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Manipulating opioid pharmacokinetics – Thinking out loud

Bamboozle

Bluelighter
Joined
Oct 24, 2003
Messages
64
I'm just going to use this thread as a means to post any information regarding how exogenous opioid use can be manipulated, for better or worse in the body. These are mostly just some random thoughts, facts and studies found regarding opiates and substances that may hopefully enhance euphoria. I am doing this a) Because it is quite interesting and may be useful and b) Because right now I am so very bored and have no means of transportation.

If you have ANY comments, suggestions, critisizims, personal notes, experiences or anything to add, please do. That's why I am posting this.

________________Notes;

Opiate receptors presynaptically inhibit transmission of excitatory pathways;
Acetylcholine, catecholamines, serotonin, and substance P.

Primary Opiate Receptors: mu, delta, kappa.

The brain's primary reward pathway is the mesolimbic dopamine system.
Neurons called dopaminergic because dopamine is manufactured, transported down the length of the neuron, for release into the synapses.

GABA normally plays a braking role on the dopaminergic cells.
Opiates and endogenous opioid neurotransmitters activate the presynaptic opioid receptors on GABA neurons.
This inhibits the release of GABA in the ventral tegmental area. Inhibiting GABA allows the dopaminergic neurons to fire more vigorously.
The release of extra dopamine in the nucleus accumbens is intensely pleasurable (no shit).

________________Stuff..;

Opiate receptor Mu is most prevalent in overall neuropharmacology
ACl & Serotonin are inhibited by Opiate receptors.
* S inhibitance due to dopamine ^ | or increases opioid effect?

Opiod euphoria is primarily caused by the Dopamine system
* hypothesized (medical) if other system exists it is not proven or observed currently.

GABA is inhibited , therefore DA neurons are more active.
* Further inhibition of GABA may increase Euphoria / duration of opioid?
* Find / investigate GABA inhibitors V.S morphine/opioids VIA medline.

Serotonin and Dopamine - mood /pleasure – Self regulate each other.
* Direct modulation / antagonization of each other, or co-incedental?
*Does inrease serotonin effect mood, pleasure or nasea w/ opioids?


________________studies;

Abstracts condensed (for relevance).

Right now I’m going to make a hypotheses that if a substance has the effect of raising analgesia (the absence of normal sensitivity to pain, typically, being in a semiconscious state) than chances are that its euphoric effect is also improved. For some strange reason the national library of medicine has few studies directly relating to increasing the euphoria of narcotics, they tend to focus more on the ‘legitimate medical uses’ of each drug. Strange I know.

5-HTP + Opioid
* To investigate serotonin.

Full studies available for reference on Medline:

Analgesic properties of a systemically-administered synthetic dipeptide of 5-hydroxytryptophan.

Synthetic peptides of 5-hydroxytryptophan (5-HTP), including N-acetyl-5-HTP-5-HTP amide (5-HTP-ACETYL-DP), specifically inhibit the binding of serotonin to serotonin binding protein. 5-HTP-ACETYL-DP also produces a long-lasting, opiate-sensitive analgesia following central, but not systemic administration.

Kappa opioid analgesia is dependent on serotonergic mechanisms.

The serotonergic dependence of mu and kappa opioid analgesia was compared in the mouse tail-flick and hot-plate assays using morphine and the selective kappa agonist, U-50, 488H, respectively. Depletion of serotonin with p-chlorophenylalanine resulted in a marked antagonism of U-50,488H analgesic potency in both assays

Both of these effects were dose-related and the latter was reversed by treatment with the serotonin precursor, 5-hydroxytryptophan. Several reputed serotonin antagonists (cyproheptadine, ketanserin and pirenperone) also antagonized U-50,488H analgesia. In contrast, the analgesic potency of morphine was only decreased slightly by p-chlorophenylalanine and reserpine, and not at all by the serotonin antagonists. Thus, kappa, but not mu, analgesia is strongly dependent upon serotonergic mechanisms in these assays. However 5-hydroxytryptophan did not enhance U-50,488H analgesia in nonpretreated mice or in mice made tolerant to U-50,488H. On this basis it appears that kappa opioid tolerance is not due to serotonergic hypofunction.

Antagonism of the analgesic effect of opioid and non-opioid agents by p-chlorophenylalanine (PCPA).

