How To Increase Orexin

Index General Discussion The Science of N How To Increase Orexin

This topic contains 30 replies, has 6 voices, and was last updated by Pereise1 1 month, 3 weeks ago. This post has been viewed 4519 times

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  • #6586
    Jason
    Jason
    Keymaster @jasonm

    @ferret Funny you mention that. Way before I got diagnosed and had my wisdom teeth removed under anesthesia, I briefly felt pretty good afterward. Like I’d finally gotten some quality sleep. The hydrocodone they gave me afterward however, made me sleep forever. I’m not sure if all opioids cause increased histamine or just some. For the orexin effect, they have to be taken chronically (at least if you’re a mouse with N) to see any benefit.

    One of the most common anesthetics used for surgery is propofol. It has an extremely short duration of action and induces deep sleep. If I had to guess it has more to do with the that than the opioids.

    #6633
    Pereise1
    Pereise1
    Participant @pereise1

    @pereise1 Okay science guy, figure this one out!

    Opiates increase the number of hypocretin-producing cells in human and mouse brain and reverse cataplexy in a mouse model of narcolepsy

    I read the full study through sci-hub and this is very interesting and promising considering that in vitro studies had originally shown the opposite effect. I consider it promising because, despite the problems related to the opioid epidemic, I don’t see this becoming a problem in us, due to the following excerpt from the study:

    Constitutive hypocretin knockout mice develop attenuated morphine
    dependence, indicated by a less severe antagonist-precipitated
    withdrawal syndrome (24).
    It has long been anecdotally noted that narcoleptic patients, who have, on average, a 90% loss of hypocretin neurons (5), show little, if any, evidence of drug abuse or addiction, despite their daily prescribed use of gamma hydroxybutyrate, methylphenidate, and amphetamines, drugs that are frequently abused. These data are consistent with our current finding of increased hypocretin cell populations in human heroin addicts, perhaps facilitating and maintaining addiction. The reduced number of hypocretin neurons in patients with narcolepsy may be related to the lack of drug addiction in these patients.

    So our biologic inability to become addicted to things should make opioids a great option for treating our illness. I’ve sometimes felt like I would love to have the ability to become addicted to things, if only to help with the constant anhedonia my EDS gives me. And as opioids are some of the most addictive substances in existence, it stands to reason that it would help with the ability to be able to enjoy things. This has actually been tried before btw, according to the study:

    In 1981, a report of a narcoleptic patient given codeine (a natural isomer of methylated morphine) for the control of Crohn’s disease symptoms described a “disappearance of his narcolepsy, cataplexy, sleep paralysis, and hypnagogic hallucinations” (31). In a second case report, a narcoleptic patient, who could not continue taking stimulant drugs because of coronary artery disease and the necessity for kidney dialysis, urged his doctor to prescribe codeine for his narcolepsy because of the reversal of narcoleptic symptoms he had previously experienced when given codeine for pain. His physician published the results indicating a “dramatic improvement in alertness and substantial reduction of cataplexy,” the defining symptoms of narcolepsy (32). A third paper (33) tested codeine on eight narcoleptic patients. Sleep diaries and patient reports revealed consistent symptom improvement compared to placebo; however, there were no significant differences in the multiple sleep latency tests (cataplexy was not tested for). This ambiguous result from a 1-week trial in three human patients appears to have ended opiate use for treatment of narcolepsy. In human studies, separating the placebo effect from the drug effect and from drug-seeking behavior
    can be difficult. We now show (Fig. 6B) that opiate treatment is effective in reducing or eliminating cataplexy in a mouse model of narcolepsy. It is possible that, with the appropriate schedule of administration and dosage, opiate agonists might be an effective treatment for human narcolepsy.

    I, for one, am willing to try it. I used to take Kratom on occasion some time ago, and found it very helpful for fatigue and anhedonia. I stopped taking it because I was scared of becoming dependent on it, but I’m dependent on dextroamphetamine as it is and at the very least, Kratom doesn’t have the tolerance problems that traditional opioids do. Matter of fact, due to its affinity to the delta opioid receptor, I feel like it actually increases my breathing capacity, unlike traditional opioids which depress breathing. That’d explain why thai and indonesian field workers will use some to increase their work output. I think I’ll buy some more Kratom to try. I’m going to China and Malaysia in September, I might pick up some Codeine otc to see if it helps or not.

