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.


The Helpless Lamb & other pernicious lies

I’m a libertarian of the right, so have little patience for those who wish to coddle parasites and “victims” with my cash.

It’s curious that many of these takers keep their hair meticulously unkempt and dreadlocked, and make damn sure that they are seen to be “keepin’ it real” and living the romance and despair of it all. Ironically, they’re making an effort to do something. Guaranteed though, if my legally extorted money wasn’t keeping them alive, they would be either dead or cleaned up and supporting themselves with work.

This guy takes on the lie of the helpless lamb pretty well, though I don’t agree with his pragmatism and contemporary Canadian conservative tendency to give up and shrug in exhaustion…

So what’s the solution? Well, I think radical change is needed.

And that should include the distribution of both hard and soft drugs, such as  marijuana, – or their substitutes – through regular medical channels, via  doctors and pharmacists.

In other words, they should be dispensed in the same way as painkillers,  sleeping pills and other potentially addictive “medicines.”

Certainly, such a change would inevitably mean further expense for our public  health system. But those costs should be offset by savings in our criminal  justice system – keeping addicts out of clogged courts and crowded jails.

…”should be offset”? bullshit…

…you don’t just quasi-legalise drugs, expand the welfare state and hope things will work out. Things won’t. They’ll just get worse and more expensive. This line of thinking serves only to damage the person and the nation; and let’s admit it: what one permits, one promotes. So lets all take a deeeep breath and just legalise the damn stuff. The author of this piece isn’t a flaky socialist liberal, but as bad as any bleeding-heart who believes in the inherent goodness of maladroits are moralists who thoughtlessly and irrationally push pandering conservative politicians to ban these market products. Besides smarmy conservative pols, organised crime, the cops and pharmaceuticals are the only ones who benefit from illegal or “controlled” drugs. The fact that they’re illegal or controlled, and therefore bloody expensive, definitely doesn’t benefit me.

Want to make big cash real quick? Sell an illegal product with a huge demand, jack up the prices because the markets are so twisted by legislation and rake it in!

Want to be a happy police chief? Push to keep a product illegal, then because it’s a great excuse, grab more arbitrary power over the citizen and because more resources are needed, rake it in!

Want to be a happy drug company? Push to legalise illegal drugs on your terms, monopolise and rake it in!

…why do I vote?

A strategy for EDS relief

‘K, so you took the “Do you have EDS” test, are pretty sure you need opiate therapy, have read the Recommended Posts, and are contemplating going to your doc looking for opiates. First of all, good luck with that, and if you’ve got a silver tongue and have managed to wheedle a long-term prescription, let me know; maybe you and I can go unicorn hunting some time and sell one to a zoo for some serious cash.

The only way you’ll legally get what you’re looking for, if you get it at all, is if you arm yourself with your own documented drug failure history and printed opinions from experts and primary studies from the web.

If you’re a virgin, you have to start from the start. The first thing to do is get yourself diagnosed. If you’re truly depressed the doctor will see it clearly as soon as you walk into his office and start talking. EDS sells its self, for sure.

Next, start going through the standard on-label antidepressants. Remember to give these meds a chance, and at the same time keep in mind that it can take months for meds to cease working, or adverse effects to develop, after a time of efficacy. But if you find a med that actually does the job, thank your particular magical sky fairy for your good fortune and get on with life. You probably don’t have EDS… …otherwise, other tactics must be employed.

Take the meds your doctor prescribes. Start keeping detailed records of types and efficacy. Make sure that they are clear and lucid, because if these drugs don’t work, you want to be taken seriously when eventually asking to go off-label for opiates. Sertraline (Zoloft) and fluoxetine (Prozac) are standard SSRIs and will probably be scripted first; so if the doc scripts these, try one or both. If they don’t work, go on to one or two SNRIs. Venlafaxine (Effexor) is standard and will probably be the first of these. Effexor has a unique profile in that it has somewhat of an opioid profile, though what that really means for us, I have no idea. Effexor has also some hellish side effects and withdrawal symptoms; I had a particularly nasty time with this drug (though I won’t go into my bad experience with the carnival ride of ADs. I don’t want to bias your perspective).

Bupropion (Wellbutrin), an NDRI, might be the next choice, then maybe something different like trazodone and on and on. Try to get through quite a few different types, and include some old-school ADs like the tricyclics and MAOIs. If these don’t work, perhaps suggest going off-label and trying something like lamotrigine or amphetamine. Again, if something works for you, breathe a sigh of relief and get on with the business of living. If not, at least you’ve kept meticulous records, eliminated possibilities and narrowed down your options and diagnoses… you can now make some choices and think about opiate therapy.