The ability of p-chlorophenylalanine (PCPA), an inhibitor of serotonin (5HT) biosynthesis to antagonize the antinociceptive effects of three classes of analgesics: opiates agonist (morphine), opiate agonist-antagonist (pentazocine) and non-steroid anti-inflammatory (aspirin and clonixin) were evaluated using the rat yeast paw test. The analgesic effect of equipotent doses of each of these drugs was abolished 48 h after PCPA (300 mg/kg i.p.) PCPA (150 mg/kg i.p.) reduced the relative potencies of morphine and aspirin to the same degree. The effect could not be attributed to a hyperalgesia or to an interaction with inflammatory mechanisms. PCPA did not alter the anti-edema activity of clonixin and it blocked morphine-induced increases in reaction times to pressure applied to the non-inflamed paw to the same extent as in the inflamed paw. The serotonin precursor 5-hydroxytryptophan (5HTP, 80 mg/kg i.p.) restored the antinociceptive activity of all four drugs. These results demonstrate serotonin can modulate sensitivity to analgesics with differing mechanisms of action.

Central action of narcotic analgesics. VII. The role of serotonin

The development of tolerance to morphine-induced motor activity of mice and rats, as well as the influence of drugs which alter the brain serotonergic functions on the development of morphine tolerance was studied.

Tolerance to morphine was induced by subcutaneous implantation of morphine-base pellets. After 72 h pellets were removed and 6 hr later motility was tested. Implantation of morphine pellets caused the development of tolerance to morphine-induced motor activity of mice and rats. Development of morphine tolerance was inhibited in mice and rats by p-chlorophenylalanine (pCPA) or reserpine, drugs which decrease content of brain serotonin.

5-hydroxytryptophan (5-HTP) inhibited the above effect of pCPA in mice, while tryptophan did not. Administration of 5-HTP, which protected serotonin stores against depleting action of reserpine decreased inhibiting action of reserpine on the development of morphine tolerance in rats. Although cyproheptadine and pizotifen did not alter the development of morphine tolerance in rats, nevertheless, it seems from these results that serotonin neurotransmission is of some importance in the development of tolerance to morphine.


Morphine analgesia and its modification by drugs altering serotonin (5-HT) and dopamine levels in the brain.

Morphine analgesia in mice was significantly potentiated by pretreatment with 5-hydroxytryptophan (5-HTP), especially with higher dose of morphine. Morphine analgesia was antagonised by reserpine. With l-dopa it was antogonised when the dose of morphine was minimal but with increased dosage of morphine, there was no significant effect.

Effect of narcotics on the uptake of serotonin precursors by the rat brain.

The extraction of 14C-tryptophan and 14C-hydroxytryptophan (5-HTP) from the blood to the brain was measured using an indicator dilution technique. Acute treatment with morphine caused a dose-related decrease in the extraction of tryptophan by the brain and a increase in that of 5-HTP.

In contrast to acute treatment with morphine, the extractions of tryptophan and 5-HTP were not significantly altered 48 hours after chronic treatment with morphine. The extraction of 5-HTP remained unchanged and that of tryptophan increased significantly 72 hours after chronic morphine treatment. these results suggest that an increase in the rate of central serotonin synthesis after acute treatment with morphine may be due to an increased uptake of 5-HTP from the blood to the brain while that after chronic treatment with morphine may be due to an increased uptake of tryptophan.

If anybody can get a hold of these abstracts please post them!

Eur J Pharmacol. 1973 Jun;22(3):339-43.
Decrease of tolerance development to morphine by 5-hydroxytryptophan and some related drugs. Contreras E, Tamayo L, Quijada L, Silva E.

Nature. 1970 Mar 21;225(238 ):1152-3.
Possible mechanism of action of morphine on brain.Eidelberg E, Schwartz AS.

Fed Proc. 1970 Jan-Feb;29(1):28-31.
Central neurohumoral systems involved with narcotic agonists and antagonists.Harris LS.

_____

Need nourishment- will be continued ..

Want to look at dopamine precursors, gaba inhibitors and enzyme-inducers.
(OTC / Supplemental) Also the nootropic angle; DMAE / vinpocetine.
 
Focus on: Dopamine & Opioid interaction.

