http://www.biopsychiatry.com/
Another "French" option is amineptine's cousin, tianeptine (Stablon). Tianeptine is a neuroprotective antidepressant that reverses the neuronal damage and lasting misery caused by uncontrolled stress. Chronic stress causes dysphoria by inducing corticotropin-releasing factor (CRF2) receptor stimulation of dynorphin release. The endogenous opioid peptide dynorphin activates the unpleasant kappa opioid receptors. Tianeptine acts both as a non-sedating anti-anxiety agent and a non-stimulating mood-brightener. Its use increases extracellular dopamine concentration in the nucleus accumbens and, at higher doses, in the frontal cortex. Uniquely in clinical medicine, tianeptine acts as a selective serotonin reuptake enhancer. Its puzzling efficacy as an antidepressant illustrates how little modern psychiatric medicine really understands about mind, mood and depression. Like other contemporary antidepressants, tianeptine's therapeutic action presumably depends on downstream adaptations both between and within neurons occurring over a period of several weeks. Chronic tianeptine use reverses stress-induced hippocampal dendritric atrophy and amgydaloid dendritic hypertrophy, which is just as nasty as it sounds. But the precise molecular mechanisms are obscure. Tianeptine/Stablon is not licensed in North America primarily because its patent has expired.
REBOXETINE (EDRONAX); ADRAFINIL (OLMIFON); MODAFINIL (PROVIGIL)
<a href="http://www.reboxetin...tml">Reboxetine (Edronax) is a relatively well-tolerated, relatively selective "noradrenergic" agent. Crudely, whereas serotonin plays a vital role in mood, noradrenaline is essential to maintaining drive, vigilance and the capacity for reward. There's a fair bit of evidence that chronically depressive people have dysfunctional and atypical noradrenergic systems - particularly their alpha2- and beta-adrenoceptors. Reboxetine itself typically doesn't have the disruptive effects on cognitive function or psychomotor performance common to older clinical mood-brighteners - though alas antimuscarinic effects are still not completely absent. Multiple interactions between the different monoamine systems make it hard to target one neurotransmitter system without triggering a cascade of effects on the others. But NorAdrenaline Reuptake Inhibitors (NARIs) - and dopaminergics like amineptine (Survector) - may be especially useful in drive-deficient "anergic" states where the capacity for sustained motivation is lacking; and for melancholic depressives with a poor ability to cope with stress. Reboxetine can be safely combined with an SSRI, though there is evidence that NARIs themselves indirectly enhance central serotonin function by a mechanism that doesn't depend on reuptake inhibition. More surprisingly perhaps, preliminary studies suggest reboxetine can actually reverse tranylcypromine-induced hypertensive crises. The "cheese effect" is triggered by ingesting tyramine-rich foods. Thus NARIs plus MAOIs may prove a potent form of combination-therapy if first options fail. EMSAM, the transdermal selegiline patch, is probably the safest choice of MAOI.
Depressive hypersomniacs who fare poorly on SSRIs, or can't get hold of amineptine or EC-licensed reboxetine, might consider trying a so-called eugeroic ("good arousal") agent instead. Alpha1-adrenergic agonists like adrafinil (Olmifon) and modafinil (Provigil, Alertec) are centrally-acting psychostimulants that can brighten mood and sharpen mental focus. They stimulate the noradrenergic post-synaptic receptors, increase glutamatergic transmission, and activate the wakefulness-promoting orexinergic neurons, thereby boosting alertness, memory, mood, motivation and energy. At sensible dosages, they are remarkably free of side-effects. Modafinil was licensed by the FDA as Provigil for the treatment of narcolepsy in Dec 1998; and in September 2003, an advisory panel to the FDA endorsed its use for treating shift work sleep disorder and sleep apnea. However, the significance of these prescribing indications is rapidly being eroded. Modafinil and adrafinil are now mainly used off-label as so-called lifestyle drugs.
What's missing, crucially, is the therapeutic enrichment of hedonic tone via a combination of mu opioid pathway enhancement and prolonged stimulation of meso(cortico-)limbic dopamine function.
