any plants with the action of naloxone?

[t st tantra]

am interested in the low dose treatment with naloxone but not in naloxone.

so is there a plant compound that does something similar?

t s t .

[mac]

I don't have alot of knowledge or education on these sort of things & this is a little over my head forgive me if im way off most of my info comes from wiki

Anyhow plants ,plant compound's drugs that have similar effects to Thebaine, or Thebaine derivative's i guess would be somewhere to start looking ?

Thebaine may not be used therapeutically but naloxone is one of drugs on the list of drugs derived form Thebaine, others include oxycodone, oxymorphone, nalbuphine, naltrexone, buprenorphine and etorphine.

something that may be of interest

Dihydroetorphine is a potent analgesic drug (painkiller),[1] which is used mainly in China. It is a derivative of the more well-known opioid etorphine, which is used as a very potent veterinary painkiller and anesthetic medication, primarily for the sedation of large animals such as elephants, giraffes and rhinos.

Dihydroetorphine is a semi-synthetic opioid, used mainly as a strong painkiller for humans.[2] It is several thousand times stronger than morphine (between 1000x and 12000x more potent depending what method is used for comparison), although it is poorly absorbed when taken orally. Sublingual forms of dihydroetorphine are used in China at doses ranging from 20 to 180µg, and are reported to cause strong analgesia and relatively mild side effects compared to other opioids, although all the usual opioid side effects such as dizziness, sedation, nausea, constipation, and respiratory depression can occur. Transdermal patches of dihydroetorphine have also been developed.[3]

Dihydroetorphine is considered to be somewhat less addictive than many other opioids, and is also sometimes used in China as a substitute maintenance drug for opioid addicts,[4] in a similar way to how the related drug buprenorphine is used in western nations

Sounds promising between 1000x and 12000x more potent than morphine with relatively mild side effects, but no mention of tolerance ?? id ask my GP but i doubt he has any info on Dihydroetorphine & will just write up another script for tramedo

Edited March 10, 2009 by mac

[cactophyle]

Fentanyl (aka Duragesic) is also 1000x more potent that morphine, and it is available as a patch. But I don't recommend it -- it is the most physically addicting material I've ever encountered and the wd's are the worst! Low side-effects is a marketing gimic -- all opioids have the same side effects. I've tried a lot of stuff, including suboxone (w/naloxone), and I have to say that I consider good old Morphine to be the safest and most manageable.

I am actually on naltrexone (ULDN I think the therapy is called) daily to prevent opioid tolerance currently, and it does seem to help. I hear ULDN treatment minimizes wd too, and I think this is true, as does Kratom tea seem to be helpful. I would say Kratom is the most naloxone/naltrexone-like substance in that regard. But I don't know of anything containing a natural naloxone/naltrexone analog.

Is your purpose to save your girlfriend if she OD's, or are you trying to keep your own tolerance down? I guess it depends on what your goals are. Since you don't want the real Naloxone I assume you're dealing with a 'habit' that your doctor doesn't know about, or you want to avoid emergency room visits, neither of which sounds good.

[t st tantra]

i'm interested in plants which may help people ,usually being treated by a doctor,to deal with the development of tolerence so they can obtain relief from chronic pain at a low dose of opioid for a long period of time.

t s t .

[Conan Troutman]

Interesting topic and not one I have ever really considered...until now

Though I have found a recent interest in the plant based indolic opioids and in particular, Picralima nitida (fam. Apocynaceae) which is said to have both agonist and antagonist properties and interestngly looks quite similiary related to mitragynine.

Mitragynine:

Akuammine

Akuammine, an indole alkaloid, is the most abundant active alkaloid found in the seeds from the tree Picralima nitida, commonly known as Akuamma.

The dried seeds from this plant are used in traditional medicine throughout West Africa, particularly in Ghana as well as in the Ivory Coast and Nigeria. The seeds are crushed or powdered and taken orally, and are mainly used for the treatment of malaria[1] and diarrhoea, and as a painkiller. An enterprising Ghanaian hospital started manufacturing standardised 250mg capsules of the powdered P. nitida seed, and sold them around the country where they became widely accepted as a safe and effective pain relief product. This then led researchers to try and discover the active component of the seeds.

P. nitida seeds contain a mixture of alkaloids producing antipyretic and antiinflammatory effects along with analgesia.[2][3] Several of these were shown to bind to opioid receptors in vitro, and two compounds, akuammidine and ψ-akuammigine, were found to be potent μ-opioid agonists, although not particularly selective. Surprisingly the main alkaloid from the seeds, akuammine, was found to be an opioid antagonist when tested in vitro and canceled out the effects of the active agonist components.[4]

Given the confirmed activity of the whole seed extract in humans, this makes it likely that akuammine is in fact being metabolised once inside the body to form an active metabolite, in a similar way to how the closely related compound mitragynine is metabolised to the more active 7-hydroxymitragynine.

Akuammine is the main alkaloid found in the seeds, comprising 0.56% of the dried powder, indicating that the 250 mg "Picap Capsules" sold commercially should contain approximately 1.4 mg of akuammine, plus 0.085 mg akuammidine and 0.015 mg ψ-akuammigine. Akuammine is structurally related to both yohimbine and mitragynine, both of which are alkaloid plant products with uses in medicine.

