Mirtazapine is good for coming off of amphetamines because of it's antagonistic effects on dopamine, as well as Norepinephrine. However, Mirtazapine will have no effect on tolerance to amphetamines because it has no effect on the NMDA receptor.
Mirtazapine could in theory potentiate amphetamine the next day because of it's inverse agonistic effects on the α2A-adrenergic receptor. However, because it antagonizes dopamine, blocks the dopamine transporter, antagonizes adrenaline (at all sites except the α2A site), and blocks the norepinephrine transporter - this is very unlikely.
Brace yourself:
"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!"
Source: http://www.drugs-forum.com/forum/showthread.php?t=132860
FYI the reason i responded to the suggestion of mirtazapine in this thread the first place was because i've been on both speed and mirtazapine together in the past (for around 2 months), i stuck to a low dose of both the whole time, as i said, nothing noticed on tolerance reduction but euphoria was consistent the whole time as was some agitation (not anxiety). I have never done mirtazapine by itself so i don't know how much that contributed.
