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What happens to phenylethylamine when combined with selegiline?

Neuroprotection

Bluelighter
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Many of you have probably heard of the phenylethylamine (PEA) Selegiline combination. Given that PEA is rapidly and extensively metabolised by maoB when taken alown, Selegiline is used to inhibit this process allowing PEA TO ENTER THE BLOODSTREAM, reach the brain and once there to hang around long enough to have major psychoactive affects.
My main question is, why are the affects of the combination very short lived compared to amphetamine?
What is happening to the PEA, is it broken down via a another pathway or simply excreted unaltered?
 
Im very supprised to find no response to this thread. It doesn't sound like a complicated question, but then again I must admit I have tried looking online but found nothing. Please could anyone with the answer reply asap because this question has never left my mind.
 
Amphetamine is metabolized by 3 enzymes.
PEA is metabolized by like 10; among those, PEA has the highest affinity for MAO-B, but completely inhibiting that enzyme doesn't impinge upon its metabolism by other enzymes.

Also, ingested PEA is psychoactive even without an MAO-B inhibitor provided the dose is high enough (e.g., 0.5-2 grams), although the effect is shorter compared to ingesting PEA while on an MAO-B inhibitor.
 
I really wouldn't recommend this, there are reports of people developing severe addiction to this combination and it's not totally safe either. PEA, like tyramine, is a TAAR1 agonist and triggers the release of NE (and DA). If you know anything worthwhile about MAOIs you would see the potential for hypertensive crisis there. Keep in mind that L-methamphetamine and L-amphetamine are produced as metabolites of selegiline and act to increase blood pressure via the same mechanism of TAAR1 agonism and NE release, it's just overall a hugely unnecessary risk. PEA is also metabolised by many other enzymes than MAO-B so it's not a very long lived high anyway. Many people get away with this combination but you may not be so lucky. Do not even consider it without monitoring your blood pressure and having someone around who can take you to hospital/call an ambulance should things take a turn for the worst. Go slow and titrating your dose. You can always take more and it's better to have a few failed attempts than taking a massive dose and heading straight to hospital, or worse. I advise against this combination in any situation but unless you are already taking selegiline for other reasons, why not just take amphetamine, cocaine, etc? If you must try this however, stick to selective MAO-B inhibition (rasagiline would be even better than selegiline due to the lack of amphetamine metabolites). Do not use something unselective like Phenelzine or Tranylcypromine. There are reports of hypertensive crisis from combining small doses of PEA with these, most likely due to the lack of active MAO-A to catabolise the NE that is released.

Please be safe. MAOIs really aren't to be fucked with.
 
Hi
Thank you for your concern. I don't intend to take the PEA/selegyline combination myself and just like you would never encourage its use by others. Rather I just wondered where the PEA goes when it's main metabolic pathway is inhibited by selegiline. Thankfully you and the others in this thread have answered my question. I think MAOIs have fantastic potential on their own and I would love to try Selegyline for a few weeks to see if it would alleviate excessive tiredness and lack of motivation. Also you mentioned the risk of high blood pressure as a result of the above mentioned combination. For those that will continue to use the MAOI plus other drugs combination, would it be useful to keep a calcium channel blocker e.g. verapamil or isradapine, on hand to quickly reduce blood pressure in the event of a hypertensive crisis?
Thanks
 
Nifedipine, a calcium channel blocker, used to be the go to for MAOI related hypertensive crises but this is no longer recommended. I am unsure of the usefulness of other drugs with this mechanism of action. An α1 blocker (ie. prazosin) or α2 agonist (ie. clonidine) would be good to have on hand. Benzodiazepines would be very good too as they'll reduce the blood pressure both directly and indirectly by relieving the severe anxiety that naturally comes when one realises they're having a hypertensive crisis. Don't even think about using β-beta blockers for this type of situation though (ie. propranolol) that's for sure!

