When noradrenaline kicks too much ass…

…it’s a nice idea to crank it down a bit.

I have it in my head that serotonin and noradrenaline aren’t my best friends (Effexor, an SNRI, was an absolutely horrid experience). I’ve often thought this. And I’ve often thought that the holy grail of happiness, monoamine neurotransmitter balance, being understood, too-high noradrenaline might be an ignored problem for many depressives.

Noradrenaline (norepinephrine) is a nasty little chemical when it misbehaves. It serves various functions, but as a stress hormone it can get out of hand when our mental state gets out of hand. When it’s good, it provokes a temporary fight-or-flight response, provides anti-inflammatory help around neurons, helps with decision-making; when it’s not good it can cause anxiety, and thus some damage (hypertension, adrenaline (its downstream product) and cortisol overflow, neuronal toxicity and on and on…). So in my opinion any means of kicking down NA might not be a bad idea if there aren’t too many negative side-effects. 

I wonder if one can reduce NA by reducing nutritional precursors (egg, meat, nuts, dairy, soy); I know I do better when I eat less protein; others may also. Tyrosine and phenylalanine (tyrosine’s precursor) are needed to produce NA (and therefore, adrenaline), so reducing intake of these sources is an interesting question…

…on the other hand, I know that I can never have too much dopamine (that’s why I love opiates: all the dopamine goodness without the NA release), so I’m curious about finding a way to lessen NA production because DA is the precursor for NA; and the less protein I eat, the less DA I produce and the less beneficial DA effects I get… I really would like to be able to chow down on more protein.

~So… how to reduce an overproduction of noradrenaline without reducing dopamine…

…this is my folly.

Dopamine beta hydroxylase converts dopamine to noradrenaline, which then converts to adrenaline. In my searches I stumbled upon and found ways to inhibit this step in conversion. For example, Etamicastat is a novel (?) drug used for the treatment of heart failure and hypertension, but I wonder how well it would work off-label for help with NA overload, once it’s approved for sale. There are other DβH inhibiting drugs around (disulfiram, dopastin, bupicomide, tropolone), but who knows which can legally be used off-label?… though I really think it might be worth a try…

…I might even try, myself.

Interestingly, fusaric acid is a natural DβH inhibitor. It is isolated from Fusarium fungi, and one species, Fusarium venenatum, is used for some kind of whacked-out neolithic foodstuff marketed as Quorn. Though used in research, fusaric acid is considered a toxic by-product… curious, though.

Refractory depression & kappa system over-activation?

Sometimes I wonder if Nature likes us much. She seems to hate to see nice people who deserve it in an unconditionally happy state. Sometimes I think that she thinks that we are still in the paleolithic, and really happy people are impractical idiots who don’t have the wit to perceive danger, so quickly weed themselves out of the gene pool before reproducing to their full potential… so she does something about it. She “helps” them…

…is happiness an anomaly? I know this question is beat to death and naive, and I’m being facetious. Considering modern hunter-gatherers, primitive localist cultures supposedly most in line with our “ideal emotional state”, one might believe that perfect emotional homeostasis is more prevalent per capita with them because they live in an environment with stressors more compatible with our evolution compared to industrial cultures, and maybe it is; but even with these Peoples, emotional states go crooked, and when they do, they don’t twist toward unbridled joy.

Our bodies have a disheartening way of efficiently maintaining a skewed emotional equilibrium that, for too many of us, leans away from euphoria. Euphoric people are rare, though we’ve all known that guy/girl who seems to be in a constant and enviable state of bliss, always living in a sunrise. Not much seems to trigger a bad mood in these people. I have to wonder if, woe not being within a normal state of equilibrium, this state of apparent irrational cheerfulness isn’t a defect as well, albeit a lucky and fortunate one (though the line between happy and manic might be thin; and how much of a cost in longevity might this state of chronic “up” incur? On the other hand, does depression produce as much or more longevity-sapping in a body?).

I’m looking at the role of kappa (κ) opioid receptors and dynorphin endogenous opioid peptides and the implications for depression from a faulty κ system. Have some refractory depressives been given the curse of an overactive κ system? If so… shit. But, if so, despite the overwhelming complexity and interaction of our amazing/intimidating biology, maybe this is a good enough place as any for a depressive to start looking for some long overdue answers.

