LDN for Psoriasis: Good Treatment But Still Not a Cure

Low Dose Naltrexone (LDN) is a popular alternative treatment not only for psoriasis. Still the most people do not get it and are clueless about the reasons why and how Naltrexone in low dosages works for so many chronic inflammatory and degenerative diseases.

Many doctors, chiropractors and naturopaths agree that LDN is quite an effective and relatively very safe treatment for many diseases.

Since I am absolutely sure that psoriasis is an Autonomic Nervous System dysfunction rather than autoimmune disease (or some form of immune disease) I do agree that potent drug like Naltrexone may improve or even completely clear up psoriasis.

Naltrexone affects the neurons substantially so there is a chance of improvement of psoriasis.

I say a chance because it is relatively easy to guess the biochemistry outcomes of the immune system compared to guessing the biochemistry outcomes of nervous system.

But what if the secret power of Naltrexone lies somewhere else?

What if it is not about its direct effects on the nervous system?

How does naltrexone exactly contribute to improvement of psoriasis?

One theory is that taking this drug which blocks the opioid receptors makes the brain produce own endorphins because it “thinks” that there is an endorphin deficiency.

But if you think about this theory it sounds kind of weird.

If the opioid receptors were blocked with Naltrexone then what purpose would the endorphins serve?

And are they (endorphins) even anti-inflammatory? Maybe and maybe not!

The researchers found out that one of the endogenous endorphins – beta-endorphin – affected the inflammation differently in two inbred rat strains.[8]

The another group of researchers proved that beta-endorphins in cultured human articular chondrocytes (knee cartilage) increased the levels of two strongly pro-inflammatory messengers: IL-1 Beta and TNF-Alpha.[9]

 


In order to investigate if beta-endorphins anti-inflammatory effect in cartilage-damaging states is mediated via tumor necrosis factor-alpha (TNF-alpha) and interleukin-1 beta (IL-1 beta), we examined its influence on these two cytokines in vitro. Human articular chondrocytes were obtained from patients undergoing total knee arthroplasty and stimulated with beta-endorphin (60-6000 ng/ml). Protein levels of TNF-alpha and IL-1 beta were measured by ELISA in supernatants from articular chondrocyte cultures. beta-Endorphin significantly increased the levels of IL-1 beta for all concentrations used after 15 min incubation, and when stimulated with 600 and 6000 ng/ml after 24 h incubation. The opioid-induced increase in IL-1 beta was blocked by naltrexone in the group tested. TNF-alpha expression was also significantly stimulated by 60 and 600 ng/ml beta-endorphin after 15 min, an effect blocked by naltrexone in the group tested. These findings indicate that the mechanism of beta-endorphins anti-inflammatory influence in cartilage-damaging states is not apparently mediated via these two cytokines modulation.

Abstract Source: Andjelkov N, Elvenes J, Martin J, Johansen O. Opiate regulation of IL-1beta and TNF-alpha in cultured human articular chondrocytes. Biochem Biophys Res Commun. 2005 Aug 12;333(4):1295-9.

 

So, maybe the answer is that endorphins are generally pro-inflammatory and it is just our feeling that they should be anti-inflammatory because they attenuate the pain.

They do attenuate the pain but as this study proved, beta-endorphin application increased the nasal congestion which “is mediated through direct neuroendocrine receptor activation independent of mast cell activation and that during the allergic reaction there is a beta-endorphin/mast cell interaction that enhances the mediator response to nasal allergen challenge.” [10]

So, attenuation of pain is not the same thing as elimination of the inflammation.

This is also the case of the opiate king – Morphine.

This drug is strongly pro-inflammatory even though we might get an impression that the exact opposite is true.

It is a well known fact that opiate receptors agonists induce the histamine release as you can see in the picture below where the veins are clearly visible due to morphine induced histamine release.

Author: James Heilman, MD for Wikipedia
CC License Link: https://creativecommons.org/licenses/by-sa/3.0/deed.en

 

Image Source: Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yin. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6325-30.

 

The next picture below presents how a TLR4 antagonist abolishes the morphine induced inflammation.

“TLR4/MD-2 antagonists abolish morphine-induced proinflammatory activation in vitro and in vivo.
(A)
A strategy of potentiating opioid analgesia by disrupting the non-neuronal TLR4/MD-2 complex.
Upper:
Opioids activate CNS immunocompetent cells by triggering a signal transduction cascade mediated by TLR4 (dimeric form in complex with MD-2).
This results in the release of the cytokine intercellular mediator IL-1β and other proinflammatory factors, which suppresses the desired opioid-induced neuronal analgesic effect.
Lower:
In the presence of TLR4-signaling antagonists such as inhibitors of the critical TLR4/MD-2 interaction, CNS immunocompetent cells remain in the resting state. Opioids (red star) then show higher analgesic efficacy by binding solely to opioid receptors (orange hexagon) on neurons.
[7]
Image and Text Source: Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yin. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6325-30.