Supplements that may increase dopamine:

NADH
St. John's wort
tyrosine
phenylalanine
Mucuna pruriene
CDP-choline
theanine

Medications that may increase dopamine:

Deprenyl / Wellbutrin (bupropion) / Uprima (apomorphine) / Mirapex (pramipexole) / Permax (pergolide) / Dostinex (cabergoline) / Requip (ropinirole)


________________Phenylalanine + Opioid

L-phenylalanine (LPA) serves as a building block for the various proteins that are produced in the body. L-phenylalanine can be converted to L-tyrosine and subsequently to L-dopa, norepinephrine, and epinephrine.

D-phenylalanine (DPA) is not normally found in the body and cannot be converted to L-tyrosine, L-dopa, or norepinephrine. DPA appears to influence certain chemicals in the brain that relate to pain sensation.

DLPA is a mixture of the essential amino acid LPA and its mirror image DPA. LPA is found in most foods that contain protein. DPA does not normally occur in food, but when synthesized in the laboratory, half appears as LPA and half as DPA. The combination supplement (DLPA) is often used because both components exert different health-enhancing effects.

___________________Stuff..;

The brain responds to pain signals by producing and activating morphine-like hormones called endorphins. This pain relief effect lasts for about 30 hours (longer than known analgesics), and without side-effects when given frequently.

It was discovered that d- and dl-Phenylalanine (DLPA), but not l-Phenylalanine, inhibit several of the enzymes responsible for endorphin destruction. DLPA appears to restore endorphin levels to a normal range, while simultaneously producing a reduction in pain. It often equals or exceeds morphine or other opiate derivatives in its effect and is non-addictive.

A 1991 study confirmed that DLPA could be used in combination with morphine to reduce the dosage of the opiate and lower its undesirable side effects.

D-phenylalanine has also been shown to promote the action in the brain of the small protein molecules known as endorphins and enkephalins. These are natural, morphine-like biochemicals that reduce pain and promote mild euphoria. D-phenylalanine is thought to work by inhibiting the enzymes that normally break down endorphins and enkephalins. This allows endorphins and enkephalins to stay active longer, thus enhancing mood and preventing the perception of pain . D-phenylalanine can also be converted in the body into the compound phenylethylamine, which is thought to have mood-boosting effects.

________________studies;

DL-phenylalanine markedly potentiates opiate analgesia - an example of nutrient/pharmaceutical up-regulation of the endogenous analgesia system.

DL-phenylalanine (DLPA) often appears to potentiate pain relief and also ease depression in patients receiving opiates for chronic non-malignant pain. An analysis of this phenomenon suggests that it may be mediated, at least in part, by up-regulation of the 'endogenous analgesia system' (EAS).

Since serotonin and enkephalins are key neurotransmitters in the EAS, it is reasonable to predict that measures which promote serotonin activity (such as 5-hydroxytryptophan and serotonin-reuptake inhibitors) as well as enkephalin activity (such as D-phenylalanine, an enkephalinase inhibitor) should potentiate EAS-mediated analgesia - a view consistent with much previous medical research.

Comprehensive support of the EAS with well-tolerated nutrients and pharmaceuticals may amplify the analgesic efficacy of chronic opiate therapy, while enabling dosage reductions that minimize opiate side-effects. Analogously, this approach may complement the efficacy of acupuncture and other analgesic measures that activate the EAS.

Analgesic effectiveness of D-phenylalanine in chronic pain patients.

Enkephalins are a biochemical pathway for endogenous analgesia. A number of compounds inhibit degradation of enkephalins within the body. One of these compounds, D-phenylalanine (DPA), has been shown to increase the pain threshold in animals. It is hypothesized that this naloxone reversible analgesia is induced by DPA blockage of enkephalin degradation by the enzyme carboxypeptidase A.

The analgesic action of d-phenylalanine in combination with morphine or methadone

The analgesic action of D-phenylalanine (D-Phe) is well known. It has been demonstrated in hot-plate tests on mice that combining D-Phe with narcotic analgesics already with doses inactive on separate application. In combination with D-Phe, a dose of morphine less by half compared to its unique use does not reduce analgesic activity in rats, but after six weeks of treatment some undesirable side effects like dependence, behavioural disorders and growth retardation are markedly lowered. These results suggest the possibility to design a combined drug similarly effective as well-introduced narcotic analgesics, but better tolerated.
 