    #6636
    TheRabbitKing
    TheRabbitKing
    Keymaster @deathrabbit

    I’ve had opiates for my weird pains and also for the lapchole last summer. They either seem to do nothing or make me ill and nauseated. I’ve not had any of the stronger stuff like morphine or oxycodone. Kind of afraid to. Percocet was a weird bad time

    My current jam: Anathema - Springfield

    #6640
    Jason
    Jason
    Keymaster @jasonm

    @pereise1 Have you had cyp2d6 testing done? Codeine is one of the drugs that will either make you sick, work as intended, or do next to nothing depending on your genotype since its the metabolite of codeine that is active rather than the parent drug.

    I’m still perplexed as to how the opiates are doing what the study suggests since neurogenesis was ruled out. It makes me wonder if the mu opioid action, which suppresses orexin firing (according to the study you posted previously on this thread) is causing a compensatory response but that doesn’t really make sense entirely either. Some opiates and indeed kratom, increase histamine quite potently and supposedly PWN have increased histamine neurons.

    @deathrabbit Percocet actually is just oxycodone mixed with with tylenol. If you’re opioid naive and too high of a dose is given, they’ll make you sick just as you describe, btw!

    #6644
    Ferret
    Ferret
    Moderator @ferret

    Thanks @pereise1 for the info.
    Question: I would also be interested to know what the long term use of opiates might be because they usually cause constipation… which can cause long term problems with the colon… and the gut is the backbone of the immune system.

    #6652
    Jason
    Jason
    Keymaster @jasonm

    Ferret reminded me of something, opioids taken long term can cause hypogonadism in men, further limiting their viability. Not sure exactly how they do this.

    #6654
    TheRabbitKing
    TheRabbitKing
    Keymaster @deathrabbit

    I forgot about the constipation of doom. When I was on the norco, I didn’t poop for like 8 days, then one day my body decided to flush and I lost 8 lbs of brown. Not exaggerating even a little.

    My current jam: Anathema - Springfield

    #8450

    Schills
    Participant @schills

    I’m still perplexed as to how the opiates are doing what the study suggests since neurogenesis was ruled out. It makes me wonder if the mu opioid action, which suppresses orexin firing (according to the study you posted previously on this thread) is causing a compensatory response but that doesn’t really make sense entirely either. Some opiates and indeed kratom, increase histamine quite potently and supposedly PWN have increased histamine neurons.

    Caveat, take anything I write with a grain of salt as I am not a doctor, or scientist by any stretch of the imagination.

    “A study in cocaine-addicted rats reports long-lasting increases in the number of neurons that produce orexin — a chemical messenger important for sleep and appetite — that may be at the root of the addiction. The study, performed by researchers at Rutgers University, New Jersey, was published in Biological Psychiatry. Restoring the number of orexin neurons to normal, or blocking orexin signaling in the brain, made the rats no longer addicted, suggesting the increased orexin neurons to be essential brain changes that cause the addicted state.”

    https://www.sciencedaily.com/releases/2018/09/180912111856.htm

    While this would appear to conflict with opiates increasing the number of Orexin producing, that perception is tied to how these drugs make us “feel,” the neurological effect of cocaine and opiates is to increase the amount of dopamine in the brain.

    We know that low levels of Orexin are associated with low levels of dopamine.

    “Additionally, in a final set of experiments, we used in vitro voltammetry in brain slices from wild type (WT) and hypocretin knockout (KO) mice to examine whether a complete loss of hypocretin signaling would produce deficits in dopamine signaling. Hypocretin KO and WT mice were sacrificed and recording and stimulating electrodes were positioned within the NAc core to allow for measurement of locally-evoked dopamine release (España et al., 2010). Table ​Table11 shows that under baseline conditions, hypocretin KO mice displayed reductions in both evoked dopamine release and dopamine uptake rate, again indicating that hypocretin neurotransmission is necessary to maintain normal levels of dopamine signaling.”

    https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3423791/

    At first glance elevated numbers of orexin producing neurons in the brians of both cocaine and heroine addicts appears to be contradictory. The commonality between the two is dopamine. Heroine and cocaine cause the brain to be flooded with dopamine, which is suppressed by GABA, which stimulates the production of Orexin. The levels of dopamine produced through cocaine and heroine use may far surpass the brains ability to produce GABA, forcing the brain to increase the number of GABA producing neurons, with the increased levels of GABA surpassing the brain’s ability to produce Orexin stimulating the production of new orexin producing neurons.

