Jakeperson
Bluelighter
This is copied from another drug forum, shouldn't be too hard to find. I found it very interesting but I was wondering how much fact there was to it and how good this theory is.
Please excuse the SWIM
Please excuse the SWIM
Main Thesis: SWIM believes that taking Mirtazapine (brand name Remeron) has increased his sensitivity to stimulants, Dextroamphetamine in particular, and believes that a number of pharmacological actions, described below, facilitate this phenomenon.
Bear with SWIM folks, this gets a bit scientific and it is very long and detailed. First a preface and a few disclaimers. Don't mix drugs kids; especially with out researching and understanding their pharmacological properties, health effects and talking to your doctor about it; and especially if one suffers from mental illness - any reaction could happen. SWIM is not a doctor or medical professional. All of his knowledge has come from years of depression therapy, long talks with psychiatrists, professors, doctors, therapists, psychologists, the internet, the Drugs-Forum especially, and his own independent research into the outrageously complex way of how psychoactive drugs work (or dont work) in our brains.
SWIM currently takes 45mg Mirtazapine, 15mgs dexamphetamine and Klonopin (.5mg, used when needed). He generally does not take the Klonopin at the same time or the same day as the dexedrine. He likes to go all the way up and then back down, not at the same time please! He is legally prescribed all these medications. SWIM frequently supplements with multi-vitamins, omega 3 DHA/EPA acids (imperative for brain health), b complex (folic acid very important for brain health), vitamin C, inositol, magnesium and smokes marijuana a few times a week usually. SWIM sometimes supplements with 5-Hydroxytryptophan (the chemical precursor to serotonin) on days when his depression gets the best of him.
#8 and #9 and the text below it are the main points that explains SWIMs theory of mirtazapine/amphetamine potentiation if you SWIMMers out there don't feel like getting hit with a text wall today. Other knowledgeable SWIMmers PLEASE feel free to correct SWIM if he is wrong or off base on any of this... it's all theory in the end. Okay here we go!
The relatively new Anti-depressant known as "Mirtazapine" (marketed as Remeron in the US) of the NASSA anti-depressant class (Noradrenergic and Specific Seroternergic Antidepressant) blocks a number of serotonergic and adrenergic receptors who's overactivity is thought to play a role in anxiety and negative moods. I believe, through a complex system of actions, that this medication can noticeably potentiate Amphetamine, Dextroamphetamine, probably Methamphetamine (SWIM has never tried meth) and maybe even other stimulants/stimulant-like chemicals like Ritalin or Bupropion as well; as well as other anti-depressants.
Mirtazapine primarily targets most Serotonin receptors, some Adrenergic receptors and the Histamine 1 receptor; it may have a negligible affinity for the muscarinic acetylcholine receptors and the norepinephrine transporter as well. It acts as an antagonist at all these receptors; blocking and modulating their normal neurochemical actions.
To understand SWIMs following theories, we must firstly establish the basic understanding of the disinhibitory and inhibitory roles that those adrenergic and serotonergic receptors have on their own endogenous ligands (adrenaline/serotonin) and their effects on other neurotransmitter systems when they are agonized and antagonized.
Thanks to the incredibly flawed "chemical imbalance" theory espoused by many doctors, many individuals undergoing psychiatric therapy seem to think "the more serotonin I have going on in my brain the better", and thats how SSRIs got so popular obviously. However, what we know now is that increasing serotonin binding at all of those sites isn't necessarily good, and can produce wildly different effects in different people. Pulling every 5-HT receptor in the same upward direction is not actually the best way to treat mental illnesses; and in SWIMs estimation, could make some of them worse - especially anxiety as its prevalence and intensity seem effected by almost every major neurotransmitter, and it can be reduced and increased through dozens of neurochemical regulations. When activated, especially all at once, many serotonin receptors can produce anxiety, dysphoria and other problems. This is why Mirtazapine and its NASSA analogues work with such high efficacy vs. SSRIs and SNRIs. In layman's terms, NASSAs block action at serotonin receptors indicated in dark moods/anxiety, and allow increased firing at the ones that improve mood and anxiety (mainly 5-HT1a) rather than blanketing all of them at once like SSRIs and SNRIs do.
Now for some even meatier science!