THEANINE increases dopamine & GABA.
*GABA is inhibited for optimal opioid effect, hence theanine is out.


L-Tyrosine | amino acid
Makes thyroid hormones.
Precursor to neurotransmitters noradrenalin (norepinephrine).
precursor to dopamine.
Involved in metabolism of the amino acid phenylalanine.


Note: the enitre molecule of morphine is essentially derived from two molecules of L-tyrosine.
*Perhaps pre-supplementation/loading of Dopa-precursors create more efficient morphine creation.

Engineered Mice Point to New Target for Pain Relief
The researchers report in the Dec. 24 Science that morphine prevents pain longer and more completely when administered to mice engineered to lack a protein switch called "beta-arrestin 2." Beta-arrestin normally comes into play after morphine is administered by blocking the chemical signal that morphine sends to the brain to suppress pain sensation. Thus, when the researchers genetically altered mice to lack beta-arrestin, morphine remained effective for longer periods in those mice, and lower morphine doses were required to achieve pain relief in these mice.
http://dukemednews.duke.edu/news/article.php?id=262

OFF-TOPIC / Interesting.
The cognitive and psychomotor effects of morphine in healthy subjects: a randomized controlled trial of repeated (four) oral doses of dextropropoxyphene, morphine, lorazepam and placebo

ABSTRACT
Ten healthy subjects (four male) of mean age 31 years (range 25-40) took part in a randomized double-blind four-way crossover study to examine the cognitive and psychomotor effects of repeated oral doses of dextropropoxyphene and morphine. Four treatments were compared: dextropropoxyphene napsylate 100 mg, morphine sulphate 10 mg, lorazepam 0.5 mg and placebo. Four doses of each drug were given at 4-h intervals to each subject on four separate study days at least 1 week apart. Cognitive function was assessed using choice reaction time, number vigilance, memory scanning, immediate and delayed word recall, word recognition, picture recognition, critical flicker fusion threshold (CFFT) and subjective measures of alertness, calmness and contentment.

Morphine had one major effect, which was to increase the accuracy of responding on the choice reaction time task, at every assessment. Morphine produced some sporadic effects in other tests and an increase in subjective calmness. Dextropropoxyphene impaired performance on choice reaction time and picture recognition. These data show that oral morphine may enhance performance in some measures of cognitive function, whereas dextropropoxyphene (in usual therapeutic doses) seems more likely to cause impairment. Neither opioid has substantial effects on cognition and psychomotor function compared with lorazepam.
 
I will try the following and report back:
Friday perhaps.

Oxycodone is an option. Yet most of these ellicit action on morphine, so (morphine aside) I will probubaly just use some extracted codeine > conversion > morphine.

[2 Hour prior]
Ginger Root - 1000mg
Pepto - [N/A Due to salicylate & aspirin]

[1.5 Hour prior]
5-HTP - 100mg
D-phenylalanine (DPA) - 500mg
L-phenylalanine (LPA) - 500mg

[1 Hour prior]
Tyrosine - 5g (Protein shake) - 20 min digestion

[316mg Codeine P.]

*Ginger root for nausea prevention, pepto is out as aspirin & bismuth may cause salicylate toxicity, 5-HTP for serotonin, euphoria potentiation & minor sedation (from caffeine), phenyl's as dopamine precursors and enzyme inhibition, tyrosine as dopa precursor. Choline / Vinpo et all nootropics pending upon order arrival. Spaced out tyro to avoid A.A competition. ALA taken hours before for liver protection / anti-oxidant. Comments?
 
Other than a few small things, your theory seems sound. I hope you have figured your doseage according to your spicific body type and tolerance, also take into account that if you are trying to increase the effects of the codeine (morphine in the brain) you might have to adjust dosage. I would be interested in hearing if this worked. You should also compare it to a standard NMDA antagonist to compare effects. Be safe, Have Fun.
 
Thanks for the input, and yeah the dosage will probably need some adjusting.

I was off all opioids (oxy 2x month) for the last two months, until using codeine @ 250mg (2 days ago) so I would have a baseline euphoria to compare this too (not very scientific I realize). That dose seemed too low compared to previous euphoria, versus my assumed personal maximum @ 350mg (w/ 2 Maalox + 2-3mg ativan) which made my respiratory depression very noticeable and I had to stop and concentrate on deep breathing for maybe an hour. For some reason the codeine from two days ago put me asleep for 36 hours though.

