative health claims is that there isn't any solid, undisputable proof that pure nicotine can cause cancer. At least as far as I know. Truthfully, I haven't done much research on the subject.

But from Wikipedia:

According to the International Agency for Research on Cancer, "nicotine is not generally considered to be a carcinogen."
https://en.wikipedia.org/wiki/Nicotine

How long do the beneficial effects last for you? Have you noticed any tolerance?

Galaxyshock

Yeah nicotine has short duration of action, like 2 hours. I find it's best used as occasional lift for mood and focus instead of chewing those gums all day. If you want the effects to last all day then perhaps try using a patch.

4 mg is indeed a big dose for someone who isn't taking nicotine for smoking cessation.

Some tolerance has formed, I now need a whole gum (2 mg) for the same effects and no longer experience those side effects I had initially.

Galaxyshock

I accidentally bought 4 mg Nicotine gums, meant to buy 2 mg gums. Packet of 210 gums for 40 euros. Oh well, that should last a long time lol.

I notice mild psychological addiction to nicotine, it's especially nice to chew it after my morning coffee. One side effect is that nicotine seems to cause some mild OCD-like behavior. I keep checking the same forums/websites for new content several times a day.

Neuro

Yeah, that should definitely last a long time. I wonder if they have sales on Nicotine gum so you can stock up from time-to-time?

Perhaps you chewed the nicotine gum while visiting those forums/sites? If so, why not try chewing the gum while doing something productive?

Also, it might be a good idea to chew the nicotine gum with regular gum to train your mind to associate the regular gum with nicotine. You might be able to induce a placebo effect this way.

Hehe, I probably shouldn't say this, but have you ever played Cookie Clicker? I think it should be able to at least partially satisfy that urge of getting new content. The progression in Cookie Clicker is quite lengthy to say the least, probably infinite.

Galaxyshock

Yeah 210 x 4 mg is basically 420 doses if I take half a gum. That equals to about 10 cents per dose I guess. I don't know if they have sales. It's medicinal product after all so not sure if it can be advertised the same way.

I indeed chewed nicotine gum when visiting the sites. Yeah I should try chewing the gum while doing for example some cleaning or dishes. That could "program" me to more productive behavior I guess? I think nicotine could also help as a pre-workout but I think it has negative effects on blood flow though?

Haven't played Cookie Clicker, maybe I'll try it out.

I have fasting blood tests this morning so I can't consume anything but water. I notice mild craving for nicotine but more I crave coffee lol. So I think nicotine addiction isn't much of a problem for me. I never got addicted to smoking either, it felty dirty and there wasn't pleasant effects to me. I only bought one pack I think to try it out of boredom.

Neuro

10 cents per dose is not bad. Right, it'd be odd to encourage people to buy nicotine with sales lol.

No idea if nicotine has negative effects on blood flow, but it should help as a pre-workout by improving focus. Maybe motivation too since it can improve mood.

Heh, you might get addicted to Cookie Clicker, but the good news is that it's mainly an idle game. You keep it open as a tab in your browser and do other things. Every few hours you can check up on it and buy more items that increase production.

I think I read that nicotine only becomes addictive when paired with an MAO-B inhibitor, or at least that's the reason why cigarettes are addictive. A compound found in cigarettes is presumably a reversal MAO-B inhibitor. I'm guessing it must have a long enough half-life to be able to raise dopamine levels but short enough to require redosing.

Galaxyshock

"Nicotine constricts blood vessels, including those in the skin and coronary blood vessels, but dilates blood vessels in skeletal muscle. Vasoconstriction of the skin results in reduced skin blood flow and reduced fingertip skin temperature."

So it actually improves blood flow to the muscles? I've been taking one 4 mg nicotine gum before lifting and haven't noticed any issues. It indeed helps with focus and also motivation as I find lifting more enjoyable.

Neuro

Hmm, if it does indeed increase blood flow to the muscles then it should be a good addition to your pre-workout. I think vasoconstriction occurs with caffeine and possibly other substances found in pre-workouts. So in effect it might be helping in that regard.

My cognition right now is not very good so I'm not sure if I'm misinterpreting this article but it seems one of the ways nicotine dilates arteries is through nitric oxide:

Cigarette smoking is a major risk factor for atherosclerosis, cerebral and coronary vascular diseases, hypertension, and diabetes mellitus. Chronic smoking impairs endothelial function by decreasing the formation of nitric oxide and increasing the degradation of nitric oxide via generation of oxygen free radicals. Nitric oxide liberated from efferent nitrergic nerves is also involved in vasodilatation, increased regional blood flow, and hypotension that are impaired through nitric oxide sequestering by smoking-induced factors. Influence of smoking on nitric oxide-induced blood flow regulation is not necessarily the same in all organs and tissues. However, human studies are limited mainly to the forearm blood flow measurement that assesses endothelial function under basal and stimulated conditions and also determination of penile tumescence and erection in response to endothelial and neuronal nitric oxide. Therefore, information about blood flow regulation in other organs, such as the brain and placenta, has been provided mainly from studies on experimental animals. Nicotine, a major constituent of cigarette smoke, acutely dilates cerebral arteries and arterioles through nitric oxide liberated from nitrergic neurons, but chronically interferes with endothelial function in various vasculatures, both being noted in studies on experimental animals. Cigarette smoke constituents other than nicotine also have some vascular actions. Not only active but also passive smoking is undoubtedly harmful for both the smokers themselves and their neighbors, who should bear in mind that they can face serious diseases in the future, which may result in lengthy hospitalization, and a shortened lifespan.
https://pubmed.ncbi.nlm.nih.gov/20868673/

Though, the article seems to be mainly focused on cigarette smoke so take it with caution.

I believe that nitric oxide is one of the targets of pre-workouts.

From a quick Google search, arginine is one such example:

l-Arginine is the substrate for vascular nitric oxide (NO) formation. Under normal physiological conditions, intracellular l-arginine levels far exceed the K(m) of NO synthase for l-arginine. However, endogenous NO formation is dependent on extracellular l-arginine concentrations, giving rise to the concept of the 'l-arginine paradox'.

Nitric oxide production in epithelial and endothelial cells is closely coupled to cellular l-arginine uptake, indicating that l-arginine transport mechanisms play a major role in the regulation of NO-dependent function.

Consistent with the data in endothelial and epithelial cells are functional data indicating that exogenous l-arginine can increase renal vascular and tubular NO bioavailability and thereby influence kidney perfusion, function and arterial pressure. The integrated effect of increased cellular l-arginine transport is to lower arterial pressure. Therefore, the use of l-arginine in the treatment of hypertension warrants investigation.

Low NO bioavailability is central to the development and maintenance of hypertension and to related endothelial dysfunction and target organ damage. We propose that l-arginine can interrupt the vicious cycle that initiates and maintains low NO in hypertension by increasing the formation of NO.
https://pubmed.ncbi.nlm.nih.gov/19076168/