BOLD ADDED FOR EMPHASIS

LINK

as above there a compounds that are much more potent than Fentanyl, many of which are related to Fentanyl (Anilidopiperidines) and are classed as ultra-potent such as Remifentanil but also other semi-syntheic drugs like Etorphine, Acetorphine which are several thousand times the potency of morphine and are commonly used in veterinary for large animals.

Might also be worth noting tolerance and dependance can largely be attributed to half-life short acting compounds are seen to be more 'addictive'. The ultra-potent and short acting Anilidopiperidines top the list.

[cactophyle]

i'm interested in plants which may help people ,usually being treated by a doctor,to deal with the development of tolerence so they can obtain relief from chronic pain at a low dose of opioid for a long period of time.

t s t .

Sorry, I'm new here. I think I just saw in an old Salvia thread that you were researching chronic pain back then too. You probably should expand your search for Naltrexone and Naloxone, because both are potent opioid antagonists, the latter being shorter acting requiring repeated dosing I believe.

The treatment I think you are interested in is called Ultra Low Dose Naltrexone (ULDN) therapy and is supposed to prevent the tolerance of opiates (for pain) by taking very small doses of opioid antagonists on a regular basis. The synthetic opioid Suboxone contains an ultra low dose of Naloxone, but it's purpose is supposedly to prevent injection of the drug since it is commonly prescribed in addiction treatment in the place of Methadone. Here is an example of what you might find if you Google "ULDN": http://jpet.aspetjournals.org/cgi/content/full/300/2/588. Erowid: http://www.erowid.org/pharms/naloxone/naloxone.shtml, and http://www.erowid.org/pharms/naltrexone/naltrexone.shtml.

Conan: You are correct that the short acting opiods cause the most intense withdrawals, as is the case with fentanyl.

[t st tantra]

yes the uldn idea is what has sparked my interest but i prefer plants to synthetics.......

t s t .

vinca major,think thats the common weedy one,seems to contain vincamajoridine which is synonymous with akuammine.........synchronicity that i harvested some yesterday for the first time in a year or more.......the alchemist put me on to vinca root,its fine stuff,closest to vinpocetine i've found so far......

http://www.springerlink.com/content/ux67530263844116/

yohimbine needs to be looked at too.....has nmda interactions but maybe kappa opiod too could explain some things?

Edited March 28, 2009 by t st tantra

[cactophyle]

It would seem impossible to me to attempt to use a natural source of Naloxone for ULDN type therapy. The problem is that the dosage needs to be in the range of 2mcg -- which is, of course, ultra low -- and due to the variability of alkaloids in botanicals getting the dose anywhere near that presents a major problem. It is likely that the result of attempting to consume a botanical for this purpose would be too high a dose of Naloxone/Naltrexone, resulting in decreasing the effect of the prescribed opioid (OR instant withdrawal sickness!), which is the exact opposite of the desired outcome.

If your goal was to diminish withdrawal symptoms then you would surely have better luck. Kratom and Ibogaine are most recognized for this as I assume you are aware.

[t st tantra]

while some may dis homeopathy ,it would still be a useful method for preparing any dilution required........

t s t .

Naltrexone, and its active metabolite 6-β-naltrexol, competitve antagonists at μ- and κ-opioid receptors, and to a lesser extent at δ-opioid receptors.

am reading through the links,thanx,judging by the kinds of diseases being treated with ldn alone, it might work for rls......

so what is the required ratio,eg what is a normal dose? and what is the ldn dose? and the ratio of one to the other?

In general, in people with diseases that are partially or largely triggered by a deficiency of endorphins (including cancer and autoimmune diseases), or are accelerated by a deficiency of endorphins (such as HIV/AIDS), restoration of the body's normal production of endorphins is the major therapeutic action of LDN.

Edited April 1, 2009 by t st tantra

[cactophyle]

I'm not dissin' homeopathy ... I just don't find Naloxone that interesting. Well, plus I have an endless supply of it!

[t st tantra]

Naltrexone in the large 50mg size, originally manufactured by DuPont under the brand name ReVia, is now sold by Mallinckrodt as Depade and by Barr Laboratories under the generic name naltrexone.

LDN prescriptions are now being filled by hundreds of local pharmacies, as well as by some mail-order pharmacies, around the US. Some pharmacists have been grinding up the 50mg tablets of naltrexone to prepare the 4.5mg capsules of LDN; others use naltrexone, purchased as a pure powder, from a primary manufacturer.

The usual adult dosage is 4.5mg taken once daily at night. Because of the rhythms of the body's production of master hormones, LDN is best taken between 9pm and 3am. Most patients take it at bedtime.

Because LDN blocks opioid receptors throughout the body for three or four hours, people using medicine that is an opioid agonist, i.e. narcotic medication — such as Ultram (tramadol), morphine, Percocet, Duragesic patch or codeine-containing medication — should not take LDN until such medicine is completely out of one's system. Patients who have become dependant on daily use of narcotic-containing pain medication may require 10 days to 2 weeks of slowly weaning off of such drugs entirely (while first substituting full doses of non-narcotic pain medications) before being able to begin LDN safely.

http://www.lowdosenaltrexone.org/

t s t .

Edited April 1, 2009 by t st tantra

[t st tantra]

Tolerance, Addiction, and Effective Pain Management

by K. Trout

Originally Published at Opioids.com

archived by erowid September 2001

"Millions of people suffer needlessly from agonizing pain because physicians have been reluctant to use ‘high-risk' opioids"

Crain & Shen 2000

"The first thing they told us in medical school is that no one has ever died from pain but plenty of physicians have had their careers destroyed trying to help people who are in pain."