Endorphins make us feel good and relaxed and they (partially) switch us (or at least we feel it this way) to parasympathetic state (rest-digest-repair). [11]

Now when you know how pro-inflammatory the endorphins and natural as well as (semi-)synthetic opiates may be, it is time to reveal to you the principle why Naltrexone most likely works for psoriasis and many other diseases.

Yes, psoriasis and many other diseases…

That is exactly the most interesting – Naltrexone is able to improve multiple health conditions – including those considered to be autoimmune. Whether it is a Crohn’s disease, Ulcerative colitis, Multiple Sclerosis, Fibromyalgia, Psoriasis, Rheumatoid arthritis and even Cancer.

I think that the TLR-4 (Toll-like Receptor 4) blocking effects of Naltrexone are what really helps with inflammation and subsequently all those debilitating chronic diseases.

Science about the LDN for psoriasis

Actually, I couldn’t find any relevant scientific study about the Naltrexone effects on psoriasis.

So, we have to make a conclusion based on the scientific data of the Naltrexone effects on other chronic inflammatory diseases.

Especially the Crohn’s disease is very similar to psoriasis in my opinion. The inflamed spots in the small intestine vs. inflamed spots on the skin.

Naltrexone, inflammatory diseases, TLR-4 and endotoxins

In “Low-dose naltrexone therapy improves active Crohn’s disease” study the authors present the data regarding the positive effects of low-dose Naltrexone on Crohn’s disease.

The group of 17 patients was involved in study – they took the 4.5mg of Naltrexone daily for 12 weeks.

The symptoms of the disease “decreased significantly (P= 0.01) with LDN, and remained lower than baseline 4 wk after completing therapy. Eighty-nine percent of patients exhibited a response to therapy and 67% achieved a remission (P < 0.001). Improvement was recorded in both quality of life surveys with LDN compared with baseline. No laboratory abnormalities were noted. The most common side effect was sleep disturbances, occurring in seven patients.”[1]

Opioid-inactive isomer of Naloxone which is chemically and functionally similar to Naltrexone as TLR-4 inhibitor reverses the multiple models of chronic neuropathic pain in rats.

The functional difference between the Naltrexone and Naloxone is that Naltrexone is administered orally, has a longer half-life and the onset of effects is delayed compared to Naloxone. Therefore Naloxone is used mostly in emergency situations of drug overdose and is administered by injection.

 


The present studies reveal that the TLR4 contributes to neuropathic pain in another major model (spinal nerve ligation) and to long established (2-4 months) neuropathic pain, not just to pain shortly after nerve damage.

(+)-Naloxone inhibited signaling by TLR4 but not TLR2. These studies provide evidence for broad involvement of TLR4 in neuropathic pain, both early after nerve damage and months later.

These studies demonstrated that (+)-naloxone, a systemically available, blood-brain barrier permeable, small molecule TLR4 inhibitor can reverse neuropathic pain in rats, even months after nerve injury. These findings suggest that (+)-naloxone, or similar compounds, be considered as a candidate novel, first-in-class treatment for neuropathic pain.
” [3]

 

In other words this study suggested if not proved indirectly that the TLR-4 receptor activation by endotoxin may be the cause of the many cases of neuropathic pain in humans as well.

So maybe the neuropathic pain you have been experiencing since some physical trauma is potentiated by the endotoxins.

Inflammation induced by TLR-4 receptors is involved in more diseases, disorders and events in the body than you might think.

One of the outcomes of TLR-4 activation in pregnancy is a preterm birth.

Naloxone was found to effectively suppress the preterm birth in mice induced by endotoxin induced inflammation.[5]

 


Toll-like receptor 4 (TLR4) activation by bacterial infection, or by sterile inflammatory insult is a primary trigger of spontaneous preterm birth. Here we utilize mouse models to investigate the efficacy of a novel small molecule TLR4 antagonist, (+)-naloxone, the non-opioid isomer of the opioid receptor antagonist (−)-naloxone, in infection-associated preterm birth. Treatment with (+)-naloxone prevented preterm delivery and alleviated fetal demise in utero elicited by i.p. LPS administration in late gestation. A similar effect with protection from preterm birth and perinatal death, and partial correction of reduced birth weight and postnatal mortality, was conferred by (+)-naloxone administration after intrauterine administration of heat-killed E. coli. Local induction by E. coli of inflammatory cytokine genes Il1b, Il6, Tnf and Il10 in fetal membranes was suppressed by (+)-naloxone, and cytokine expression in the placenta, and uterine myometrium and decidua, was also attenuated. These data demonstrate that inhibition of TLR4 signaling with the novel TLR4 antagonist (+)-naloxone can suppress the inflammatory cascade of preterm parturition, to prevent preterm birth and perinatal death. Further studies are warranted to investigate the utility of small molecule inhibition of TLR-driven inflammation as a component of strategies for fetal protection and delaying preterm birth in the clinical setting.
” [5]

 

Take a look at the next picture and read the description to understand how the endotoxins/LPS induce the inflammation.