    As a non-scientist this suggests to me a cycle of artificial orexin, dopamine and gaba could stimulate the regeneration of orexin neurons in Type I and Type II narcoleptics.

    #8452

    Schills
    Participant @schills

    The earlier studies suggesting opiates were not effective in treating narcoloepsy is based on Naloxone, and Naltrexone showing no positive benefits for narcoleptics. https://med.stanford.edu/content/dam/sm/narcolepsy/documents/publications/ProgNeurobio52.pdf.

    The problem is Naloxone stimulates serotonin, not dopamine; https://www.ncbi.nlm.nih.gov/pubmed/3979585; while naltrexone is a dopamine antagonist; https://www.ncbi.nlm.nih.gov/pubmed/19630726. the absence of dopamine stimulation would appear to explain why neither Naloxone, nor Nalrexone effectively treat narcolepsy further supporting the guess elevated dopamine levels, and not the means of elevating dopamine, (e.g. cocaine verse heroine/codeine/morphine) that causes the increase in orexin neurons in the brains of drug addicts.

    #8477
    Pereise1
    Pereise1
    Participant @pereise1

    The earlier studies suggesting opiates were not effective in treating narcoloepsy is based on Naloxone, and Naltrexone showing no positive benefits for narcoleptics. https://med.stanford.edu/content/dam/sm/narcolepsy/documents/publications/ProgNeurobio52.pdf.

    The problem is Naloxone stimulates serotonin, not dopamine; https://www.ncbi.nlm.nih.gov/pubmed/3979585; while naltrexone is a dopamine antagonist; https://www.ncbi.nlm.nih.gov/pubmed/19630726. the absence of dopamine stimulation would appear to explain why neither Naloxone, nor Nalrexone effectively treat narcolepsy further supporting the guess elevated dopamine levels, and not the means of elevating dopamine, (e.g. cocaine verse heroine/codeine/morphine) that causes the increase in orexin neurons in the brains of drug addicts.

    The problem is, Naloxone and Naltrexone are opioid receptor antagonists, doing the opposite of what opioids like codeine or norco would do. Anecdotally, I’ve been trying Kratom every other day for the last 10 days, and even on days when I don’t dose, I feel better emotionally at least. Not exactly more awake, but I feel like I enjoy things more than before, like music and conversation. So it’s probably increasing my natural opioid receptors, and the orexin receptors involved in glee and enjoyment, but maybe not the orexin receptors involved in wakefulness. Still, I’ll take what I can get, and it doesn’t feel addictive in the slightest so I’ll keep trying it.

    #8479

    Schills
    Participant @schills

    As a non-scientist, I am just looking at a synopsis of the literature by researchers in the field who categorized Naloxone, and Naltrexone along with Codiene and morphine to further the proposition opiodates do not have a posiive effect on narcoleptics. So I think we’re viewing things from the same perspective, these studies mischaracterized Naloxone and Naltrexone.

    There is also the oddity of a group of drugs that usually make people sleeep, having positive wakefulness benefits for narcoleptics, and a separate group of drugs, which usually have the opposite effect of opiates, producing the same effect on the brain e.g. both opiate, and cocaine addicts having more Orexin neurons than the average person.

    The only thing that made sense to me was both of these drug types produce elevated levels of dopamine, which may stimulate elevated GABA production which in turn may stimulate the growth of additional Orexin neurons.

    #8722

    sleepyfrog
    Participant @sleepyfrog

    I’ve just started codeine 15mg qid. Which I think is the lowest dose shown to be effective based on the limited published literature.

    I expect it will take around 2-3 weeks to see if there is any benefit.

    #8724
    Ferret
    Ferret
    Moderator @ferret

    @sleepyfrog
    Please watch very carefully how often your bowels move. Should be a minimum of once per day or, ideally, after every meal.
    If you become constipated (which is a well known side effect of codeine) please consider taking a Senokot stool softener or equivalent.

    #8906

    sleepyfrog
    Participant @sleepyfrog

    I’ve just completed the first 17 days of codeine.

    Firstly

    My diagnosis is NT2/IH so experience my not be applicable to other conditions.

