Why ARE ephedrine, cocaine, or amphetamines so much more potent than caffeine?

[cowardescent]

I haven't taken cocaine before but ADHD meds in America and ephedrine once from my bodybuilding friend. I have to say that it blows caffeine out of the water.

I might be suffering from sleep apnea/ADHD/narcolepsy so that's why caffeine doesn't work on me but compared to these two drugs, it's fucking shit. When I took Adderrall, I went 14 hours without feeling tired or taking a nap. This never happened on caffeine. I used to feel a bit energized and then fall asleep two/three hours later.

 

[ions]

Ephedrine and amphetamines are closely related to the neurotransmitter adrenaline, noradrenaline, dopamine, PEA. So they bind well to the adrenergic and serotonergic receptors in the brain. Cocaine is dissimilar in chemistry, but must still bind to these receptors as well as it's a local anasthetic leaving you feeling numb in the nose or mouth.

Caffeine is a purine, like the base pairs in DNA. If you're looking as to what it binds to to give a kick, check out erowid.org or psychonautwiki.org.

I write to molecules strictly from their structure and receptors they could bind to.

 

[G_Chem]

I think the problem with caffeine too is it’s so commonly used most people have a tolerance to it. It’s actually a pretty decent stimulant, and if I’m needing some real energy the combo of caffeine and Amphetamine beats either alone.

But as you said the one issue it does have is it’s often short duration. Caffeine is strange in that it’s effects and duration can vary wildly depending on a bunch of factors, it could last anywhere from 1-2hrs up to 6-7.

The other stimulants provide a much longer more steady duration.

Question too, is ephedrine worth a damn? Like is there any euphoria to it or pure stimulation? If comparing caffeine to ephedrine in the feel good department which is better?

-GC

 

[Nagelfar]

Ephedrine and amphetamines are closely related to the neurotransmitter adrenaline, noradrenaline, dopamine, PEA. So they bind well to the adrenergic and serotonergic receptors in the brain. Cocaine is dissimilar in chemistry, but must still bind to these receptors…

A major factor to distinguish is that the receptors which amphetamine binds to are the transporter site ligands and not the actual signalling receptor sites. The neurotransmitters themselves are still required in the synaptic cleft, it elicits their increase, like a third party, where the internal dopamine & serotonin is transported to where it needs to be to make a stimulant response.

Amphetamine is a substrate and cocaine is an external ligand at the same site (on DAT & SERT), but neither are receptor agonists. There are secondary effects from their structure, such as sigma with cocaine and TAAR with the amphetamine class, however.

 

[Skorpio]

Caffeine has kind of two main mechansims of action. Like ions said it is a purine, and it acts as an antagonist of the adenosine A2A receptors. These receptors normally mediate feelings of tiredness when activated, so blocking them causes wake fullness (this is different than stimulation, which comes from increased dopamine and norepinephrine signalling, which is the primary mechanism of action of all the drugs you listed.

Second caffeine is a phosphodiesterase inhibitor. When G alpha coupled g protein coupled receptors (such as beta adrenergic receptors or D1 dopamine receptors), the molecule adenosine mono phosphate (AMP) gets converted to cyclic adenosine mono phosphate(cAMP) by the enzyme adenylyl cyclase. cAMP acts as a second messenger sequential to (Gs) receptor activation, which activates many enzyme targets in the cell to exert it's effects. cAMP is broken down by phosphodiesterase, to terminate this signal (cells have loads of phosphodiesterases to break down a wave of cAMP, so that its timing is precise).

Caffeine inhibits phosphodiesterases that break down cAMP, so the effects of any Gs coupled receptor will be magnified. Some of the actual stimulation works through increasing the "gain" on existing norepinephrine and dopamine signaling.

 

[4meSM]

There are many reasons. For starters, they have different mechanisms.

As @G_Chem said, caffeine can actually be a fairly strong stimulant at the right dose, but daily or regular use renders it almost useless. I recently took caffeine again after a 1-2 months break and I got a very significant mood boost, increased motivation and even felt euphoric for a while.
We all have heard the phrase "I can't function without my morning coffee". People basically end up taking it multiple times a day just to prevent withdrawal, which basically consist of fatigue and difficulty concentrating (+ headaches in heavy users).