 

“The TLR4 signaling pathway. When LPS is bound to the bacterial outer membrane or present in intact outer membrane vesicles, its toxic potential is not released, and as such, these molecules were termed “endotoxins”. As soon as LPS is released, this is changed. Free LPS is bound by LBP and transferred to CD14. MD-2 then binds the LPS and forms LPS-MD-2-TLR4 complexes. Dimerization of two of these complexes then occurs. Dimerization of TLR4 molecules leads to the recruitment of adapter molecules: MyD88, the TIR-domain containing adapter protein-inducing IFN-β (TRIF) and the TRIF-related adapter molecule (TRAM). A signaling cascade is initiated, which eventually leads to the degradation of the IKK complex, which frees the transcription factor, NF-κB. NF-κB then moves into the nucleus and starts transcription of pro-inflammatory cytokines, such as IL-6 and TNF-α. Via a different pathway, initiated by different adapter molecules, type I interferon genes are also transcribed, leading to the production of IFN-α/β.”[12]
Image and Text Source: Reindert Nijland, Tom Hofland and Jos A. G. van Strijp. Recognition of LPS by TLR4: Potential for Anti-Inflammatory Therapies. Mar. Drugs 2014, 12(7), 4260-4273

Now you should understand why scientists are actively working on synthesizing the TLR4 antagonist (blockers) and stronger analogues of Naltrexone.

One of the newly synthesized compounds similar to Naltrexone is called “1j” which showed the 75 times better TLR-4 antagonist activity than Naltrexone “and the ratio of its cell viability IC50, a measure of its toxicity, to TLR-4 antagonist activity (140 μM/1.4 μM) was among the best of the new analogs. This compound (1j) was active in vivo; it significantly increased and prolonged morphine analgesia.”[6]

Also the other TLR-4 antagonist – a former anti-sepsis investigational drug Eritoran – significantly decreases the IL-6 and TNF-alpha production by human immune cells.[4]

However, the TLR4 antagonists are present also naturally in herbs and plants – one of them is a Chinese herb – Sparganium stoloniferum (containing the sparstolonin B) used in a Traditional Chinese Medicine for its anti-inflammatory properties.[2]

Testimonials: Naltrexone for psoriasis

I tried to find some positive testimonials about the Naltrexone effects on psoriasis. Here are some but I am sure you can find many more on the web and mostly if you ask in some psoriasis groups on Facebook.

Here is an excerpt from a testimonial mentioning the LDN and its effects on psoriasis:



My naturopath didn’t know if it would help psoriasis, but she had good luck with other AI’s so she thought I’d be a good candidate.

It isn’t a cure. The effects tend to last a month or so after stopping LDN. It won’t help everyone. But neither do the other therapies. It takes about 2-3 months to know for sure if it is helping.

Interestingly, NOW all my specialists have taken notice because my skin is so much better. I am involved with an 8 year psoriasis ‘quality of life’ research program and even those folks have started tracking the LDN findings.

” by DCrist

https://psoriasisclub.org/archive/index.php?thread-2342.html

 



I have had P for about 30 years, struck me in early adulthood. Early years with P not very bad, but last ten years
have increased coverage and intensity. Early years a small
portion of body was affected. Now I have it from top of my
head to bottom of feet.

– by quail”

http://ldn.proboards.com/thread/824

 


Hello all,
I am giving update on LDN and psoriasis. I am so much improved versus the last three months, it is unbelievable.
I have tried so many things that cost several times more per month/year with little results. Thank you Dr. Bihari and thank you Brenda. My psoriasis coverage has gone from 70% to less than 45% in less than two weeks. In this statement I am being conservative. I guess this is from trying so many things in MY battle.

