Friday, February 19, 2010

Low Dose Naltrexone (LDN) and the Liver

note - this post title really should be "Naltrexone and the Liver" as the studies below all are based on full strength naltrexone and not LDN.

Low Dose Naltrexone, or LDN, is an FDA approved medication.
"Naltrexone itself was approved by the FDA in 1984 in a 50mg dose for the purpose of helping heroin or opium addicts, by blocking the effect of such drugs. By blocking opioid receptors, naltrexone also blocks the reception of the opioid hormones that our brain and adrenal glands produce: beta-endorphin and metenkephalin."

Although naltrexone itself is an FDA-approved drug, the varied uses of LDN still await application to the FDA after related scientific clinical trials. LDN (in the 3mg or 4.5mg dosage) has not yet been submitted for approval because the prospective clinical trials that are required for FDA approval need to be funded at the cost of many millions of dollars.

Naltrexone is a prescription drug, so your physician would have to give you a prescription after deciding that LDN appears appropriate for you.

Many doctors will not prescribe LDN, as they are not aware that it is FDA approved and that various clinical trials for various disorders have been done or are in progress. The other reason is because of the "Black Box Warning" for full strength Naltrexone due to adverse liver effects on obese patients using 300mg.

Full-dose naltrexone (50mg) carries a cautionary warning against its use in those with liver disease. This warning was placed because of adverse liver effects that were found in experiments involving 300mg daily. The 50mg dose does not apparently produce impairment of liver function nor, of course, do the much smaller 3mg and 4.5mg doses.

Further studies have shown that LDN is actually beneficial to the liver in low doses - however, most of the studies done used much higher doses of Low Dose Naltrexone.

Study of hepatotoxicity of naltrexone in the treatment of alcoholism.
Since a black box warning was issued by the Food and Drug Administration regarding the use of the opiate antagonist naltrexone (NTX), many clinicians have been concerned about current labeling of the potential hepatotoxicity risk of NTX in the treatment of opiate dependence and alcoholism. Despite many reports that demonstrated that the use of NTX did not cause elevation of liver enzymes, controversy concerning whether NTX is hepatotoxic continues. The current study monitored 74 alcoholic patients who received 25mg of NTX daily in the first week and then 50mg of NTX daily for the rest of the 12-week period. After the 12-week treatment, levels of the hepatic enzymes alanine aminotransferase (ALT) and aspartate aminotransferase (AST) did not show any elevation, except in one subject, and the results strongly support that NTX did not induce abnormalities in liver function tests or elevate the liver enzymes. Instead, a statistical significance of decreasing levels of ALT and AST in the liver was shown throughout the study. These findings provide further support that NTX is not hepatotoxic at the recommended daily dose and may be beneficial for patients with elevated liver enzymes.
PMID: 16839858 [PubMed - indexed for MEDLINE]

Effects of long-term treatment with naltrexone on hepatic enzyme activity.Mean plasma levels of hepatic enzymes did not show significant modification in the course of treatment with naltrexone.

PMID: 1686854 [PubMed - indexed for MEDLINE]
Naltrexone: report of lack of hepatotoxicity in acute viral hepatitis, with a review of the literature.
Many clinicians appear to be concerned about the potential hepatotoxicity of the opiate antagonist naltrexone (NTX) and this may be one reason why it is not used more widely in treating both heroin and alcohol abusers. Some much-quoted early studies noted abnormalities in liver function tests (LFTs) in very obese patients taking high doses, although there was no evidence of clinically significant liver dysfunction.

We describe a heroin abuser in whom clinical and laboratory manifestations of acute hepatitis B and C appeared a few days after the insertion of a subcutaneous naltrexone implant. A decision was made not to remove the implant but the hepatitis resolved completely and uneventfully well within the normal time-scale. A review of the literature indicates that even when given at much higher doses than are needed for treating heroin or alcohol abusers, there is no evidence that NTX causes clinically significant liver disease or exacerbates, even at high doses, serious pre-existing liver disease.

PMID: 15203443 [PubMed - indexed for MEDLINE]

Naltrexone protects against lipopolysaccharide/D-galactosamine-induced hepatitis in mice.
Results demonstrated that post-treatment with naltrexone (20 mg/kg, i.p.) significantly attenuated the deleterious liver function in mice treated with LPS/D-gal. It was also found that naltrexone significantly inhibited the elevation of plasma tumor necrosis factor-alpha (TNF-alpha) caused by LPS/D-gal. The overproduction of nitric oxide (NO) and superoxide anions induced by LPS/D-gal were also significantly reduced by naltrexone. Moreover, infiltration of neutrophils into the liver of mice 12 h after treatment with LPS/D-gal was also decreased by naltrexone. In conclusion, the beneficial effects of naltrexone on LPS/D-gal-induced hepatitis result from its inhibition of pro-inflammatory factors and antioxidant effects. Thus, naltrexone is of therapeutic potential for treating liver injury.