In addition to what has been said, amphetamine is a pretty strong TAAR-1 agonist (trace amine-associated receptor), this receptor is thought to play an important role in cognition.
It's involved in many important processes such as the modulation of the dopamine system (mood, reward circuits, etc... ), glutaminergic activity and even in the endocrine system (blood sugar regulation, hormone release...). Amphetamine is even a stronger agonist than methamphetamine. On the other hand, cocaine and ephedrine are very very weak TAAR-1 agonists, IIRC.
And of course caffeine or xanthines in general don't interact with this receptor since they have a very different structure.

 

[AlphaMethylPhenyl]

Basic pharmacodynamics questions

 

[Snafu in the Void]

caffeine is certainly the least potent, however for me I'm actually the most sensitive to caffeine. 100mg of caffeine in general will give me horrible anxiety, stomach ache, headache, irritability.

meanwhile I could snort plates of cocaine or amphetamines and never get any of those unpleasant symptoms.

Just my unique body chemistry

 

[plumbus-nine]

There were some more potent analogues of caffeine around, yet never had the desire to research them, sounds like jittery nightmare to me.. Ephedrine too is just different, not necessarily stronger as you can overdose on plain coffee too ... as has been said, these PEAs are different, working on different systems ... just that PEA itself gets immediately broken down by MAO-B so you need to add like an a-methyl in amph.

We have thingies like methylated aminorex derivates which blow amphs out of the water

 

[Gaffy]

Got it

 

[Angless]

Adenosine receptor antagonism (caffeine's primary mechanism of action) indirectly promotes neurotransmitter release (i.e., monoamines and acetylcholine), which endows caffeine with its stimulant effects. This indirect promotion as a result of antagonism is because adenosine's biological purpose serves as an inhibitory regulator of the central nervous system. Specifically, adenosine suppresses activity when the body believes it is in need of rest.

Amphetamine is more stimulating than caffeine for two reasons.

(1) Amphetamine is a potent full agonist of trace amine-associated receptor 1. TAAR1 is a neuromodulator that, upon interacting with amphetamine, dose-dependently increases the activity of the neurotransmitters dopamine and norepinephrine in the brain. It also triggers the release of several other hormones (e.g., epinephrine) and neurotransmitters (e.g., serotonin and histamine) as well as the synthesis of certain neuropeptides (i.e., cocaine and amphetamine regulated transcript (CART) peptides, which are the result of increased dopaminergic activity in the nucleus accumbens)

(2) Amphetamine inhibits vesicular monoamine transporter 2 (VMAT2). In the absence of amphetamine, VMAT2 will normally move monoamines (e.g., dopamine, histamine, serotonin, norepinephrine, etc.) from the intracellular fluid of a monoamine neuron into its synaptic vesicles, which store neurotransmitters for later release (via exocytosis) into the synaptic cleft. When amphetamine enters a neuron and interacts with VMAT2, the transporter reverses its direction of transport, thereby releasing stored monoamines inside synaptic vesicles back into the neuron's intracellular fluid.

By interacting with both VMAT2 and TAAR1, amphetamine releases neurotransmitters from synaptic vesicles (the effect from VMAT2) into the intracellular fluid where they subsequently exit the neuron through the membrane-bound, reversed monoamine transporters (the effect from TAAR1). In summary, these two biological targets are the reason behind why Amphetamine is as 'potent' as it is with regard to central nervous system activity, at least when compared to caffeine.

Also, for the people mentioning caffeine tolerance, it was my understanding that tolerance to the effects of caffeine occurs for caffeine-induced elevations in blood pressure and the subjective feelings of nervousness. But for positive effects such as feelings of alertness and wellbeing, sensitisation occurs instead and confers amplified effects with repeated use of the same dose.

It's also worth mentioning that amphetamine too causes sensitisation in low doses, like those used to treat ADHD, with respect to reward-related cognition (particularly incentive salience). This is probably one of the mechanisms that serves to improve establishment of routine and regular goal-driven behavior in people with ADHD who take amphetamine everyday, despite some physical and cognitive effects undergoing tolerance after dose titration (such as the anorectic effect, euphoria, noticeable increases in blood pressure/heart rate).