It is possible that duloxetine (Cymbalta, Xeristar, Yentreve), licensed by the FDA in autumn 2004, and milnacipran (Ixel, Dalcipran, Toledomin), available in Europe, may be more effective than venlafaxine (Effexor) for a segment of the population that can benefit from dual serotonin-noradrenaline reuptake inhibition. Pain-ridden depressives in particular may respond well to this class of drug. Many depressed people suffer from poorly-defined aches and pains, persistent fatigue, and shoulder-, neck- and back-pain. Duloxetine relieves both the somatic and emotional symptoms of depression. Unlike venlafaxine, duloxetine exerts its more balanced serotonin and noradrenaline reuptake inhibition throughout the dosage range. Duloxetine also weakly inhibits the reuptake of dopamine, and shows minimal affinity for the histamine and cholinergic muscarinic receptors. Its side-effect profile appears to be relatively benign. Yet an authentic wonderdrug for mental health remains elusive. Early expectations that duloxetine would show superior efficacy in melancholic depressives have not yet been convincingly borne out in controlled clinical trials. Ill-served by mainstream medicine, victims of melancholic and retarded depression may actually do better on dual noradrenaline-dopamine reuptake inhibitors such as delicensed nomifensine (Merital) and/or mu opioid agonists/kappa opioid antagonists such as buprenorphine (Temgesic, Buprenex, Subutex).
A synthetic analogue of the natural hormone melatonin, agomelatine is a potent melatonin receptor agonist and a serotonin 5-HT2C receptor antagonist.
Contemporary medical orthodoxy classifies drug-induced bliss as an "adverse side-effect" of opioid analgesics - even in the terminally ill. Yet we could all do with having our native endorphin systems enriched. Later this century and beyond, the customised site-selective successors to today's opioid drugs may play a critical role in promoting emotional super-health. For example, one of the most exciting research breakthroughs in recent years has been the synthesis of JDTic. JDTic exerts a sustained anti-anxiety and mood-brightening effect: it is the first orally active selective kappa opioid antagonist. Kappa is the "ugly" opioid receptor whose endogenous ligand is dynorphin. The dynorphin/kappa-opioid receptor system is implicated in the unpleasant states of mind caused by chronic uncontrolled stress. Repeated use of cocaine, heroin, ethyl alcohol and other euphoriant drugs induces a compensatory up-regulation of the dynorphin/kappa-opioid receptor system too, causing anxiety, anhedonia and dysphoria. Whereas mu receptor agonist opioids induce euphoria by enhancing dopamine release in the nucleus accumbens, activation of kappa opioid receptors inhibits dopamine release from the mesolimbic terminals. This deficiency is subjectively unpleasant because the mesolimbic dopamine system regulates hedonic tone and the capacity to experience (and anticipate) happiness. Dopamine also modulates the threshold of pain perception. As of 2011, controlled clinical trials of JDTic or its analogues (e.g. zyklophin) in humans have yet to begin. But results in non-human "animal models" are encouraging.
I can verify that stress will eventuall burnout your cognitive capacity. Also you will certainly lose effectiveness of something like caffeine and adderall. I have had best results mixing things that raised oxytocin and endorphins with adrenergic and dopiminergic cholinergic serotinergic combinations. Caffeine no longer seems to be worth using. I really suggest pursuing the idea of a dynorphin antagonist and a CRF secretion inhibitor.
Surprisingly things like Frankincense Essential oil can control CRF abnoralities, amygdala, and hippocampus abnoralities. So can bacopa.
These are characteristic in that they do not act as dopamine reuptake ihibitors or NARI.
I would think of a stack something to this effect.
Clary Sage EO
Frankincense EO
Valerian EO
Theanine/Magnolia/Phellodendron
Lemon EO
Aniracetam/Piracetam
Sulbutamine
Fish Oil
Modafinil/Yohimbe/Adrafinil
Wellbutrin/Tianeptine
Schizandra
Cordyceps
Rhodiola
Bacopa
Mushroom Complex containing Reishi and Lion's Mane
Yerba Mate in small amounts
Decaf Green Tea
No Coffee whatsoever
The next step would be an unknown source for dynorphin control as well as opioid function. Schizandra is pretty good, but I think Kava or Kratom might be a better opioid. The whole challange however in this post is - getting away with using pro dopaminergics and opioids without inducing tolerance.
I have read countless threads about NMDA antagonism or Ibogain or DXM or salvia.
Frankly, I have to point out that most psychoactive stimulants heavily release PEA at some point - leading to mu and delta opioid receptor agonization. Ultimately, they all carry risk of tolerance and crash.
High states of dopamine/acetylcholine/adrenaline are impossible to sustain because of neuroendocrinological negative feedback mechanisms.
So you would be looking at low dose dynorphin control and mu and delta opioid receptor sensitizers as the next step to perfecting this stack...
It is the kappa opioid receptor stimulation that results in the listlessness and uselessness of narcotics, otherwise narcotics would be extremely constructive for accomplishing absolute plethoras of work, utterly superhuman intellectual performance.