1. 5-HT1a is not blocked by mirtazapine. (this is very important)
- 5-HT1a agonism improves anxiety and depression; agonizing many other 5-HT receptors tends to do the opposite and create anxiety/mood instability; like when hallucinogens activate 5-HT2a, producing hallucinations, perceptual alterations, euphoria etc, but also commonly producing anxiety, paranoia and radical emotional shifts.
1a. SSRIs/SNRIs increases synaptic serotonin so it can bind to the 5-HT1a receptor more often; but they don't stop it from binding to the other 5-HT receptors as well. As I mentioned above, this is partly why SSRIs and SNRIs have so many negative side effects, from agonizing 5-HT receptors that don't necessarily produce positive effects through activation.
1b. 5-HT1a activation also causes a cascade release of quite a few hormones like oxytocin(facilitates love and bonding) and even beta endorphin(reduces pain, improves mood). B endorphin could contribute to anti-depressant/anxiolitic and the possible analgesic effects of some AD's indicated in conditions like fibromylagia. Increased oxytocin likely contributes to reduced aggression, pro-social behavior and tranquility. This is just one example of a scarcely understood, minor anti-depressive quality many antidepressants exhibit.
2. 5-HT2a is also blocked by Mirtazapine and plays an anti-psychotic role and reduces anxiety, paranoia, delusions and the apparent intensity of hallucinogens and other serotonergic drugs like MDMA (SWIM has experienced this with respect to Psilocybin, needing to ingest up to 5 grams just to have an unremarkbly short and boring trip, thanks a lot 5-HT2a antagonism!). This 5-HT2a blocking makes remeron a theoretically successful adjunct for Schizoid, dissociative and/or perceptual disorders.
3. 5-HT2b, 5-HT2c and 5-HT7 receptors are normally activated by serotonin and produce anxiety and regulate mood; Mirtazapine blocks these as well.
4. 5-HT3 receptor blocking by Mirtazapine reduces nausea and increases appetite. (anti-emetics that reduce nausea, diarhea and vomiting like "Odansetron" are 5-HT3 antagonists) Increased binding to 5-HT3 from increased synaptic serotonin due to SSRI/SNRI treatment seems to be the common cause of nausea and appetite problems associated with this antidepressants; Mirtazapine in this regard is considered a very POTENT anti-emetic.
5. Mirtazapine has a small affinity for the Norepinephrine transporter, which is probably clinically insignificant in the scope of its other actions; however, the Norepinephrine transporter is responsible for recycling about 10% of dopamine as well as it's own norepinephrine. This co-recycling is partially responsible for the efficacy of Serotonin Norepinephrine Reuptake Inhibitors, and could be assumed to play a small role in Mirtazapine's anti-depressive qualities.
6. It has not been specifically studied yet, but has been theorized that Mirtazapine may block 5-HT6 receptors to an extent like it's NASSA analogue Mianserin. Antagonization of 5-HT6 disinhibits Glutamate, Noraderenaline, Dopamine and Acetylcholine. Again, antagonization at this receptor would improve anxiety and depression through increased dopamine, glutamate and noradrenaline. Increased Acetylcholine through theoretical 5-HT6 blockade could be the partial cause of Mirtazapine noticeable cognitive improvement and nootropic effects (SWIMs memory ability has increased by several volumes since starting mirtazapine and can remember almost anything perfectly, even while being a stoner and a Klonopin user).
7. Mirtazapine is a Histamine 1 antagonist, leading to an overwhelmingly powerful initial sedation. The first weeks of therapy are very hazy and groggy and SWIM can attest that it helped him sleep more, deeper and loner than any Benzodiazepine or Z-drug (ambien, zaleplon etc) ever did. Histamine receptors down regulate and reduce sensitivity quickly, and users of Mirtazapine might find other anti-histamines like Diphenhydramine (benadryl) are less effective due to this sensitization; SWIM is barely effected by H1 Antagonists since starting Mirtazapine. In this respect Mirtazapine acts as an excellent sleep aid for the first few weeks/months, but over time appears to develop more stimulant like effects, especially as the dose is increased, which I will explain further down.
8. Mirtazapine's most important mechanism of action is that it antagonizes Alpha1, Alpha2a and Alpha2c adrenergic receptors; and may also inhibit Alpha1b adrenergic to an extent as well. In a normal brain, the adrenergic receptors inhibit neuronal serotonin firing.