I'm also looking into different antihistamines right now for nausea and maybe ichyness but with the 5-htp don't want to use anything sedative. Maybe a small cyanocobalmin injection would help with alertness / mood.

I will drop the dosage to either 280-300, with a re-dose of 50mg (which may be useless considering the metabolic nature of codeine) or just compensate with oxy's @ 10:1 mg.
 
Good topic: only had time to quickly look at this, but:

for itching i found the antihistimine cetirizine to be very effective

5HTP sounds good in theory, i would go for 100mg doses
DL phenylanaline + L Tyrosine, with Folic Acid (all of the amino acids must be taken on an empty stomach - due to protein binding).


To lengthen the opiate experience - tagamet (Cimetidine) and supposedly grapefruit juice; due to their action on Cytochrome P450 enzyme CYP3A

Vitamin C is supposed to deplete methadone (for example) faster


some others on the site below
http://adhpage.tripod.com/potentiators.htm
 
First, kudos to everyone who has read & understood most of the thread, I have tried to uber-trunctuate all the abstracts and make my conclusions brief, though the final product is still quite extensive. All data still being carefully examined and conclusions will be altered before I am done.

Enzymatic manipulation is one of the few verified ways to increase drug effectiveness, so there is not much more to divulge regarding that topic. *Perhaps finding some sort of standardized grapefruit extract and megadosing would be effective?

The antihistamines are a great deal trickier to figure out. The anti-cholinergic nature of most of them will either hinder the euphoria with over-drowsiness, and potentially over-inhibit ACl release (Note: Opioids would also contribute) *or* act to enhance the opioid as Anticholinergic’s diminish the effect of ACl; (ACl; can counteract the effect of dopamine). This topic will need further consideration.

I will look into cetirizine, although I believe most people on here also use promethazine. Meclizine looks anti-sedative & effective also.

________________Studies..;

Increased probability of GABA release during withdrawal from morphine.

Opioid receptors located on interneurons in the ventral tegmental area (VTA) inhibit GABA(A)-mediated synaptic transmission to dopamine projection neurons. The resulting disinhibition of dopamine cells in the VTA is thought to play a pivotal role in drug abuse. The regulation of GABA release during acute withdrawal from morphine was studied in slices from animals treated for 6-7 d with morphine.

The results indicate that the probability of GABA release was increased during withdrawal from chronic morphine treatment and that this effect resulted from an upregulation of the cAMP-dependent cascade. Increased transmitter release from opioid-sensitive synapses during acute withdrawal may be one adaptive mechanism that results from prolonged morphine treatment.

Immediate and "day-after" effects of morphine on dopamine and serotonin metabolism in various structures of the rat brain.

The effects of a single dose of 20 mg/kg ip of morphine on dopaminergic and serotonergic systems in the limbic (cortex, nucleus accumbens) and extrapyramidal (striatum) structures were investigated in rats.

We have demonstrated that a single large dose of morphine produces a biphasic change in limbic dopaminergic and serotonergic structures, with an initial activation followed by significant inhibition 24 h later. In contrast, the striatum depression of dopamine level was observed during the initial phase with normalization on the next day.

Co-administration of dextromethorphan with morphine attenuates morphine rewarding effect and related dopamine releases at the nucleus accumbens.

Morphine is one of the most effective analgesics in clinic to treat postoperative pain or cancer pain. A major drawback of its continuous use is the development of tolerance and dependence. In our previous study we found that a widely used antitussive agent in clinics, dextromethorphan [(DM); also known as a non-competitive N-methyl- d-aspartate (NMDA) antagonist], could prevent the development of morphine tolerance.

In the present study, we further investigated its effect on morphine addiction. Conditioned place preference (CPP) test and behavioral sensitization of locomotor activity were used to investigate the drug-seeking related behaviors, which were in correlation with psychological dependence. Our results showed that co-administered DM was able to abolish completely the CPP effect induced by morphine, but had no effect on morphine-induced behavioral sensitization.