I recommend going to a doctor who will read your research and drug history and listen with interest and sincerity. You should be able to get a good read on his attitude right from the start; and if he isn’t into it or is an opiate dumdum, maybe tactfully ask him to refer you to someone less timid, or find someone yourself.

In my opinion, the first opiate used should be buprenorphine. It is a legal opiate with an interesting profile of action used in withdrawal therapy and is becoming relatively popular as an off-label antidepressant… if you can find a willing doc. Also, despite my reservations, low dose naltrexone (LDN) seems to be having a good effect on some depressives, though I wonder how much of this is placebo. Nevertheless, if bupe doesn’t do it or you can’t find a doc to prescribe, it can’t hurt to try it, and who knows? it might just be the ticket.

However, if everything has been done under the sun and you haven’t found relief, you might have to look for shade under the big guns. This is where the full agonist opiates/opioids come in, and where the adventure, for better or worse, begins. There are a few ways to procure opiates; some legal, some not so much, but one can with some effort find them (my blog gives some ideas). There doesn’t seem to be much difference in efficacy between opiates, though codeine doesn’t like me too much. As well, I have made it clear in this blog that when dosing, the object is to achieve relief without a shred of the nod(!). Again, if one goes into nod territory, one goes into drug abuse territory and the whole raison de plus gets shot to hell…

…don’t do this…

…just don’t.

I refuse to acquire a guilt trip because my good intentions get ignored and someone’s life goes down the tubes.

So just don’t do it. Don’t turn a potential gift into a curse.

~There is one fairly sure way to get what you’re looking for without riding the med-go-round; if you’re already addicted (and really, how many opiate abusers aren’t simply self-medicating depressives?) and don’t have the will to stay out of the nod, you can go into methadone or bupe therapy. This will help you get back on track and focus on life because you don’t have to worry about scoring and fixing, your jones is satisfied without the obsessive distraction of euphoria, and both bupe and ‘done have a fantastic anecdotal efficacy for depression; in fact, if going into ‘done therapy wasn’t such a pain in the ass, it would be my first choice above bupe, despite its troublesome half-life. And if you’re not addicted, you have to be pretty desperate for answers to try this approach and lie; but, well, who am I to judge; no one should be dictating what drugs an adult can take anyway… bloody patronising…

…which brings me to the downside of this approach. Titrating off these drugs can be more painful than heroin(!), and odds are, this therapy will become part of your medical records (which might create a different perception than scripting opiates simply for depression); also, methadone therapy requires a daily trip to the clinic which inconveniently cuts into one’s day.

Whatever you do, study and read, read and study, weigh the pros and cons and be honest with your motives. If you make your life your highest value, the choices you make should keep you on the right track.

Good luck to you…

Post-acute withdrawal syndrome & EDS: a PAWS for thought

When one hears vanilla horror stories about opiate addiction, the talk usually targets abrupt withdrawal following a tolerance level developed over time; this is a nasty state immediately following cold-turkey that lasts from a few days to, uncommonly, many weeks depending on the opiate involved and the person kicking (age, length of addiction, tolerance and amount, etc). However, most don’t realise that kicking is the easy part; who but the experienced has heard of post-acute withdrawal syndrome? Who but the experienced understands that PAWS, not the initial painful kick, is the reason why the ex-user becomes a re-user? Hell, even the oft-referenced and usually quite accurate Wikipedia when perused doesn’t really get into it until specifically unearthed, as a kind of aside, or curiosity.

PAWS has implications for the EDS depressed. Because depression during PAWS is increased to levels not experienced pre-opiated, one must make a difficult and informed decision. I can understand that it is better to be judged by twelve than to be carried out by six if antidepressants just don’t do it and existential despair is the only road ahead; but a possible lifetime of dependence is a frightening investment because, though the brain usually goes back to its pre-opiate state subsequent to kicking after some time… there is evidence that a somewhat unretracted state is possible…

…do you wanna roll the dice?

I suppose if I was a sixty year old man the decision to become dependent would be a no-brainer, provided I had permanent access to product. But a young person has more to think about… looking at a future married with kids and a lifetime of potential difficulties because of opiates, even if small non-abusive doses are taken. As well as PAWS, complications like hypogonadism and adrenal dysfunction, though usually reversible, are possible, and enough to scare any young person away from potential refractory depression relief via opiates (but that’s another post).