8a. Since 5-HT1a isn't blocked at all, the disinhibition of serotonin by adrenergic antagonism increases synaptic levels and allows more activation at 5-HT1a receptors by the brains own endogenous serotonin. This makes Mirtazapine a functional "indirect agonist" for 5-HT1a, as it isn't actually activating the 5-HT1a directly, but is simply allowing more serotonin to available to activate it more frequently on its own.
8b. Increased 5-HT1a neuronal firing ALSO increase dopamine activity as well; explaining partially the mildly stimulating effects of SOME anti-depressants that don't act directly on dopamine. Still, this is only part of Mirtazapine's anti-depressant mechanism of action.
9. As mentioned before, Mirtazapine antagonizes the 5-HT2c receptor (especially at higher doses 45-90mg), which has been discovered to regulate and actually block dopamine and noradrenaline activity in many parts of the brain; especially the pleasure centers.
9a. In a "normal" unmedicated brain, serotonin that activates at the 5-HT2c site tells the brain to reduce dopamine production and release. Antagonism of the 5-HT2c serotonin receptor results in a disinhibition of that dopamine in the nucleus accumbens, ventral tegmental area and other parts of the mesolimbic and mesocorticol reward pathways. This leads Mirtazapine to produce more stimulant effects the higher the dosage used; especially after histamine receptors down regulate following a few weeks of daily administration. SWIM no longer takes his Remeron at night, but in the morning due to this exact reason. SWIM almost always gets a nice "head buzz" for a few hours after taking Remeron. The increased dopamine production/release in the reward pathways may help explain the mild euphoric properties; especially in high doses (90-120mg+).
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Now if you're still following all this (if you aren't it's okay, neuroscience is a magical and insane world) then these paragraphs are the part most critical to understand:
Taking into regard Amphetamine's Dopaminergic, Serotonergic, Adrenergic and Noradrenergic activity, SWIM theorizes that the dopamine, noradrenaline and serotonin disinhibitions caused by Mirtazapine work in a synergistic way with each other. SWIM also believes Mirtazapine to be the perfect drug to "take the edge off" the anxiety amphetamine can produce. Here's why:
Amphetamine reverses the serotonin pump, releases dopamine and noradrenaline and inhibits the reuptake of dopamine as well. Without Mirtazapine's antagonization of many the aforementioned serotonin receptors, the extra serotonin from amphetamine is likely one of the guilty parties in the anxiety, paranoia and paradoxical effects some stim users experience. However, with Mirtazapine's extensive 5-HT antagonism, the extra serotonin summoned by amphetamine will have fewer serotonin receptors to bind to and theoretically instead be almost totally focused on the 5-HT1a receptor: reducing anxiety and increasing mood.
- Increased 5-HT1a activation, as I mentioned before, also increases dopamine throughout the brain. Amphetamine, working primarily through dopamine increases, would clearly benefit from this increase. Theoretical synergy once again.
Furthermore, the aforementioned blockade of 5-HT2c serotonin receptors disinhibits dopamine in the most important cerebral parts to us SWIMmers: The Mesolimbic dopamine pathway. The pleasure center baby! SWIM theorizes that this disinhibition allows amphetamine to not only have access to more stores of dopamine, but to allow it to release more and at a higher rate when it does open those depots.
SWIM could launch tangents into dozens of different topics on our emotional/mental perception and its basis in the mathematics of neurons, their receptors and neurotransmitters and how drugs effect those perceptions through chemical mediations... but thats a whole other post for the future! I digress.
SWIM apologizes for the length, but hope you all read it and maybe understood it. SWIM is interested to hear your thoughts Drugs-forum!
EDIT: Sorry forgot to include links to sources!!
5-HT2c info:
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1939890/?tool=pmcentrez
and
http://www.ncbi.nlm.nih.gov/pubmed/15056702
Mirtazapine Clinical Overview
http://www.ncbi.nlm.nih.gov/pubmed/10446735
Wealth of knowledge on amphetamine and amphetamine related compounds (MDMA, MDA, meth etc)
http://archives.drugabuse.gov/pdf/monographs/94.pdf
Synergistic Effects of Combined Administration of Mirtazapine and a Stimulant compound
http://www.faqs.org/patents/app/20090239783
Read more: http://www.drugs-forum.com/forum/showthread.php?t=132860#ixzz1bXVu4cwn
) (and in practice, SWIM means "someone who IS me"