 

[Jabberwocky]

It's also worth mentioning that amphetamine too causes sensitisation in low doses, like those used to treat ADHD, with respect to reward-related cognition (particularly incentive salience). This is probably one of the mechanisms that serves to improve establishment of routine and regular goal-driven behavior in people with ADHD who take amphetamine everyday, despite some physical and cognitive effects undergoing tolerance after dose titration (such as the anorectic effect, euphoria, noticeable increases in blood pressure/heart rate).

I agree with this but it is a highly contentious topic online for the many many people who turn up here and on other forums saying “my ADHD meds don’t work anymore because I’ve become tolerant of them”. If your ADHD-related behavioural and cognitive performance declines over time after first improving following stimulant dose titration your problems may not be ADHD (which is pretty hard to diagnose conclusively because so much data is self-reported). That’s why psychiatrists are so resistant to increasing doses after a year or two of being on the stimulant. It shouldn’t be necessary if you really have ADHD. Though obviously there are exceptions to this.

 

[Angless]

That’s why psychiatrists are so resistant to increasing doses after a year or two of being on the stimulant. It shouldn’t be necessary if you really have ADHD. Though obviously there are exceptions to this.

Definitely. I only got bumped up from 30mg of Dexamphetamine a day to 40mg a few months ago, despite having taken my previous dose pretty much everyday for the last few years, because I had gained 20 or so kilograms over that period of time and my doctor and I agreed that if I could tolerate it, it'd be fine to have my dose adjusted back to 0.5mg/kg like it was when I first started. Obviously weight influences pharmacokinetics, given that amphetamine readily dissolves into several tissues throughout the body after ingestion in order to express TAAR1. Come to think of it, my circumstance is not really that different from the groups of kids who sometimes get their doses titrated up after puberty in order to accommodate for gains made in height and weight (the difference being that I'm an adult, not an adolescent. I say sometimes because it goes without saying that the most accurate way to titrate would be on a dosage-benefit basis, rather than just giving someone 0.3mg/kg-1mg/kg for the hell of it. Although there is some evidence that weight-based dosing in mind may be able to combat the rare phenomenon of medication suddenly ceasing maximum therapeutic efficacy at a later date, despite cognitive arousal and reward-related cognition not undergoing tolerance within the therapeutic range. But it'd obviously be a rare exception, given that the anorectic effect that these class of drugs confer tends to provide a resistance against large gains in weight once you're an adult (I only gained so much weight because I had an eating disorder before being treated for ADHD, and amphetamine increases my incentive salience towards eating so I don't feel like a garbage can).

Anyway, that's my oversharing done. I believe the only reason I was successful having a conversation about it with my doc, without them being reluctant to my request, was because of the privilege of having an educated background on these class of drugs, as well as my somewhat okay verbal fluency. In any event, there's a small minority of people who have genuine reasons to talk about their medication's effectiveness with their doctor way after titration, but I realize some are more succesful than others with that discussion topic because some people just can't verbalise the language as to why they believe a dose increase would confer improvements, and why at this very appointment they're choosing to bring it up, y'know? I guess that's the hurdle with treating a medicalised disorder.

 

[Jabberwocky]

Yes. On the one hand I think doctors are becoming more used to patients doing research before their visit and asking informed questions about drugs and other treatment. But on the other hand doctors can be pretty intellectually arrogant if they think they are dealing with someone formally ‘under-educated’ in their view. I find that thanks to my age, wearing a suit to appointments and dropping a few comments about my PhD into the early stages of the relationship puts me on a more or less equal footing with the doctor. I don’t often not get what I want. Though I’ve recently found that younger lady doctors are immune to my act and are very resistant to prescribing benzos and z-drugs under any circumstances. Whereas my psychiatrist dispenses them like candy.

 

[CFC]

I will accept people saying "caffeine isn't potent" only when I can be assured they aren't habitual consumers of caffeine. As someone who only ever drinks decaffeinated beverages because I find caffeine to be far too potent (especially in its direct effects on the heart), try taking a tolerance break for a few months. Then have that nice strong cuppa joe. See how it goes...