    Dosage

    Days 1-5 4 x 15mg spread evenly through the day

    Days 6-10 5 x 15mg, I took an additional tablet before going to bed

    Days 10-14 2 x 15mg upon waking and then 4 x 15mg spread evenly throughout the day

    These dosages all had a small but noticeable on my alertness and other symptoms

    Day 15 I doubled the dose to 5 x 30mg.

    This was more interesting, my alertness increased as the day progressed and by early evening I was very alert and this effect persisted until around 4.30am.

    This indicated that the alerting effect persisted longer than the half-life of the drug.

    Day 16

    5 x 15mg followed by 2 x 15mg, 2 x 15mg, 2 x 15mg, 1 x 15mg

    I found 3 published scientific studies that investigated the effect of morphine in the CNS. Criteria was humans, not for pain and must include dose used.

    On the basis of these I decided to try a larger initial dose of 75mg the next morning.

    Despite my lack of sleep I experienced my best alertness for years.

    Day 17 [today]

    When I awoke I felt pretty bad, I think due to the long gap between the last dose from the previous day, approx 11 hours.

    Issue is the development of tolerance and balancing the dose to avoid withdrawal, maintaining alertness and being able to sleep.

    I went to the doctor and we agreed that we would try dose ranging over the next couple of weeks.

    Step 1 Try various loading doses in the morning to find out at what dose response to the alerting effect tapers off, and to see how long the effect persists and how long it takes for any tolerance issues to kick in.

    One I’ve established the optimal first dose, and the duration oof the single dose effect I will have the information to plan the next step.

    No side effects, the alertness took around 1.5-2.0 to kick in following the first dose.

    At the lower doses I couldn’t tell that I had taken anything, at the higher doses I felt something for a few minutes prior to the alertness kicking in. Hard to describe but not sedation or euphoria and it wasn’t dramatic.

    My thoughts

    I was surprised at the dramatic acute improvement in my symptoms following the higher doses. I expected that any benefit would gradual and there would be a slow improvement over time, but it seems to work more like a switch.

    Also

    There are at least 4 biochemical systems in the brain that morphine has a stimulatory effect on. 3 of these seem to be impaired in people with narcolepsy.

    I want to double check the evidence regarding the impairment of these systems in narcoleptics before I post any details regarding this. The evidence for the stimualatory effect of morphine on these systems is clear and well documented.

    #9034

    sleepyfrog
    Participant @sleepyfrog

    Its been 2 weeks since I started dose ranging for codeine.

    After the first week I analyzed the subjective assessment of my alertness against the amount and timing of the doses taken.

    Taking a loading dose did not help, there was no evidence that taking a single dose higher than 45mg had any additional benefit over 45mg.

    However, doses lower than this had smaller effect on alertness.

    If I went for more than 8 hours without taking any dose my alertness would drop significantly.

    A dosage of 45mg 4 or 5 times day seemed optimal, for a total daily dose of between 180-225mg. This is roughly equivalent to a morphine dose of 18-22.5mg per day.

    From the UCLA article, the sole subject with narcolepsy and used morphine for pain at a dose of 2 x 10mg per day for 9 years, had a much larger number of hypocretin neurons than the control.

    Effect on symptoms

    Dramatic improvement in daytime alertness
    Reduction in sleep paralysis and sleep inertia to almost zero.

    Side effects

    No euphoria, or anything that could be considered recreational.

    After I started on the higher dose ie 150mg/day or greater I was unable to go to sleep, this coincided with the improvement in alertness during the day.

    I thought that this may be related to the alerting effects of codeine, but the sleepless persisted even if I scaled down or stopped codeine administration 8 hours before going to bed.

    After 2 weeks the sleeplessness started to abate and I have now had adequate, but not not great, sleep quantity for the past 4 nights. It maybe have been some sort of rebound effect from the brain’s response to the abnormal chemistry caused by the disease.

    I’ll persevere with the current dose for the next 4 weeks to see if the effect is sustained and then review with my doctor. Hopefully my sleeping pattern will continue to improve.

    I definitely got an acute benefit. And likely a long term benefit as well [from changes in receptors levels etc], but the effects of sleep deprivation make it a little challenging to be certain, and its still a little early.

    I should have a better idea in 4 weeks time, but at this stage it looks very promising.

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