Tiede ja LDN

Vaikutusmekanismi

Naltreksoni on opioidiantagonisti, jota käytetään lähinnä päihdevieroituksessa sekä joidenkin psykiatristen häiriötilojen kuten syömishäiriöiden, addiktioiden ja pakkomielteiden hoidossa. Se salpaa mu- ja kappa- ja jossain määrin myös delta-opioidireseptoreja. Sen puoliintumisaika on noin neljä tuntia ja sen farmakologiselta aktiviteetiltaan vastaavan metaboliitin 6-beta-naltreksolin noin 13 tuntia. Plasman huippupitoisuudet saavutetaan noin tunnissa. Sillä ei ole tiettävästi vaikutusta mihinkään maksan sytokromi P450 -järjestelmän entsyymeistä. Narkoottisia aineita lukuunottamatta ainoa raportoitu yhteisvaikutus on psyykenlääke tioridatsiinin kanssa, jota Suomessa ei ole enää myynnissä.

Naltreksonin normaali käyttöannos vaihtelee välillä 50-300 mg. Tämä annos salpaa opioidireseptorit kokonaan tai lähes kokonaan ja aiheuttaa useimmiten ikäviä sivuvaikutuksia, kun endorfiinien toiminta estetään lähes täysin. Pieniannoksinen naltreksoni (tai matala-annoksinen naltreksoni) tarkoittaa hoitoa, jossa annos on kuitenkin vain 1,75 mg-5 mg (yleensä 3-4,5 mg) ja se salpaa reseptorit vain osittain ja lyhyeksi aikaa. Tämä stimuloi kehoa tuottamaan enemmän endorfiineja ja enkefaliineja, opioidipeptidejä jotka tunnetaan parhaiten kivun lievittämisestä ja mielialan kohottamisesta. Niillä on kuitenkin paljon muitakin vaikutuksia elimistössä, erityisesti immuunijärjestelmän ylläpitämisessä. Niiden on osoitettu esimerkiksi lisäävän luontaisten tappajasolujen määrää ja aktiivisuutta. Myös monista syöpäkasvaimista on löydetty opioidireseptoreita. Lisäksi naltreksoni voi lisätä dopamiinin eritystä kappa-opioidireseptorin kautta.

Beetaendorfiinista, leu-enkefaliinista ja met-enkefaliinista (tunnetaan myös opioidikasvutekijänä (OGF)) löytyy paljon tutkimuksia, jotka osoittavat niiden roolin eri sairauksissa. Monissa erilaisissa neurologisissa ja immuunijärjestelmän sairauksissa beetaendorfiinin tai enkefaliinien pitoisuudet on todettu liian alhaisiksi tai niiden eritysrytmi poikkeavaksi. Normaalisti suurin osa elimistön endorfiineista erittyy aamuyöllä. Siksi LDN otetaan yleensä ennen nukkumaanmenoa, jotta endorfiinien eritystä pystytään stimuloimaan mahdollisimman paljon. LDN-hoidon kehittänyt neurologi Bernard Bihari on osoittanut LDN:n nostavan beetaendorfiinitasoja jopa 200-300 %.

LDN auttaa säätelemään immuunijärjestelmää, mutta sitä voidaan pitää myös immunostimulanttina, koska se stimuloi luontaisten tappajasolujen eli NK-solujen toimintaa. Sen käyttö autoimmuunisairauksissa perustuu teoriaan, että autoimmuunisairaudet eivät johdu immuunijärjestelmän yliaktiivisuudesta vaan aliaktiivisuudesta. Asia ei toki ole aivan näin yksinkertainen, sillä immuunijärjestelmä on äärimmäisen monimutkainen koneisto ja mahdollistaa hyvin moninaiset häiriötilat liika- ja vajaatoiminnan lisäksi. Useat uudehkot tutkimukset kuitenkin tukevat tätä teoriaa autoimmuunisairauksista immuunipuutoksina, kuten myös se, että LDN useimmiten lievittää oireita, eikä johda sairauden pahenemiseen. LDN vaikuttaa olevan erityisen tehokas MS-taudissa, minkä syyksi on ehdotettu sitä, että se vähentää typpioksidisyntetaasin aktiviteettia ja siten peroksinitriitin muodostumista. Peroksinitriitti on yhdistetty myös esimerkiksi krooniseen väsymysoireyhtymään, fibromyalgiaan ja PTSD:hen.