Some other things to keep in mind if one is having a hypertensive crisis (or approaching one) is to stay as calm as you can. Breathe slow and deep, do not eat or drink and do not lay down - stand and *lightly* pace if you feel you need to. You can also try gently warming yourself by applying extra clothing, heat packs or turning up the temperature of the room. Do not rapidly heat yourself though by having a hot shower, jumping in a jacuzzi or sitting in front of a fire/heater. Of course, don't rely on all of this and seek medical attention if and when things get dangerous.

I really hope you get the benefits you want from selegiline. I take tranylcypromine and it's been by far the best medication I have ever taken, especially for fatigue and motivational aspects of my depression. High dose moclobemide was second, so yay for MAOIs!
 
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I'm glad you benefit from MAOI treatment. I have read some good things about Tranylcypromine, mainly that it is non-selective but also has greater selectivity for MAOb enzyme. In addition, it may be somewhat neuroprotective. According to one study I read, tranylcypromine completely prevented Neuron death and damage caused by MPTP and Beta Amyloid peptide. I'm not sure what to make of this study, I think protection against MPTP toxicity would be an obvious affect as MAOb is required to activate MPTP 'which itself isn't toxic' into the highly neurotoxic MPP+ ion.
Do you mind expanding on your experience with tranylcypromine, Im just fascinated to find someone who is on this substance and hasn't demonised it.
What are the positive aspects of the drug?
Do the positives where off over time ie does tolerance develop?
What, if any sideaffects are there and how strong are they?
 
The neuroprotective aspect is pretty cool. I admittedly don't know much about that and should look into it more. I don't know how selective it is for the B isoform of MAO. I suspect it is not hugely clinically significant as it is typically characterised as unselective. Moclobemide is considered selective for MAO-A but actually inhibits MAO-B by 20-30% from memory so it would stand to reason any MAO-B selectivity in the case of Tranylcypromine is significantly less than this, considering how it is classified. Just my theory at least, hope it made sense (I had a lot of pregabalin last night). Tranylcypromine is also a dopamine releasing agent, just like amphetamine though less potent (1/10 I believe), in addition to its MAO inhibition.

Delving into the positive aspects for me, I have experienced an markedly increased tolerance for stress with things like work - when things get crazy at my job (phlebotomy) I am totally unfazed. I couldn't believe how strong this effect is as I am usually someone highly negatively affected mentally by stress. There is a noticeable stimulant effect, though mild, but unlike amphetamine or meth (in my opinion), there is a motivational push behind it. On day 2 I started working out and returned to eating vegan, meal prepping everyday. It's really allowing me to just push through life getting done what I need and want to do. It makes me feel as young, energetic and happy as I should for a 24 year old. The constant fatigue, lack of motivation and every other aspect of my depression and anxiety that has weighed me down for the last 10 years and really hindered my ability to move about the world in the way that I want has all lifted. The noticeable part of the stimulant effect, in the sense of a buzz, has gone away so there is some tolerance there I suppose, but I would still say it stimulates me in that I feel like I have a normal energy level that I can't remember having since being in my teens.

The main side effect for me is insomnia, some nights are really hard to fall asleep. I have always struggled with this to an extent though so I don't know how much of it really is the Tranylcypromine. I do get occasional low diastolic blood pressure which can make me feel a bit faint for a few seconds when I stand up, nothing like the severe orthostatic hypotension some speak of. Also I do experience a slight drop in my mood and energy (comparable to a caffeine crash in severity) in the afternoon if I take it all in the morning without a midday dose. I suspect this is due to the dopamine releasing effect wearing off throughout the day. All in all, side effects are pretty minimal and can be attenuated. The diet is also not as hard as it seems just looking at it. I still eat soy sauce, vegemite, protein powder, tempeh, miso soup, kimchi, sauerkraut, fake meats, all the beans and nuts I want, drink wine and kefir. Nothing has spiked my blood pressure. That being said everyone taking Tranylcypromine should exercise the caution with these foods as professionally advised. Everyone's tyramine sensitivity is different so people should experiment with tiny amounts first and monitor their blood pressure for the next 2 hours to see if there is a rise.