Comment from an emergency room physician requesting anonymity (2001)

A major problem faced by narcotics users and abusers is the well-known development of tolerance when an opiate is given repeatedly over a period of time. This is directly responsible for a number of the problems associated with narcotic use and abuse since increasing tolerance requires that steadily larger doses be used to achieve the same effects or degree of pain relief.

This also underlies much of the crime associated with street addiction as the cost of maintaining a habit also escalates along with the dosage, often leading addicts to turn to drug dealing, prostitution or criminal activities to enable them to afford their daily dose.

Many experienced junkies, especially if heroin users, address this problem by taking regular breaks from their drug of choice, allowing their tolerance to diminish and their effective dosage to also be decreased. Due to the unpredictable quality of unregulated black-market street drugs this can actually be potentially dangerous if they then acquire material of greater potency than they were expecting. (Junkies who relapse after recovery face a similar risk when they return to use.)

Some users employ materials like cimetidine (Tagamet) [R.A.H. 2000] to retard drug metabolism and thereby maximize their effectiveness. [An interesting but unrelated point worthy of further investigation is the report of Peterson et al. 1983 indicating that use of cimetidine one hour before and after administration of large amounts of cocaine to rodents prevented hepatic toxicity and liver damage. Pellinen et al. 1994 also reported a prevention of "metabolism-related hepatotoxicity" by use of Cytochrome P450 3A inhibitors.]

Other users recommend grapefruit juice (Anonymous 2000) to interfere with the metabolism of the opiates by the liver and small intestinal Cytochrome P450 enzyme CYP3A and thus attempt to maximize their per dose effects, blood concentration and duration. While this has been reported by many users to be effective at maximizing per dose results this does not affect the development of tolerance.

Presently many questions remain, as there is also been some conjecture made that administration of grapefruit juice might interfere with the conversion of codeine to morphine due to its lesser inhibition of some CYP subfamilies. This does not seem to be the case; Caraco et al. 1996 reported (in animals) that if codeine was coadministered with selective inhibitors of CYP3A4 this could result in increased morphine production and enhanced effects due to "shunting into the CYP2D6 pathway" (as CYP2D6 would NOT be affected).

It is worth noting that I can thus far locate NOTHING in the *scientific* literature specifically supporting the use of grapefruit juice to increase the general effectiveness of opiates or even that CYP3A is responsible for the metabolism of heroin. Although, it is certainly reasonable to assume that CYP3A is responsible for its metabolism since it is proven as such for other opioids such as codeine (Caraco et al. 1996) and fentanyl (Feierman & Lasker 1996)

Reports of successful application, circulating orally among users (Anonymous 2000 & 2001) and posted on web-based bulletin boards, are common enough that this should be investigated further.

It is important to keep in mind that grapefruit juice can also prove problematic due to the elevated levels of bioavailable drug, requiring a reduction of the dosage. Sometimes it can even be dangerous if certain other drugs are being used. The combination of grapefruit juice with some specific pharmaceuticals has produced many serious problems and even some deaths. (Ameer & Weintraub 1997; Dresser et al. 2000)

Another practice reportedly employed by some narcotic users is combining hydroxyzine with opiates to potentiate their effects. This is said to produce a rough doubling of intensity with the addition of unwanted side effects like a dry mouth. [Anonymous 2000] It appears to have no effect on the development of tolerance.

An interesting approach is the combination of opiates with the opiate antagonists naloxone or naltrexone in miniscule amounts. The combination of less than 0.001% of what would be a normal dose of the antagonist with an opiate allows a far greater response ("at least 50%") to the opiate which in turn permits a much lower effective dose to be used. It is also said to prevent respiratory depression, tolerance and addiction. This approach has apparently been patented (Crain & Shen 1996) and is being commercially developed by Pain Therapeutics. [R.A.H. 2000; Crain & Shen 2000]

Another interesting comment was made by Karl Jansen (2001) concerning the administration of small oral doses of ketamine being found to be of use in chronic pain clinic for "greatly reducing" the development of tolerance (via blockade of NMDA receptors).

However, many people are unaware that both enhanced effectiveness of narcotic analgesics AND prevention or reversal of tolerance is readily achievable through the oral use of up to 200-250 mg of Proglumide [(DL)-4-Benzamido-N,N-dipropylglutaramic acid]. [see Ott 1999; Watkins et al. 1984]

The work of Watkins suggests there may be a therapeutic dosage window with diminished results above it but more detailed work to define this is apparently lacking.

Rather than simply augment the action of the opiates, proglumide actually interferes with the anti-opioid activity of the neuropeptide CCK.

The chronic administration of opiates, or spinal cord and other CNS injuries, elevates the level of Cholecystokinin (CCK) that is present. Such elevated levels exert an antagonistic effect on opioid activity resulting in significantly diminished analgesic effects. (Watkins et al. 1984; Xu et al. 1993 & 1994)

It is this rise in CCK levels that directly leads to the condition known as drug tolerance and the corresponding increase in its anti-opioid activity that requires the opiate user to use increasingly larger amounts to achieve the same effects.