P.S. I can see real skin again. I want to remember my start date on LDN, so I can have a good log.

http://ldn.proboards.com/thread/824?page=2

 



This an update after 46 nights on 4.5mg liquid LDN.
I am doing great, very few new psoriasis lesions, I feel P is
well under control. I am using very little topical medication as
of now. I am able to sleep without melatonin or any other
sleep aid, this is amazing because it felt like I would never be
able to sleep normally again without a sleep aid when I started LDN. My skin is clearer now than it has been in 30
years, and this is my worst time of year for flare ups.
I feel so good, even my attitude has changed. I have more
energy, I am losing weight without much effort. Like I said
I feel great!
I want to thank everyone for the encouragement,
quail

http://ldn.proboards.com/thread/824?page=2

 


Hey all,

After 84 nights on LDN!
I am amazed at the progress I have had on LDN. My psoriasis
has went from a nightmare to a good dream. I hope to share
this with many others. I missed my last appointment with
my derm due to uncontrolled circumstances, and have re-
scheduled. I look forward to the next three months.
I missed one night taking my LDN, the next day I was
dragging A. I feel good every day after taking 4.5mg LDN,
as good as I have ever felt in my life, this stuff works.
” – by quail

http://ldn.proboards.com/thread/824?page=3

 

 

You can find some videotestimonials regarding the LDN and psoriasis on LDNResearchTrust.com

Conclusion

Is it worth to take LDN for psoriasis?

Well, nobody can answer this question for you but you.

Naltrexone is a well researched drug marketed for many years so you should have enough information to learn about the pros and cons.

The main purpose of Naltrexone is to treat the substance addictions and all that LDN thing is actually an “off-label” use when the patient takes usually 4.5mg of Naltrexone daily. This is a much lower dosage considering that the standard tablets of Naltrexone contains the 50mg of it.

 

References:

1) Smith JP, Stock H, Bingaman S, Mauger D, Rogosnitzky M, Zagon IS. Low-dose naltrexone therapy improves active Crohn’s disease. Am J Gastroenterol. 2007 Apr;102(4):820-8.

2) Liang Q, Wu Q, Jiang J, Duan J, Wang C, Smith MD, Lu H, Wang Q, Nagarkatti P, Fan D. J Biol Chem. 2011 Jul 29;286(30):26470-9.

3) Lewis SS, Loram LC, Hutchinson MR, Li CM, Zhang Y, Maier SF, Huang Y, Rice KC, Watkins LR. (+)-naloxone, an opioid-inactive toll-like receptor 4 signaling inhibitor, reverses multiple models of chronic neuropathic pain in rats. J Pain. 2012 May;13(5):498-506.

4) Czeslick E, Struppert A, Simm A, Sablotzki A. E5564 (Eritoran) inhibits lipopolysaccharide-induced cytokine production in human blood monocytes. Inflamm Res. 2006 Nov;55(11):511-5.

5) Peck Yin Chin, Camilla L. Dorian, Mark R. Hutchinson, David M. Olson, Kenner C. Rice, Lachlan M. Moldenhauer and Sarah A. Robertson. Novel Toll-like receptor-4 antagonist (+)-naloxone protects mice from inflammation-induced preterm birth. Nature, Scientific Reports 6, Article number: 36112 (2016)

6) Selfridge BR, Wang X, Zhang Y, Yin H, Grace PM, Watkins LR, Jacobson AE, Rice KC. Structure-Activity Relationships of (+)-Naltrexone-Inspired Toll-like Receptor 4 (TLR4) Antagonists. J Med Chem. 2015 Jun 25;58(12):5038-52.

7) Xiaohui Wang, Lisa C. Loram, Khara Ramos, Armando J. de Jesus, Jacob Thomas, Kui Cheng, Anireddy Reddy, Andrew A. Somogyi, Mark R. Hutchinson, Linda R. Watkins and Hang Yin. Morphine activates neuroinflammation in a manner parallel to endotoxin. Proc Natl Acad Sci U S A. 2012 Apr 17;109(16):6325-30.

8) Stanojević S, Mitić K, Vujić V, Kovacević-Jovanović V, Dimitrijević M. Beta-endorphin differentially affects inflammation in two inbred rat strains. Eur J Pharmacol. 2006 Nov 7;549(1-3):157-65.

9) Andjelkov N, Elvenes J, Martin J, Johansen O. Opiate regulation of IL-1beta and TNF-alpha in cultured human articular chondrocytes. Biochem Biophys Res Commun. 2005 Aug 12;333(4):1295-9.

10) Baumgarten CR, Schmitz P, O’Connor A, Kunkel G. Effects of beta-endorphin on nasal allergic inflammation. Clin Exp Allergy. 2002 Feb;32(2):228-36.

11) Rabkin SW. The interrelationship of morphine and the parasympathetic nervous system in digoxin-induced arrhythmias in the guinea-pig. Clin Exp Pharmacol Physiol. 1988 Aug;15(8):565-73.

12) Reindert Nijland, Tom Hofland and Jos A. G. van Strijp. Recognition of LPS by TLR4: Potential for Anti-Inflammatory Therapies. Mar. Drugs 2014, 12(7), 4260-4273

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