~The crux of the issue is that EDS depression can be controlled or eliminated with rational opiate therapy; but… a lifetime of opiate use will probably be necessary and, who knows, might in the long run make depression worse with decades of use or when one is forced by circumstances to quit dosing… and the future is filled with circumstances…

…but then again, what about decades of “legitimate” antidepressant use?

No one said making this choice would be easy.

The dragon chaser

Years ago some mates and I were hanging around Gastown in Vancouver one warm, drizzly afternoon. Walking along the old cobblestone, we passed by an ancient chowder house and went in for a bowl. This place was renowned for its cheap but delicious fare, so attracted an eclectic bunch, from blue-collars to businessmen to bums. We walked in, sat at the bar bench, ordered, and waited in impatient anticipation. I started people-watching and noticed this bedraggled guy, long disheveled hair sticking out from under an abused weathered toque, sitting in apparent religious meditation over his nutriment. After a minute, looking lost in the aether, he promptly plunked down face-first into his bowl of seafood chowder, then shot back up, bobbled a bit, twitched once or twice, eyelashes blinking chowder, clams and squid easing their way down his face and back into the bowl… and proceeded to chow down with absolutely zero self-consciousness…

…yeah …you know those toy glass birds that you saw in old Bugs Bunny cartoons? They sort of filled up with water while “drinking”, their heads down in the drinking glass on the rim of which they were perched; then when filled with water, gravity popped them back up, drained the water, then dunked their heads back down into the glass again. Kinda genius actually…

…anyway, this guy sorta looked like one of those birds… but a broken one.    ;D

~This floating in and out of consciousness is called “nodding” or going “on the nod”. This state is the junky’s ideal, the ultimate in escape, the dreaming back into mother’s womb… and one that you want to avoid if your motive is simply relief from refractory chronic depression.

This is important to consider, because when naive people talk about the “living hell” that is addiction, they are innocently referring to the aforementioned state. People don’t understand that, though daily dosing with any amount will leave one with a pet monkey, there is a profound difference between someone taking O for depression therapy and a “dragon chaser”, one who tries to recapture a coveted state from back in time when an addict first met the Poppy Goddess, the siren who let him ride her serpent to heaven…

…sadly, brain chemistry and biomechanics dictate that an addict’s first flight to paradise is his last… this must be accepted gracefully, yet despite that over time the euphoria will be less and less with each subsequent dose, people are stubborn. Overdose in livingrooms and on urine-soaked mattresses in back alleys is achieved in two ways: either by mixing substances, or taking ever higher doses of one substance, one day being roasted chasing a winged ophidian that deep inside the junky knows would never again be caught.

~From my experience, the difference between a user searching for answers and a dragon chaser is not levels of addiction, nor even the dependence/addiction attitudes, but one of head space… a user’s therapeutic intentions are good because he is desperately clinging to life and doing what he perceives as truly the best thing for his life in this particular case, as in every other, while a dragon chaser is conscious of what he’s doing, riding a one way train to that filthy back alley, yet paradoxically in a state of hopeful denial. The therapeutic user maintains his life as his highest value, so his life remains his reference point if he is forced to kick the habit or make a painful change. The dragon chaser is irrational, makes the drug a value higher than self, and gives up on self the moment he makes his choice and takes that first hit.

The reasons for being rational about this are obvious; there is no need to make a list. But we should always keep in mind that the body is in a state of homeostasis. It is always trying to maintain equilibrium, so it’s in our best interest as users to keep tolerance as low as possible, understanding that it is imperative to keep unnatural synaptic plasticity and other forced biological states to a minimum. The rational user knows that the nod, even an almost unnoticeable nod at lunchtime, is not a normal state and anything that feels this good can’t be good for us. If we don’t educate ourselves and try to understand as much as possible about what we’re doing to our brain chemistry, biomechanics and bodies in general, and do our best through diet, motion and stress reduction to mitigate potential harm to our shrines, we may find ourselves in much the same predicament as the dragon chaser; maybe not on a urine-soaked mattress in an alley, but on a sweat-soaked mattress in a hospital.

Opiates: why do I come alive? Why do you fall asleep?

My dad is pretty much a down the line straight shooter. He’s fairly conservative, so a reliable source of uncoloured opinion. One evening we were visiting and he mentioned that he was in pain. I can’t recall exactly what it was, but I think it might have been either his shoulder or a pulled back.