By employing the microdialysis technique in free-moving animals, we also determined the extracellular level of dopamine and serotonin metabolites in the shell region of the nucleus accumbens (NAc) in its response to morphine with/without DM. A significant increase in dopamine metabolites following morphine administration was demonstrated in the NAc. This increase by morphine could be attenuated by co-administered DM, whereas DM itself did not show any effect. Based on our results, it is speculated that DM may effectively attenuate morphine-induced psychological dependence. Neurochemical analysis revealed that the effect of DM could be through its action on the dopaminergic mesolimbic pathway, which could be activated by morphine and attributed to the cause of rewarding.

Morphine increases 5-HT metabolism in the nucleus raphe magnus: an in vivo study in freely moving rats using 5-hydroxyindole electrochemical detection.

It is concluded that morphine clearly increases the metabolism of serotonin (5-HT) in the NRM, and one could speculate that the increase in 5-HIAA results from 5-HT release. Such a release could be due either to 5-HT terminals originating in the periaqueductal gray, or to somato-dendritic mechanisms.

Morphine analgesia without development of tolerance in reserpinized mice.

The relationship between the brain monoaminergic mechanism and morphine tolerance was examined in reserpinized mice. These results may suggest that suppression of the development of tolerance to morphine analgesia is not attributed to the reduction of brain norepinephrine and dopamine by reserpine. Morphine analgesia without development of tolerance in reserpinized mice may indicate the dissociation of the analgesic effect from tolerance liability.

Central action of narcotic analgesics. VI. Further studies on the participation of serotonin in the action of analgesics.

The effects of agents changing the cerebral serotonin (5-HT) level on the action of morphine, codeine, fentanyl and pentazocine were tested in rats with the tests of catalepsy and analgesia (hot plate).

In addition, the effect of analgesics of the level and turnover of cerebral 5-HT was studied. Depression of the cerebral level of 5-HT usually antagonized the behavioral effects of analgesics, but the effect varied with the agent depressing the 5-HT level. The serotonergic influences in catalepsy seem to be more pronounced than in analgesia.

An increase in the cerebral level of 5-HT may potentiate the analgesic and prolonged the cataleptogenic effects of some drugs (morphine and pentazocine), not affecting the effect of others (fentanyl, codeine). The potentiation by morphine of the turnover of cerebral 5-HT in rats is not a common property of analgesics agents.

Central action of narcotic analgesics. V. Participation of serotonin in the mechanism of action of narcotic analgesics.

The influence of serotonergic system on the changes in locomotor activity of mice and rats brought about by morphine, fentanyl, codeine and pentazocine and on morphine induced catalepsy in rats was studied.

p-Chlorophenylalanine (pCPA) did not affect the behavioral changes produced in mice by morphine, fentanyl, codeine and pentazocine but reduced the behavioral depression produced by these drugs in rats.


5-Hydroxytryptophan (5-HTP) but not tryptophan (TP) reversed the action of pCPA on the effect of morphine and fentanyl. After reserpine the depression produced in rats by morphine and fentanyl was more pronounced. TP did not change the depression produced by combination of reserpine and morphine but counteracted the depression observed after combination of reserpine and fentanyl. In mice reserpine protected against hypermotility produced by morphine or fentanyl and TP potentiated the depression produced by the combination of reserpine and morphine or reserpine and fentanyl.

Serotonin precursors, 5-HTP and TP evidently potentiated the morphine induced catalepsy. pCPA counteracted only the enhancement of the catalepsy observed after TP administration. Naloxone abolished the catalepsy after combined treatment with morphine and TP. Similarly but weaker acted cyproheptadine. The results suggest that the serotonin system plays a role in the effects of morphine and fentanyl on rat locomotor activity. An increase in the cerebral serotonin level increases the morphine catalepsy in rats.

Effects of morphine on release of acetylcholine in the rat striatum: an in vivo microdialysis study.

These findings indicate that morphine exerts an inhibitory influence on striatal ACh release in freely moving rats and that this inhibitory effect is mediated by the nigro-striatal dopaminergic system.

Antinarcotic effects of the standardized ginseng extract G115 on morphine.