This anti-opiate effect can be prevented or even reversed through the administration of CCK inhibitors such as proglumide. (Watkins et al. 1984)

Besides just interfering with the adverse action of CCK on opiate activity, proglumide is also known to augment the analgesic effect of opiates. Often this can provide a higher quality of analgesia for those patients who suffer from an incomplete response to pain medications.

Watkins & coworkers reported that proglumide reversed morphine tolerance and also 1) hastened the onset of analgesia, 2) increased the peak levels, and 3) prolonged the duration.

They suggested that not simply did this indicate that effective narcotic doses could be decreased but it also indicated that proglumide might be able to enhance the effects of other procedures, such as acupuncture, which involve endogenous opiates. (Watkins et al. 1984)

Proglumide is a nonselective CCK inhibitor that was formerly employed as an anti-ulcer medication (Hahne et al. 1981). It shows NO analgesic effects of its own.

Although proglumide is now considered to be an obsolete pharmaceutical due to changes in our understandings of ulcer etiology, it has already seen extensive pharmacological and toxicological testing proving its safety and has been approved for use in humans.

It has largely fallen into disuse but is still available in bulk via chemical houses or as a pharmaceutical in Europe and Africa sold under the trade name Milid and Milide.

Other CCK inhibitors show similar properties (Idänpään-Heikkilä et al. 1997; Xu et al. 1993). However, beyond simply having seen previous use in humans, proglumide is both inexpensive and nontoxic. (Ott 1999)

Proglumide is not some sort of magic bullet for completely eliminating the risk of tolerance development and addiction as its effects are only effective for a limited duration before tolerance to IT begins to develop. (After 8 days its effectiveness begins to wane) The work of Kellstein & Mayer 1990 suggests that successful therapeutic/maintenance applications will probably require its discontinuation for a week after each week of use. More work is needed to better define the precise parameters of its effective use for this purpose.

Despite this, proglumide has already demonstrated itself to be of value both in pain management and as an adjunct to maintaining a narcotic addiction within a larger program of harm reduction (Anonymous 2000; Ott 1999).

What is fascinating is how few drug educators, drug treatment facilities or even drug users are aware of this despite it being readily available information for nearly 20 years.

If development of tolerance and the high price of a sustained addiction are truly as serious of a problem as we all agree that they are, one can only wonder how it is that, despite the tools existing to remove or at least reduce this problem, there seems to be no interest or research except on a limited scale related to specific small areas of chronic pain management and understanding.

The current misguided approach of substituting methadone is commonly reported to actually cause MORE perceptual and thinking problems than the opiates it replaces PLUS methadone is known to cause physical damage to internal organs that are not encountered with opiate use itself.

Harm reduction approaches would benefit greatly by using proglumide as a cornerstone and making it readily available to both narcotic users and abusers.

Those who will most certainly object include organized crime and drug dealers who enjoy the obscene profits reaped from escalating drug tolerances, and possibly also the so-called "drug educators" that sadly often seem to be the ones most in need of some factual education.

There are many problems associated with opiate use and abuse. While the majority of these are legal in origin, the most sensible approach would be to ameliorate [or mitigate] those that aren't.

Increased analgesic effectiveness and prevention of tolerance are two obvious areas where harm reduction is readily possible TODAY. Both sufferers of chronic pain and narcotic addicts stand to benefit from having their needs met and their health risks simultaneously decreased.

As this is first and foremost a health problem, the current approach of harm maximization is both counterproductive and unacceptable. To a rationale or caring mind it might even be perceived of as unethical and amoral.

Not only do sufferers of chronic pain and narcotic addicts stand to benefit from such harm reduction approaches but, by decreasing drug-associated crimes, a significant area of the true "drug problem" can be directly addressed, thereby benefiting society as a whole.

References:

Ameer, Barbara & Randy A. Weintraub (1997) Clinical Pharmacokinetics 33 (2): 103-121. "Drug Interactions with Grapefruit Juice."

Anonymous (2000 & 2001) Personal interviews with assorted opiate users & abusers.

Caraco, Y. et al. (1996) Drug Metab. Dispos. 24(7): 761-764. "Microsomal codeine N-demethylation: cosegregation with cytochrome P4503A4 activity." [Y. Caraco, T. Tateishi, F.P. Guengerich & A.J. Wood] [Abstract from PubMed]

Crain & Shen 1996: See patent references farther below.

Crain, Stanley M. & Ke-Fei Shen (2000) Pain 84: 121-131. "Antagonists of excitatory opioid receptor functions enhance morphine's analgesic potency and attenuate opioid tolerance/dependence liability."

Dresser, G.K. et al. (2000) Clinical Pharmacokinetics 38(1): 41-57. "Pharmacokinetic-Pharmacodynamic Consequences and Clinical Relevance of Cytochrome P450 3A4 Inhibition." [George K. Dresser, J. David Spence & David G. Bailey]

Entheogen Review; POBox 19820, Sacramento, CA 95819-0820. [www.entheogenreview.com]

Feierman DE, & J.M. Lasker (1996) Drug Metab. Dispos. 24(9):932-939. "Metabolism of fentanyl, a synthetic opioid analgesic, by human liver microsomes. Role of CYP3A4." [Abstract from PubMed]

Hahne, W.F. et al. (1981) Proceedings of the National Academy of Science (USA) 78 (10): 6304-6308. "Proglumide and benzotript: Members of a different class of cholecystokinin receptor antagonists." [W.F. Hahne, R.T. Jensen, G.F. Lemp & J.D. Gardner]