PMID: 19023176 [PubMed - indexed for MEDLINE

Lack of hepatotoxicity with naltrexone treatment.
In summary, chronic administration of naltrexone in doses up to 300 mg/day for periods up to 36 months does not significantly change hepatic function, as measured by SGOT and SGPT levels.

PMID: 7983232 [PubMed - indexed for MEDLINE]

Opioid receptor blockade reduces Fas-induced hepatitis in mice.

PMID: 15389866 [PubMed - indexed for MEDLINE]

Naltrexone, an opioid receptor antagonist, attenuates liver fibrosis in bile duct ligated rats.

CONCLUSIONS: This is the first study to demonstrate that administration of an opioid antagonist prevents the development of hepatic fibrosis in cirrhosis. Opioids can influence liver fibrogenesis directly via the effect on HSCs and regulation of the redox sensitive mechanisms in the liver.

PMID: 16543289 [PubMed - indexed for MEDLINE]

Opioid system blockade decreases collagenase activity and improves liver injury in a rat model of cholestasis.
CONCLUSION: Opioid receptor blockade improved the degree of liver injury in cholestasis, as assessed by plasma enzyme and liver MMP-2 activities. The beneficial effect of naltrexone may be due to its ability to increase liver SAM level and restore the SAM : SAH ratio.

PMID: 17295775 [PubMed - indexed for MEDLINE]

Effect of oral naltrexone on pruritus in cholestatic patients.

CONCLUSION: Naltrexone can be used in the treatment of pruritus in cholestatic patients and is a safe drug showing few, mild and self-limited complications.

PMID: 16534857 [PubMed - indexed for MEDLINE]

Opioid peptides and primary biliary cirrhosis.
Patients with liver disease have increased plasma concentrations of the endogenous opioid peptides methionine enkephalin and leucine enkephalin. As an initial investigation to determine whether opioid peptides contribute to any of the clinical manifestations of hepatic disease nalmefene, a specific opioid antagonist devoid of agonist activity, was given to 11 patients with cirrhosis. They all experienced a severe opioid withdrawal reaction on starting the drug. In the nine patients with primary biliary cirrhosis pruritus was greatly alleviated, fatigue seemed to improve, and plasma bilirubin concentration, which had been rising, showed a modest fall in all except one patient. These results indicate that blocking opioid receptors has an effect on some of the metabolic abnormalities of liver disease.

PMID: 3147046 [PubMed - indexed for MEDLINE]
Pharmacokinetics of long-acting naltrexone in subjects with mild to moderate hepatic impairment.

Long-acting naltrexone is an extended-release formulation developed with the goal of continuous naltrexone exposure for 1 month for the treatment of alcohol dependence. The influence of mild and moderate hepatic impairment on naltrexone pharmacokinetics following long-acting naltrexone 190-mg administration was assessed. Subjects with mild (Child-Pugh grade A) and moderate (Child-Pugh grade B) hepatic impairment (n = 6 per group) and matched control subjects (n = 13) were enrolled. Naltrexone and 6beta-naltrexol concentrations were determined over a period of 63 days following a single intramuscular dose. Naltrexone and 6beta-naltrexol concentrations were detected in all subjects through 28 days. Total exposure (AUC(0-infinity)) of naltrexone and 6beta-naltrexol was similar across all groups. The long apparent half-lives of naltrexone and 6beta-naltrexol (5-8 days) were attributed to the slow release of naltrexone (long-acting naltrexone exhibits absorption rate-limited elimination or "flip-flop" kinetics); elimination was not altered in subjects with hepatic impairment. Based on pharmacokinetic considerations, the dose of long-acting naltrexone does not need to be adjusted in patients with mild or moderate hepatic impairment.

PMID: 16239359 [PubMed - indexed for MEDLINE]

High-dose naltrexone and liver function safety.

Studies have found naltrexone useful in the treatment of diseases other than opiate addiction in which endogenous opioids presumably play a role, such as alcoholism and eating disorders. Some of these studies involve high doses (100-200 mg bid). Because investigational studies with high doses (300 mg/day) reported clinically significant increases in liver enzyme levels, the authors measured a spectrum of liver function parameters in response to high doses of naltrexone in a double-blind, crossover trial (100 mg bid) followed by an open-label period (200 mg bid). They observed no adverse clinical or laboratory changes in liver function in association with high-dose naltrexone therapy in eating disorders.