The study was undertaken to determine the antagonism of morphine analgesia by the standardized ginseng extract G115 from Panax ginseng, the inhibitory effects of orally administered G115 on the development of morphine-induced tolerance and physical dependence, the hepatic glutathione levels, the inhibitory effects of intraperitoneally administered G115 on the dopamine receptor supersensitivity, and the reverse tolerance to the locomotor accelerating effect of morphine. G115 significantly inhibits the development of morphine-induced tolerance and physical dependence, the hepatic glutathione level decrease induced by morphine multiple injections, the development of morphine-induced dopamine receptor supersensitivity, and reverse tolerance to the locomotor accelerating effect of morphine. It did not, however, antagonize morphine analgesia.

*Potential for lowering tolerance?
*Herbal narcan?
 
[EDIT - The only decent thread we have in this forum and you troll it up... fuck that]
 
Last edited by a moderator:
An excellent potentiator is proglumide, which works through the NMDA system. It is used for some stomach medication in europe, and i procured some tablets and found it to be pretty good stuff. I forgot the brand name, starts with an M, but its cheap..........

Also, quinine is widely over-looked, and as i've said many times before, 250mg capsules are available at aquarium stores with the brandname "quinsulex". It works suprisingly well.

Cimetidine and grapefruit juice, and other cytochrome p450 inhibitors do not really make the high any better, it only lenghtens it, and doesnt work on codeine. There are definately much better potentiators.

There are other drugs ive experimented with as potentiators, clonidine (which supposedly has an effect on certain opiate receptors), luvox, phenergan, 5-htp, atarax, ketamine (dxm is worthless), and even quinoline anti-biotics, like cipro, which according to a medical journal I read, had been found to potentiate methadone.

I think your experiments are note-worthy, and opiate potentiators are interesting, but why beat around the bush, if you want to get seriously high go get some oxycodone or heroin instead of codeine. Potentiators are usefull, but ive tried many, and there still is no substitute for simply a stronger drug......
 
I would like to see the results from your tests with all the potenators. Please post them sometime!:)
 
negrogesic said:

I think your experiments are note-worthy, and opiate potentiators are interesting, but why beat around the bush, if you want to get seriously high go get some oxycodone or heroin instead of codeine. Potentiators are usefull, but ive tried many, and there still is no substitute for simply a stronger drug......

I have access to stronger opiates like morphine, hydro and oxy - but right now at least, prefer the less pronounced effect that codeine has. Plus using codeine I have more room for error, and changes in degree of euphoria can be notably observed. I actually prefer and use Oxy moreso but I just want to experiment with the lesser first. The reason I'm investigating opiate potentiators, rather than simply increasing the dose is because;

a) Just increasing the dose/drug is the fastest way to accentuate tolerance. Important when you consider the speed at which this occurs with opoids. Plus tolerance in itself has a multiplicity of short/longterm side effects.
b) Potentiators can work on different pathways, sero/dopa/gaba etc .., and therefore have some unique effects that do not occur through normal opioid metabolism.
c) Due to lots of time and interest, I have already self researched the following in depth; aMSH and its peptides, glucose disposal agents,(nondiabetic) insulin & cyanocobalmin use, and recently Nootropics. So this is next, although will be a harder topic to use in the future for legitimate submission.

Hope that answered some of your questions. If you could actually report on the effects and dosages you used with your experiments that would be greatly appreciated. Notably; proglumide, phenergan, 5-HTP and quinine.
 
I agree with the use of Codeine for your experiment. Also quinine was mentioned above but I would use caution with that for I believe it changes the permeablity of the blood brain barrier. As with all true experiments you should keep it to one variable, have a control, and repeat, but in the case of repetition be carefull. Dont forget to publish results.
 
Thought i'd add this. supposedly, according to reports i have read quinine is added when H is made in many countries. This is of particular interest as i remember the high of pharm diamorph is not as intense as street H.

Like the idea of a herbal narcan, the Thais or Cambodians use Heanto, not sure of it efficacy - as you see all these poor sould puking violently, there must be something to this as it seems to act like a pure antagonist.
 
phreex, i doubt it, u close 9 outta 10 threads, everyone hates u, so the odds dont look good for this post, nothing personal.
 
plz help, how can one use this information to potentiate hydrocodone/oxycodone? or can you just use the same potentiators as are used for codeine?
 
Tri-nity[/i] [B]phreex said:
Who's everyone? You?
^Seriously...but that's really not important, I'm not gonna get this thread off track.

Very interesting study, intelligent, well thought out... just curious, have you recieved formal education for this type of stuff or has all this been learned through personal experiance and the internet?
 
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