Idänpään-Heikkilä, J.J. et al. (1997) Journal of Pharmacology and Experimental Therapeutics 282 (3): 1366-1372. "Prevention of Tolerance to the Antinociceptive Effects of Systemic Morphine by a Selective Cholecystokinin-B Receptor Antagonist in a Rat Model of Peripheral Neuropathy." [Juhana J. Idänpään-Heikkilä, Gisèle Guilbaud & Valérie Kayser]

Jansen, Karl (2001) e-mail correspondence with Jon Hanna (Book reference is to Ketamine: Dreams & Realities by Karl Jansen; see www.maps.org)

Kellstein, David E. & David J. Mayer (1990) Brain Research 516: 263-270. "Chronic administration of cholecystokinin antagonists reverses the enhancement of spinal morphine analgesia induced by acute pretreatment."

Ott, Jonathan (1999) Entheogen Review 7(2): 62-73. "Jonathan Ott Speaks…Part Two." (Interviewed by Will Beifuss & Jon Hanna in 1998) (Proglumide comments are on p. 69)

Pain Therapeutics, Inc., 250 E. Grand Avenue, STE 70, San Francisco, CA 94080

Peterson, F.J. et al. (1983) Gastroenterology 85(1): 122-129. "Prevention of acetaminophen and cocaine hepatotoxicity in mice by cimetidine treatment." [F.J. Peterson, R.G. Knodell, N.J. Lindemann & N.M. Steele] [Abstract from PubMed]

Pellinen, P. et al. (1994) Eur. J. Pharmacol. 270(1): 35-43. "Cocaine N-demethylation and the metabolism-related hepatotoxicity can be prevented by cytochrome P450 3A inhibitors." [P. Pellinen, P. Honkakoski, F. Stenback, M. Niemitz, E. Alhava, O. Pelkonen, M.A. Lang & M. Pasanen] [Abstract from PubMed]

R.A.H. (2000) Entheogen Review 9(3): 145-147. "Opiate Potentiation."

Watkins, L.R. et al. (1984) Science 224: 395-396. "Potentiation of Opiate Analgesia and Apparent Reversal of Morphine Tolerance by Proglumide." [L.R. Watkins, I.B. Kinscheck & D.J. Mayer]

Xu, X.-J., et al. (1993) Neuroscience Letters 152: 129-132. "Up-regulation of cholecystokinin in primary sensory neurons is associated with morphine insensitivity in experimental neuropathic pain in the rat." [X.-J. Xu, M.J.C. Puke, V.M.K. Verge, Z. Wiesenfeld-Hallin, J. Hughes & T. Hökfelt]

Xu, X.-J., et al. (1994) Pain 56: 271-277. "Chronic pain-related behaviors in spinally injured rats: evidence for functional alterations of the endogenous cholecystokinin and opioid systems." [Xiao-Jun Xu, Jing-Xia Hao, Åke Seiger, John Hughes, Tomas Hökfelt & Zsuzsanna Wiesenfeld-Hallin]

Additional information that was not used or referenced above:

CCK activity as opioid antagonist

(See also CCK inhibitor references below),

Faris, P.L. et al. (1983) Science 310-312. "Evidence for the neuropeptide cholecystokinin as an antagonist of opiate analgesia." [P.L. Faris, B.R. Komisaruk, L.R. Watkins & D.J. Mayer]

Itoh, S. et al. (1982) Eur. J. Pharmacol. 80: 421-425. 'Caerulein and cholecystokinin suppress B-endorphin-induced analgesia in the rat.' [s. Itoh, G. Katsuura & Y. Maeda]

Nichols, M.L. et al. (1995) J. Pharmacol. Exp. Ther. 275: 1339-1345. "Regulation of morphine anti allodynic efficacy by cholecystokinin in a model of neuropathic pain in rats." [M.L. Nichols, D. Bian, M.H. Ossipov, J. Lai, & F. Porreca]

Wiesenfeld-Hallin, Z. & X-J. Xu (1996) Regulatory Peptides 65: 23-28. "The role of cholecystokinin in nociception, neuropathic pain and opiate tolerance."

CCK inhibitors enhancing opioid analgesia and/or preventing tolerance

Dourish, C.T. et al. (1988) Eur. J. Pharmacol. 147: 469-472. "Enhancement of morphine analgesia and prevention of morphine tolerance in the rat by the cholecystokinin antagonist L-364,718." [C.T. Dourish, D. Hawley & S.D. Iversen]

Dourish, C.T. et al. (1990) Eur. J. Pharmacol. 176: 35-44. "The selective CCK-B antagonist L-365,260 enhances morphine analgesia and prevents morphine tolerance in the rat." [C.T. Dourish, M.F. O'Neill, J. Coughlan, S.J. Kitchener, D. Hawley & S.D. Iversen]

Hoffmann, O. & Z. Wiesenfeld-Hallin (1994) Neuro. Report 5: 2565-2568. "The CCK-B receptor antagonist CI 988 reverses tolerance to morphine in rats."