All in all, it's been great for me. It's the only antidepressant that has really attenuated my symptoms to the degree that I can focus on real life self improvement. The demonisation of the drug is unwarranted in my opinion. It's really not as dangerous or difficult to use as people make it out to be. Sure, I can't take MDMA or other stimulants anymore, but that is probably for the better. I can still at least use LSD and nitrous which are and always have been my main substances of choice. I experience severe worrying headaches when I smoke any amount of any cannabis now (and did while on high dose Moclobemide too). They are not officially contraindicated substances and I don't get a blood pressure rise from doing so, so I'm not sure I'm in any real danger when I get stoned, but the pain and anxiety (it's sent me to ER 3 times) it triggers are not worth the high for me anymore. As far as I know this is pretty unique and I've never heard of people having trouble with cannabis and MAOIs before so don't be scared off if you are thinking about MAOI therapy people! I would recommend it to anyone with depression and anxiety that has found little relief on the usual medication merrygo-round of SSRIs, SNRIs, NRIs, TCAs, TeCAs, SARIs, SMSs and so on, especially if they have significant lethargic and amotivational features.

If you have any more questions or anything you'd like me to expand on just ask :)
 
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There is a noticeable stimulant effect, though mild, but unlike amphetamine or meth (in my opinion), there is a motivational push behind it.

That may very well be due to a loss-of-function mutation in one of their biomolecular targets in dopamine neurons; their motivational effects are entirely mediated through mesolimbic dopamine release into the nucleus accumbens shell, which assigns motivational salience to stimuli and tasks/goals.

You get a hypertensive crisis, preceded by a banging headache in the back of your skull
I've used the transdermal selegiline patch in combination with immediate-release Adderall (40 mg + 20 mg three hours later) and phenethylamine (500 mg at a time, re-dosed based upon duration of effect) all at the same time. I didn't notice any particularly pronounced/strong or long-lasting effects of that combination relative to just taking amphetamine alone; but, similar to what I stated above, that could very well be due to the fact that I have a loss-of-function mutation in my MAO-B gene. If that were indeed the case, selegiline wouldn't have any particularly marked effects on PEA metabolism in my body. The lack of noticeable effects for me from that combination could also just be due to poor transdermal drug absorption though. :p
 
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Thanks for that informative reply :) It has made me consider tranylcypromine in a new light. If I have any more questions I will ask.
 
Hi, I have a few extra questions. It's okay if you can't answer them.
1) Is it safe to add a minute amount of 5HTP to a non selective MAOI supervised by a doctor? I know this can be dangerous but I have heard of doctors potentiating MAOI's with tiny doses of dextroamphetamine.
2) Have you ever taken nicotine with tranylcypromine? I only ask because I read a study that claimed that this medication turned nicotine from being a mild reward to an extremely rewarding substance in rats. So you think this has potential to treat severe tobacco dependence?
3) In one of your posts you mentioned the compound Prazosin. It seems interesting, do you know much about its sedative effects?
Thanks
 
It seems interesting, do you know much about its sedative effects?
It's an inverse agonist at alpha-1 adrenergic receptors; those receptors are expressed on dendrites that noradrenergic neurons synapse onto in the brain. Some of the noradrenergic pathways in the CNS are part of the ascending reticular activating system, which is mediates arousal. Prazosin inhibits the output neurons of the noradrenergic pathways in that system, in turn causing sedation.

If you're asking about what dose causes sedation, when I used it without a tolerance to it, 2 mg would always put me to sleep in less than 30 minutes.
 
I have not tried using 5-HTP since taking TCP. I'm sure it is safe up to a certain point and would start slow. I do consume nicotine everyday in the form of an oral spray and cigarettes every other day. Still struggling with the old smoking! I feel like TCP makes me crave nicotine more whereas Moclobemide made me crave it less, interestingly. Prazosin can be sedating to some people, in my experience it just drops my blood pressure way too low for my liking. I find Clonidine to be superior as a sedative - in fact it's my #1 for that purpose. Not sure how long tolerance develops to prazosin but I certainly imagine the potential for rebound hypertension exists as a withdrawal symptom.
 
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