PMID: 9097868 [PubMed - indexed for MEDLINE]

Effect of liver cirrhosis on the systemic availability of naltrexone in humans.

CONCLUSIONS: Our data suggest the occurrence of important changes in the systemic availability of naltrexone and 6 beta-naltrexol in liver cirrhosis; such alterations are consistent with lesser reduction of naltrexone to 6 beta-naltrexol and appear to be related to the severity of liver disease. This must be considered when administering naltrexone in conditions of liver insufficiency.
PMID: 9314128 [PubMed - indexed for MEDLINE]

Hepatic safety of once-monthly injectable extended-release naltrexone administered to actively drinking alcoholics.

RESULTS: There were no significant differences in alanine aminotransferase, aspartate aminotransferase, or bilirubin levels between the study groups at study initiation or at subsequent assessments. Gamma-glutamyltransferase in the XR-NTX 380 mg group was lower compared with placebo at weeks 4, 8, 12, and 20. Both high (>3 times the upper limit of normal) liver chemistry tests (LCTs) and hepatic-related adverse events were infrequent in all study groups. In patients who were drinking heavily throughout the study, obese subjects, or those taking nonsteroidal anti-inflammatory drugs, there was no increase in frequency of high LCTs or hepatic-related adverse events in patients receiving XR-NTX (either dose) compared with placebo. CONCLUSION: Extended-release formulation of naltrexone does not appear to be hepatotoxic when taken at the recommended clinical doses in actively drinking alcohol-dependent patients.

PMID: 18241321 [PubMed - indexed for MEDLINE]

Changes in transaminases over the course of a 12-week, double-blind nalmefene trial in a 38-year-old female subject.

A gradual return to normal in ALT and AST, while treatment with nalmefene continued, does not support the role of nalmefene as an hepatotoxin. Relapse to drinking was excluded because of normal values for the gamma-glutamyltransferase, and verification of sobriety by self-report, significant other, and breathalyzer. A virology panel ruled out the presence of viral hepatitis. Dietary intake before the elevation in LFTs contained elements that have established association with hepatocellular changes. The routine prescription of serial LFTs in alcoholism pharmacotherapy trials may be expected to reveal clinically nonsignificant elevations that could potentially be related to exogenous factors, such as dietary composition and should not be reflexively attributed to medication under investigation and/or drinking.

PMID: 7847604 [PubMed - indexed for MEDLINE]
Effects of long-term treatment with naltrexone on hepatic enzyme activity.

The influence of naltrexone on liver function in heroin addicts was studied, with respect to the metabolizing function by using the antipyrine clearance and to cellular damage by monitoring plasma levels of hepatic enzymes. The clearance of antipyrine was not affected by naltrexone treatment, and, during the study period, the use and withdrawal of benzodiazepines and alcohol did not change this parameter; moreover, there was no relationship between changes in plasma hepatic enzymes and antipyrine half-life. Mean plasma levels of hepatic enzymes did not show significant modification in the course of treatment with naltrexone.

PMID: 1686854 [PubMed - indexed for MEDLINE]

Effects of acute administration of naltrexone on cardiovascular function, body temperature, body weight and serum concentrations of liver enzymes in autistic children.

The effects of acute, orally administered naltrexone (0.5, 1.0, 1.5 and 2.0 mg/kg), a potent opiate receptor antagonist, on auscultated heart rate, systolic blood pressure and axillary body temperature were investigated before and about 1 h postdrug in 5 autistic children (4-12 years of age). In addition, an electrocardiogram was recorded on each child before and about 3 h after placebo or 2.0 mg/kg of naltrexone. Finally, the serum concentrations of the liver enzymes glutamic-oxaloacetic transaminase (SGOT) and glutamic-pyruvic transaminase (SGPT) were measured 24 h following placebo or naltrexone administration. Naltrexone had no statistically significant effects on any of these measures in comparison with baseline or placebo levels. Thus, these data provide preliminary evidence for the safety of acute administration of naltrexone in children.

PMID: 2721334 [PubMed - indexed for MEDLINE]

Naltrexone hydrochloride (Trexan): a review of serum transaminase elevations at high dosage.

In summary, evidence is presented associating typically asymptomatic and reversible elevations of serum transaminase values with high daily dosages of naltrexone. Statistical significance was found only between placebo and the 300 mg dosage. Subjects aged 40 years and over were significantly more likely to develop this finding than younger subjects. All subjects with significant elevations of transaminase values in these studies took daily naltrexone dosages higher than recommended for opioid addiction. The daily dosage of naltrexone recommended for opioid addiction did not cause abnormalities of serum transaminase values in these studies.