Hughes, J. et al. (1990) Proceedings of the National Academy of Science (USA) 87: 6728-6732. "Development of a class of selective cholecystokinin type B receptor antagonists having potent anxiolytic activity." [J. Hughes, P. Boden, B. Costall, A. Domeney, E. Kelly, D.C. Horwell, J.C. Hunter, R.D. Pinnock & G.N. Woodruff]

O'Neill, M.F. et al. (1989) Neuropharmacology 28: 243-249. "Morphine-induced analgesia in the rat paw is blocked by CCK and enhanced by the CCK antagonist MK-329." [M.F. O'Neill, C.T. Dourish & S.D. Iversen]

Watkins, L.R. et al. (1985) Brain Research 327: 181-190. "Cholecystokinin antagonists selectively potentiate analgesia induced by endogenous opiates." [L.R. Watkins, I.B. Kinscheck, E.F.S. Kaufman, J. Miller, H. Frenk & D.J. Mayer]

Wiesenfeld, Z. et al. (1990) Proceedings of the National Academy of Science (USA) 87: 7105-7109. "PD134308, a selective antagonist of cholecystokinin type-B receptor, enhances the analgesic effect of morphine and synergistically interacts with intrathecal galanin to depress spinal nociceptive reflexes." [Z. Wiesenfeld, X.-J. Xu, J. Hughes, D.C. Horwell & T. Hökfelt]

Xu, X,-J. et al. (1992) British Journal of Pharmacology 105: 591-596. "CI988, a selective antagonist of cholecystokinin type-B receptor, prevents morphine tolerance in the rat." [X.-J. Xu, Z. Wiesenfeld-Hallin, J. Hughes, D.C. Horwell & T. Hökfelt]

Grapefruit juice

Bailey, D.G. et al. (1998) British Journal of Clinical Pharmacology 46(2): 101-110. "Grapefruit juice-drug interactions." [David G. Bailey, J. Malcolm, O. Arnold & J.David Spence]

Edwards, D.J. et al. (1996) Drug Metab. Dispos. 24(12): 1287-1290. "Identification of 6',7'-dihydroxybergamottin, a cytochrome P450 inhibitor, in grapefruit juice." [D.J. Edwards, F.H. Bellevue III & P.M. Woster] [Abstract from PubMed]

Fuhr, U. (1998) Drug Safety 18(4): 251-272. "Drug interactions with grapefruit juice. Extent, probable mechanism and clinical relevance." [Abstract from PubMed]

He, K. et al. (1998) Chem. Res. Toxicol. 11(4): 252-259. "Inactivation of cytochrome P450 3A4 by bergamottin, a component of grapefruit juice." [K. He, K.R. Iyer, R.N. Hayes, M.W. Sinz, T.F. Woolf & P.F. Hollenberg] [Abstract from PubMed]

Tirillini B. (2000) Fitoterapia 71: S29-S37. "Grapefruit: the last decade acquisitions." [Abstract from PubMed]

Naloxone, naltrexone & nalmefene enhancing morphine analgesia

and/or attenuating tolerance and dependence

Bergman, St.A. et al. (1988) Arch. Int. Pharmacodyn. 291: 229-237. "Low dose naloxone enhances buprenorphine in a tooth pulp antinociceptive assay." (St.A. Bergman, R.L. Wynn, D.E. Myers & F.G. Rudo]

Crain, S.M. & K.-F. Shen (1995a) Proceedings of the National Academy of Science (USA) 92: 10540-10544. "Ultra-low concentrations of naloxone selectively antagonize excitatory effects of morphine on sensory neurons, thereby increasing its antinociceptive potency and attenuating tolerance/dependence during chronic cotreatment."

Crain, S.M. & K.-F. Shen (1996) US Patent No. 5,512,578, US Patent Office. "Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by exogenous and endogenous opioid agonists."

Crain, S.M. & K.-F. Shen (1996) US Patent No. 5,580,876, US Patent Office. "Method of simultaneously enhancing analgesic potency and attenuating dependence liability caused by morphine and other bi-modally-acting opioid agonists."

Crain, S.M. & K.-F. Shen (1998b) Trends Pharmacol. Sci. 19: 358-365. "Modulation of opioid analgesia, tolerance and dependence by Gs-coupled, GM1 ganglioside-regulated opioid receptor functions."

Gan, T.J. et al. (1997) Anethesiology 87: 1075-1081. "Opioid-sparing effects of a low-dose infusion of naloxone in patient-administered morphine sulfate." [T.J. Gan, B. Ginsberg, P.S.A. Glass, J. Fortney, R. Jhaveri & R. Perno]

Gillman, M.A. & F.J. Lichtigfeld (1985) Neurol. Res. 7: 106-119. "A pharmacological overview of opioid mechanisms mediating analgesia and hyperalgesia." (Review)

Gillman, M.A. & F.J. Lichtigfeld (1989) Int. J. Neurosci. 48: 321-324. "Naloxone analgesia: an update." (Review)

Holmes, B.B. & J.M. Fujimoto (1993) Anesth. Analg. 77: 1166-1173. "Inhibiting a spinal dynorphin A component enhances intrathecal morphine antinociception in mice."