At any rate, I offered him a cup of liquid joy to ease the pain, and he accepted with slight trepidation. He was cautiously curious to know what opium was about, and quaffed the vile draff in as few hoists as possible…

…I’d been immersed in some computer stuff and had forgotten about his situation for a while, until I glanced his way and noticed a very passive, inanimate face where, about three hours before, a lively one had been. I chuckled and asked how he was feeling. He replied without expression, “very loose”.

He was obviously pain-free…

The next day I asked him how he’d liked it. He didn’t, really. It made him tired and kind of out of it, and his motility had slowed right down. I had noticed the previous evening that he wasn’t really enjoying the experience. This is curious from my point of view because he is an indefatigably sanguine and optimistic guy. One would have thought that a dose of O would send him into an even more pleasant state. But this wasn’t the case at all.

~Modern doctors and researchers have been pondering this difference of effects between individuals for decades. The question revolves around why a disproportionate number of addicts and prescribed depressed users come to life when opiated, while most non-addicts, who seem to have a take-it-or-leave-it attitude toward opiates, just simply don’t. They, like my dad become either tired and fall asleep, or feel unwell.

There are theories about why this is, and EDS seems to fit in nicely. I know that I come alive with each daily dose. I feel motivated and engaged; I have a drive to produce and succeed, a trait shared with most normals, and one that disappears when I don’t dose (maybe the endorphin-dopamine connection that makes normals productive and engaged is mimicked in depressives when exorphins are taken in, thereby kicking otherwise latent (?) dopamine into action). From what I’ve read, many with a disinterested view of opiates, seemingly without endorphin deficiencies feel unproductive, warm and cocooned, detached and apathetic with a sense of lazy well-being, though sometimes depressed when using for pain by doctor’s order; in a kind of cloud, disengaged from others. It’s funny to me… I simply don’t have this experience aside from some nice warmth. Maybe I’m not interested enough in euphoric doses to reach this state, but the few times that I have experimented and gone on the nod and “knew” that I had taken more opiates than my body required, I simply fell asleep. Frankly it’s boring, a waste of time and product, feels unnatural, and I don’t bother.

All of this conspires to so far convince me that many if not most chronic opiate users specifically seek this drug for a reason. I think we EDSers are indeed feeding our brains as best as we can with our primitive flower chemicals and acquire effects that lead to the typical behaviour that normals experience. I think I know this objectively, because I connect, and fit in with others around me in a way that does not happen when I’m not opiated. Apparently people don’t have the impression that I’m “different” from them. As well, no one thinks I’m high because, essentially, I’m not…

…this is interesting too. An EDSer on O doesn’t seem inebriated compared to a normal. The reason seems obvious: while a normal is adding opiates to a brain with normal endogenous opioid function/levels, an EDSer seems to be “topping up” his dysfunctional/low levels. I have no idea if this is correct, but I’ll eat a bug if it isn’t.

~The web is filled with anecdotes from John/Jane Q regarding the energizing effects of opiates on depressives (the experience of people on this bupe site being a concentrated example). As usual, I hope for investment and research into this, because an educated self-medicator who is rationally hooked on O is in a much better position than otherwise…

…it’s long past time.

SSRI fail…

I stumbled onto this 2008 meta-analysis regarding the efficacy of fluoxetine (Prozac) and related SSRI antidepressants…

Meta-analyses of antidepressant medications have reported only modest benefits over placebo treatment, and when unpublished trial data are included [!!!], the benefit falls below accepted criteria for clinical significance. Yet, the efficacy of the antidepressants may also depend on the severity of initial depression scores. The purpose of this analysis is to establish the relation of baseline severity and antidepressant efficacy using a relevant dataset of published and unpublished clinical trials.

(my emphasis)

This study was looking for a depression baseline for efficacy: the researchers concluded that how down you feel is positively correlated with how well the drugs work… sort of.

If you’re moderately depressed, you can pretty much forget it and save your cash. Spend it on candy or unicorn rides or whatever it is happy people spend their money on; if you’re severely depressed, you might get something out of it… maybe; and if you’re muttering-to-Jesus-walking-in-the-middle-of-a-busy-road-in-pajamas, severely, with whipped cream and chocolate sprinkles depressed, there’s a fair chance you’ll get something out of it. But here’s the kicker… the efficacy of treatment for this extreme type of depression was attributed not as much to the drugs as to decreased responsiveness to placebo.

…hope you have faith in your doctor’s dope.

Too bad looking for answers for depression outside of the serotonin/norepinephrine/dopamine axis and studying the endogenous opioid system seem to be evil and taboo. Or something…

…too bad I had to turn my back on the Establishment and find my own answers.

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