PMID: 3092099 [PubMed - indexed for MEDLINE]

Opioid receptor blockade improves mesenteric responsiveness in biliary cirrhosis.

The maximum pressure response to phenylephrine was decreased significantly in cirrhosis while chronic naltrexone treatment completely improved it (P <>

PMID: 18465246 [PubMed - indexed for MEDLINE]

[Antipruritic therapy with the oral opioid receptor antagonist naltrexone. Open, non-placebo controlled administration in 133 patients]

CONCLUSIONS: The oral opiate antagonists may well be an effective, well-tolerated therapy for intractable pruritus in many diseases.

PMID: 15517116 [PubMed - indexed for MEDLINE]
Endogenous opioids modulate hepatocyte apoptosis in a rat model of chronic cholestasis: the role of oxidative stress.

CONCLUSION: Our findings demonstrate that the administration of opioid antagonist is protective against hepatic damage in a rat model of chronic cholestasis. We suggest that increased levels of endogenous opioids contribute to hepatocytes apoptosis in cholestasis, possibly through downregulation of liver anti-oxidant defense.

PMID: 17403194 [PubMed - indexed for MEDLINE]

Involvement of endogenous opioid peptides and nitric oxide in the blunted chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhotic rats.

Concurrent administration of naltrexone and L-NAME also restored to normal the basal abnormalities and the blunted responses to isoproterenol in cirrhotic rats, and did not show any antagonistic effect. Based on these findings, both the endogenous opioid peptides and NO may be involved in the attenuated chronotropic and inotropic responses to beta-adrenergic stimulation in cirrhosis. It seems that the iNOS activity results in NO-induced hyporesponsiveness to beta-adrenergic stimulation in cirrhosis.

PMID: 16968416 [PubMed - indexed for MEDLINE]


Anonymous said...

Thanks much for compiling and posting these studies!
You are a leader in the naltrexone movement, and I applaud you.

I've been taking 4.5 mg for over a month, but have yet to see any benefit. I'll hang in their for a few more months. Eric Olander

Ian Hewitt said...

To all my friends in the LDN community,

You may notice a bit of excitement in the email below.

I make no apologies for that. if you can imagine, almost five years
ago I was told I had Hepatitis C and my liver function numbers were not good.
I was then informed it is the biggest cause of liver transplants in the world.
My story is here

I am writing to you so that you can add my story (if you want) to your
own websites in your own words. You all know me and have watched my progress.
I can’t imagine much that could be a better ad for LDN (and the Nodict brand
in particular.) I was only on capsules of 4.5mg from a compounding pharmacy for
a year and Nodict 50mg tablets dissolved in solution for almost
4 years. See bottom of
for the tablet in solution method. I would appreciate one of you putting my results
on the Yahoo forum, as I have been unexplainably banned, and am still a bit
disappointed that you all put up with that, considering they refused any and all explanations.

Anyway, no matter how you cut it, from 6 out of 8 indicators being quite high,
to a normal liver function test (see below) is nothing short of miraculous.
I hope you spread the news any way you can, as it gives confidence not only in
Nodict but all brands of Naltrexone worldwide. Documented proof is what most people
(like me) crave. Many of us find little comfort in anecdotal type “evidence”.
"Show me the documentation” was always my request, and now I have
indisputable proof of the efficacy of Low Dose Naltrexone that nobody can deny.


If you think I am making a big deal of thie liver function test below, it is because


As of May 2016 my Liver Function Tests has gone from six out of eight indicators being well above average, (five years ago due to Hepatitis C) to
ALL within normal range!!!!

For absolute PROOF that LDN is miraculous, simply have a look at my liver function test results above!

All the very best and may you all get the same results I have,

Cheers, Ian

Unknown said...

I have autoimmune hepatitis. I will be trying LDN. My doctor will not prescribe LDN. Now I will pretend that I am not taking LDN, due to his uncooperative behavior. My blood tests are drawn every week. This will allow me to monitor my results. I will be working on my Master's, the person who over sees the Master's program, said I could use my autoimmune information as a thesis or project to bring awareness.
I plan on exposing the lack of collaboration within the medical community, patients, and alternative options available to those who suffer. I look forward to using this product. I of course have great hopes that it will be affective for my health. I am also hopeful that I will be able to bring the finer things (LDN, better quality of life) to those around me.