Joshi, G.P. et al. (1999) Anesthesiology 90: 1007-1011. "Effects of prophylactic nalmefene on the incidence of morphine-related side effects in patients receiving intravenous patient-controlled analgesia." [G.P. Joshi, J. Duffy, J. Chehade, J. Wesevich, N. Gajraj & E.R. Johnson]

Levine, J.D. et al. (1988) J. Clin. Invest. 82: 1574-1577. "Potentiation of pentazocine analgesia by low-dose naloxone." [J.D. Levine, N.C. Gordon, Y.O. Taiwo & T.J. Coderre]

Shen, K.-F. & S.M. Crain (1997) Brain Research 757: 176-190. "Ultra-low doses of naltrexone or etorphine increase morphine's antinociceptive potency and attenuate tolerance/dependence in mice."

Proglumide

Chiodo, L.A. & B.S. Bunney (1983) Science 219: 1449-1450. "Proglumide, selective antagonism of excitatory effect of cholecystokinin in central nervous system."

Katsuura, G. & S. Itoh (1985) Eur. J. Pharmacol. 107: 363-366. "Potentiation of ß-endorphin effects by proglumide in the rat."

Lavigne, G. et al. (1987) Pain, Suppl. 4: S229. "Potentiation of morphine analgesia by proglumide for acute clinical pain." [G. Lavigne, K.M. Hargreaves, G.P. Miller, E.S. Schmidt & R.A. Dionne]

McCleane, G.J. (1998) Anesth. Anal. 87: 1117-1120. "The cholecystokinin antagonist proglumide enhances the analgesic efficacy of morphine in humans with chronic benign pain."

McCleane, G.J. (1998) The Pain Clinic 11: 103-107. "The cholecystokinin antagonist proglumide enhances the analgesic effect of morphine in chronic benign nociceptive and neuropathic pain."

Rovati, L.C. et al. (1985) Annals of the New York Academy of Science 448: 630-632. "Effects of proglumide on morphine analgesia and tolerance." [L.C. Rovati, P. Sacerdote & A.E. Panerai]

Tang, J. et al. (1984) Neuropharmacology 23 (6): 715-718. "Proglumide prevents and curtails acute tolerance to morphine in rats." [J. Tang, J. Chou, M. Iadarola, H.-Y.T. Yang & E. Costa]

Watkins, L.R. et al. (1985) Brain Research 327: 169-180. "Potentiation of morphine analgesia by the cholecystokinin antagonist proglumide." [L.R. Watkins, I.B. Kinscheck & D.J. Mayer]

Archived by Erowid with permission of Author

http://www.erowid.org/chemicals/opiates/opiates_info3.shtml

t s t .

Edited April 1, 2009 by t st tantra

[cactophyle]

Here's the info from my prescription (the pharmacy mixes it):

1mg Naltrex / 1000ml Solution

2ml twice daily

I thought it worked out to about 2mcg dosage, but I dunno. I don't think this is enough to interfere with my pain meds, but just in case, I never take them at the same time.

[t st tantra]

ok maybe i shouldnt have put the references in there!

about 1/11 th of the full dose appears to be used for low dose.though trout seems to refer to a smaller dose.

seeing refs to interaction/enhancement with naltrexone/lsd,dmt....?

t s t .

Edited April 1, 2009 by t st tantra

[t st tantra]

just a curio from wikipedia........

http://en.wikipedia.org/wiki/Proglumide

Proglumide also works as a placebo effect amplifier for pain conditions. When injected visibly to a subject, its analgesic effect is bigger than a similarly administered placebo. When injected secretely, it doesn't have any effect, whereas standard pain drugs have an effect, even if they are administered without the subject's awareness [11]. The supposed mechanism is an enhancement of the neural pathways of expectation.

t s t .

[t st tantra]

.......

t s t .

Edited April 5, 2009 by t st tantra

[sandalwood]

I tried low dose naltrexone...

it actually worked for a few days....but the side effects became too much. a ringing in the ears, and nausea.

it felt after a few days that the potentiation was too much....I became bed ridden for a day when I decided I had enough of the experiment.

the solution I prepared might have been a problem, as I know that getting particles of the pill small enough might not have been achieved as well as it could have.

I did a naltrexone treatment around 12 years ago. I was on 50 milligrams a day.

I ended up getting high on naltrexone, during a relapse. it took about 3-4 times my normal relapse dose...

once I found out that naltrexone does not seem to fully block a heroin high, at least for me, I quit taking it.

I suffered as much weight loss in naltrexone almost as I did on heroin.

I had no appetite, sexual libido was low, and I could not sleep longer than 3-4 hours at a time.

and also, I craved nicotine constantly.

a freind of mine who heard I got high on naltrexone, decided to try and use while he was on naltrexone treatment, and he ended up dying in a corner of a room, as his freinds thought he had just passed out. he was basically ignored to death.

I was lucky my relapse while on naltrexone didnt kill me.

I think the low dose naltrexone opiate tolerance augmentation hypothesis is a good one...but it might be hard for a person like me, to get accurately metered doses, even with a pill dropped into a litre of water, and then applied with an eye dropper to figure approx. dosage.

I have tried several extracts of picralima nitida, and also tried the raw seeds. I was one of the first people to import into the USA.....

all times, with all the different extracts, and the raw seeds, I felt mostly stimulant effects. no perceivable potentiation, and picralima nitida does not replace opiates either I dont think.....

but it might help on a regimine of daily use, alongside opiates, to help treat some side effects of opiate tolerance....

the antagonist potentiation/tolerance augmentation hypothesis is very interesting..especially since there are numerous natural, plant based antagonists or partial antagonists out there.

probably the most interesting medicinal that might have tolerance control use so far I have read about, and sampled...is mesaconitine...from a medicinal aconite species used in chinese and other asian medicinal systems.