There is a world to know and I’m not getting too much into κ agonism/dopamine; dynorphin links with/CREB/NMDA receptors; the fact that dynorphin is produced in different areas in the nervous system with various functions; other neurotransmitters; hormones like prolactin or enzyme connections yadayada and will mostly be ignored here. It all turns into an overwhelming mess and would just numb the mind of anyone who isn’t a geek. Hell, I’m feeling numb just writing this paragraph…

…I just want to know the kappa system’s role in depression and how to stop it.

κ receptor/dynorphin overactivity is implicated in depression. Apparently Nature in her often disappointing wisdom has forced us to prevent, in her opinion, an irrational and self-destructive state of elation (yay. thanks a lot). I don’t think we can cure an imbalance at this time, so I’d be happy enough to just control it… somehow. And since I believe that happiness is our birthright, I think it behooves me to search for a way out of this kappa mess and fight back any way I can… screw this

Dynorphin is a varying group of opioid peptides that act as neurotransmitters. Dynorphin has the strongest affinity, and is the primary peptide, for the κ receptor. It is also a very potent endogenous opioid pain-killer. Its other functions deal with learning and memory, emotional control and stress response. The problem is, unlike its relatives endorphin and enkephalin, it doesn’t make one feel good; Quite the opposite, actually. A protein called CREB activates a gene that makes dynorphin. CREB triggers this “down” by increasing dynorphin… …and stress/pain triggers the whole cascade; no stress=no dynorphin release/kappa receptor overactivity=no “down”.

Opioid peptides endorphin and enkephalin release dopamine by disinhibiting dopamine pathways and help to make us feel good. Dynorphin doesn’t like us to feel good, so inhibits dopamine release (as do kappa receptors). In fact, dynorphin inhibits dopamine more and more with repeated illicit drug use, so would rather we overdose on drugs than let us feel good.

…stupidjerkdynorphin.    ;(

So it seems that there is a mood balancing act between dynorphin and endorphin/enkephalin.

To be fair, maybe part of the role of the kappa system is involved in learning to avoid certain situations, as if to condition one what to not do, via unpleasant stimulus; [eg: rodent bites… “ouch”… kappa activation… “I feel depressed. I’m never doing that again.”] …Well, who knows? ‘Tis but a theory. And maybe κ activation makes one numb, pain-free and “down” as a survival mechanism; possibly as a way to force lucidity and introspection and help one deal with a problem in a bad situation. Speculation, I know.

So, it seems that a goal for some depressives may be to find a relatively safe method for blocking dynorphin (or whatever else may increase dynorphin activity; perhaps CREB, for example), and thus put to a stop its well-meaning but apparently misguided effects. Learned helplessness is another negative side effect of kappa overstimulation, no doubt partly because dopamine, our driving, motivating neurotransmitter, is inhibited; disinhibition would go a long way to fighting depression. Also, blocking dynorphin allows glutamate, an excitatory neurotransmitter involved in learning and memory, to be released and restore functional plasticity in the hippocampus, reversing the phenomenon of learned helplessness…

…as well, non-pharmaceutical ways to reduce stress cannot be stressed enough: relaxing enjoyable activities that produce a somewhat meditative state and help to take one out of one’s self for a while really do work. I’ve found that relaxation through the senses (charcoal burning resin like frankincense and myrrh for smell, low lighting and a warm atmosphere for sight, meditative music for hearing, caressing and sex for touch, slowly eating good whole food for taste) work well for the short-term, like at home after work. Absolutely worth it…

…but, for god’s sake, don’t start taking downers like benzo’s to try to control stress/kappa to achieve the desired effect. Jeez, the last thing we need is a dependency on these things, which are the worst, in terms of physical addiction complications… really, I would rather be hooked on opies than benzo’s any day.

~Thus, buprenorphine shines its beacon of hope once again. It is not only a partial agonist at the Mu (μ) receptor (which produces a much valued non-euphoric state for therapy), but is also a κ antagonist, which effectively blocks dynorphin from κ receptors and creates a non-depressive state. Bupe may not only be just the thing for some with endorphin deficiency syndrome, but may also help people with a skewed dynorphin/κ system or even, perhaps, general depression and dysthymia.


Btw, if you think I’ve missed something, please feel free to comment for everyone’s benefit.