 

[telepathetic]

Caffeine gives me no energy, and anxiety. Amphetamines get me binging and recklessly destroying my life. Maybe ephedrine could be a nice middle tround? Wish I could get coca tea here

 

[plumbus-nine]

Caffeine works but only when you're either mentally exhausted or built a tolerance. Agreed. But ephedrine being a stronger adrenergic agonist than amphetamine will only have the negatives of both, ever tried x-MMC? The after effects are from an ephedrine like metabolite.

Indeed I feel there's a lack of good stimulants. Somehow I think 4-MAR might fit in (always curious about why nobody ever encounters this stuff). Or bromantane. Low dose pemoline derivates? Single digit range meth is good but only without tolerance and the duration should be like MPH.

 

[telepathetic]

Caffeine works but only when you're either mentally exhausted or built a tolerance. Agreed. But ephedrine being a stronger adrenergic agonist than amphetamine will only have the negatives of both, ever tried x-MMC? The after effects are from an ephedrine like metabolite.

Indeed I feel there's a lack of good stimulants. Somehow I think 4-MAR might fit in. Or bromantane. Low dose pemoline derivates?

Didn't get anything from bromantane. Phenylpiracetam slightly helps but not much. *dafinils I need too high of a dose and aide effects aren't worth it. I did way to much 4mmc as a kid, suffered miserably. Haven't tried an RC stim since then, last time i did it i was 17 I think.

Coca tea is actually perfect for me, or a nice quid.

Maybe I could find a low dose of lsd that doesn't unhinged me too much but gives some energy.

 

[Xorkoth]

Caffeine is certainly a nice drug. I remember back in college I got into drinking coffee, and I drank a lot of strong coffee. I made a big french press in the morning tp start by day, took caffeine pills, man, I remember just feelong so euphoric and motivated, those were some great times. Then I got pretty addicted to it, had to come off. Ever since then, I use caffeine most mornings because it helps me wake up fully quicker. But it's not real strong, because I'm so used to it. That happens with any drug, over time you develop substantial tolerance and even permanent tolerance.

Ephedrine is quite strong ,during that same period of time, roughly, that I described before, I would consume 50 or 60mg of ephedrine with 300+mg of caffeine, and I swear it was better than a lot of my amphetamine-related experiences in my later years. Ephedrine can be rather euphoric, but it also carries an intense adrenal load that is not too cool. Over time that became more pronounced than anything else so I don't use it anymore. Caffeine provides the little boost without really any side effects.

Obviously cocaine and amphetamines are much stronger... this is because instead of just hitting NE/adrenal areas, they have strong action at dopamine, too. Cocaine prevents the reuptake of dopamine so you end up with a ton of it floating around and that is a very pleasant experience. Caffeine doesn't do that.

For me, caffeine is the best choice for a morning wake-up/energy boost, since it's cheap, sustainable, and doesn't have me fiending for more, or fighting a nasty comedown, or dealing with an overactivated adrenal system. And the short duration leaves me easily able to relax and sleep at the end of the day. It almost doesn't feel like a drug to me now, just a little boost, and otherwise I'm unchanged. That's what I like about it, it's just sober, with an energy boost. The others, you're high, altered, etc.

Coca tea is actually perfect for me, or a nice quid.

I got a small sample of this ne and made a tea and remember it being really nice, preferable to caffeine but kinda similar in that it faded into the background nicely. But more of a boost and a little euphoria even. I believe it is illegal to import leaves though. Otherwise I'd be grabbing myself a solid chunk of them to replace my morning caffeine pill.

 

[JackARoe]

Ephedrine causes anxiety in me as it's main effect. I have a pound of it from years ago that sits. It is a good decongestant though but none of it's effects do I like. I tried using it as a study aid in school when my classmate didn't have ritalin for our projects. Ritalin seems like coffee for the mind for me. I like it at least in the occassional setting I have had it.

I am a coffee addict. Been having it every morning for 50 years. Trying to stop is probably impossible at this point. Anyone that thinks caffeine withdrawal is easy is probably not a coffee addict.

Years ago when poppy pods were abundant and all over I use to have my poppy tea, then take a bag or two of coca tea. put the coca leaves in my mouth with some baking soda as a quid and basically had an herbal speed ball and would clean the house. Very euphoric. While the coca tea is still around after 2010 poppy pods dried up. But for years they were cheap potent and easy to get.