I checked for toxicity, by preparing the correctly handled aconite root elixir....basically boiling prepared root slices for a little over an hour and straining.

I didnt feel much with the standard dose reccomendation...but importantly, I didnt notice any toxic or negative effects.

anyway, mesaconitine is a kappa agonist, and is reported to help reduce tolerance to morphine, even if a person is habituated before the experiment. the compound is also used for pain relief....both topically, and internally.

I have thought for a few years, that it might be one of the more active ingredients in HEANTOS...????...maybe, maybe not...

but the plant is obviously one with alot of potential.

the only problem is handling the herb, and probably toxicity at some level of use

with so many natural opioid agonists and antagonists out there, and undoubtedly more such compounds waiting to be discovered...so many different structural varieties of active opioids...that I think many new discoverys, and overlooked common botanicals will have potential for those willing to push the envelope.

so are you on this low dose treatment?

t s t .

[Rizla]

I remember a Journal of Ethnopharmacology article, "Inhibition of Morphine Tolerance and Dependence by Withania somnifera", unfortunately don't have a copy but there is a vague abstract online.

http://cat.inist.fr/?aModele=afficheN&cpsidt=2802773

I haven't heard from any of my legal pain patient friends getting this to work, although I do take it occasionally as a sedative, highly effective for me. I also wonder if combining high doses of ashwaganda with opiates might be dangerous.

When Ott discussed low dose naloxone at the Mind States conf. 2007, he was talking about microgram doses, really tiny ones. No idea how he figured out the dose, I can listen to the lecture again if you're interested. He did say he got it to work.

[t st tantra]

thanx ,will look into that.

there are a few things i need to sort out in understanding this ,first is that there is low dose naloxone and ultra low dose naloxone and they are different and do different things.

t s t .

[Rizla]

The paper Ott mentioned at Mindstates '07 is from the Journal of Psychoactive Drugs, Vol. 38 #1, March 2006:

Obviation of Opioid Withdrawal Syndrome by Concomitant Administration of Naltrexone in Microgram Doses: Two Psychonautic Bioassays — Jonathan Ott

Abstract—Two psychonautic bioassays (self-experiments) in stepwise and abrupt cessation of long-term daily oral ingestion habits of 800 mg of codeine phosphate are presented. Concomitant administration of minute doses (about 0.5 mcg) of the opioid antagonist naltrexone with each dose of codeine was found in both cases to obviate the expected opioid withdrawal syndrome, resulting in asymptomatic and uneventful transitions from physical opioid dependency states to exogenous opioid-free metabolism. These experiments are analyzed in the context of a conjectured, rapid, iterative reduction and complete elimination of opioid tolerance, once acquired. It was found that coadministration of naltrexone with codeine phosphate obviated the development of both tolerance and physical dependency over several months of four daily oral doses of 200 mg, allowing abrupt (“cold turkey”), asymptomatic and uneventful withdrawal. This points the way to the biochemical substrate of opioid tolerance itself, and shows that this can easily and inexpensively be blocked, even over months of iterative oral administration of substantial doses of opioid analgesics. Finally, it suggests the opioid withdrawal syndrome is directly related to the physiology of opioid tolerance, and can be prevented by blocking tolerance itself. Even when tolerance has been acquired, this can be reduced stepwise over a matter of days, with no symptoms of opioid withdrawal syndrome.

Keywords—addiction, codeine, naltrexone, opioids, tolerance, withdrawal

The magazine can be obtained for US$25 from:

http://www.journalofpsychoactivedrugs.com/index.html

[PhoenixSon]

http://www.erowid.org/experiences/exp.php?ID=26640

some interesting info.

"Taking morinda citrifolia, ashwaghanda and bacopa daily has really helped, and I am really impressed with the potency of these herbs as potentiators for opiates."

"I will include this last experience with herbal blends and poppy seeds because it was one of the strongest inebriations I have experienced. I consumed my normal 100+ grams poppy seed dose at 6pm. I was at work and waited till I had 20 minutes left in my shift. I then took a blend of 50 mg 5-htp, 60 grms dark chocolate, methionine, protein enzyme digestant pills, schizandra, ashwaghanda. Shortly after I started feeling dizzy and somewhat nauseous, and worked extra hard to get out of work quickly. After getting off work I rode home on my bike. My arms seemd very long and far way, and my balance was fucked. The analgesia in my hands was very strong, I could barely feel them! Riding my bike was difficult and I worried about attracting attention as I was now throwing up. I vomited all the way home and laid straight down. Once reclined I felt better and could enjoy the rather intense opiate effects without any further purging. I nodded in and out of consiousness, languishing in the novelty of experiencing heavy effects from a handful of legal substances that ran me no more than 5$. I was somewhat worried about stopping breathing and tried to stay awake a few more hours.

In the morning I had a definite opiate hangover and the knowledge of a 'new blend'. I think the 5-htp and the chocolate really added to the effect. Naloxone is perported to relieve chocolate craving, and cannabanoids have been proven to interact with pain sensation, and serotonin intensifies opiate effects, as do most antideppressants. I have not repeated this blend again, and would only bring it out on special occasions. I do remember at a conference a gentleman passing out information on chocolate, I shared this recipe with him and he said that schizandra specifically intensifies chocolates effects?"