Yhä useammasta aikaisemmin selittämättömästä sairaudesta on löytynyt viitteitä autoimmuniteetista. Tällaisia ovat esimerkiksi endometrioosi, interstitielli kystiitti ja narkolepsia. Myös AIDS-potilailta on löytynyt autovasta-aineita, mutta tämä ei todennäköisesti ole se syy, miksi LDN:stä on niin paljon apua monille HIV/AIDS-potilaille. LDN tehoaa moniin muihinkin sairauksiin kuin autoimmuunisairauksiin. Todennäköisesti tulevaisuudessa löytyy yhä useampia sairauksia, joihin LDN tehoaa, vaikka onkin turha odottaa siitä ihmeparannusta vaivaan kuin vaivaan. Jatkuvasti lisääntyvä tutkimus myös varmasti vakiinnuttaa LDN:n paikan monien sairauksien hoidossa.

LDN:ään liittyen on järjestetty jo ainakin kymmenen konferenssia: neljä ensimmäistä Yhdysvalloissa, sen jälkeen kaksi Glasgow'ssa Skotlannissa, yksi Birminghamissa, yksi Irlannissa ja kaksi Yhdysvalloissa. Tämän sivuston ylläpitäjä Maija Haavisto oli Glasgow'n ja Birminghamin konferensseissa vuonna 2010 puhumassa LDN:n käytöstä CFS:n hoidossa. Hän otti valokuvia molemmista konferensseista: Glasgow ja Birmingham.

Naltreksonilla on kaksi stereoisomeeriä, joilla on toisistaan poikkeavat vaikutukset. Vain toinen salpaa opioidireseptoreita, mutta molemmat salpaavat TLR-4-reseptoria ja estäävät mikrogliojen, eräs keskushermostossa esiintyvä valkosolutyyppi, aktivaatiota ja siten vähentää keskushermoston inflammaatiota. Tällä havainnolla on mahdollisesti kaksikin merkittävää seurausta. Se voi tarkoittaa sitä, että LDN-hoidon tehoa voidaan entisestään parantaa ja/tai sivuvaikutuksia vähentää käyttämällä vain toista stereoisomeeriä, tai käyttämällä niiden sekoitusta, joissa niiden suhde on muu kuin 50/50. Toisaalta se tarkoittaa myös sitä, että lääketeollisuus voi mahdollisesti sittenkin tehdä rahaa LDN:llä ja siten myös laajat kliiniset tutkimukset saattaisivat olla mahdollisia.

Sivun alalaidassa on tietoa keskeneräisistä ja vielä julkaisemattomista LDN-tutkimuksista.

Tutkimukset ja julkaisut LDN:stä

Ghai B, Bansal D, Hota D ym. Off-label, low-dose naltrexone for refractory chronic low back pain. Pain Med. 2014 May;15(5):883-4. PMID: 24967470

Dodou K, Armstrong A, Kelly I ym. Ex vivo studies for the passive transdermal delivery of low-dose naltrexone from a cream; detection of naltrexone and its active metabolite, 6β-naltrexol, using a novel LC Q-ToF MS assay. Pharm Dev Technol. Painossa 2014. PMID: 24785567

Segal D, Macdonald JK, Chande N. Low dose naltrexone for induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2014 Feb 21;2:CD010410. PMID: 24558033

Meng J, Meng Y, Plotnikoff NP ym. Low dose naltrexone (LDN) enhances maturation of bone marrow dendritic cells (BMDCs). Int Immunopharmacol. 2013 Dec;17(4):1084-9. PMID: 24455776

Rogosnitzky M, Finegold MJ, McLaughlin PJ ym. Opioid growth factor (OGF) for hepatoblastoma: a novel non-toxic treatment. Invest New Drugs. 2013 Aug;31(4):1066-70. PMID: 23275062

Chopra P, Cooper MS. Treatment of Complex Regional Pain Syndrome (CRPS) using low dose naltrexone (LDN). J Neuroimmune Pharmacol. 2013 Jun;8(3):470-6. PMID: 23546884

Bihari B. Bernard Bihari, MD: low-dose naltrexone for normalizing immune system function. Altern Ther Health Med. 2013 Mar-Apr;19(2):56-65. PMID: 23594453

Younger J, Noor N, McCue R ym. Low-dose naltrexone for the treatment of fibromyalgia: Findings of a small, randomized, double-blind, placebo-controlled, counterbalanced, crossover trial assessing daily pain levels. Arthritis Rheum. 2013 Feb;65(2):529-38. PMID: 23359310

Smith JP, Field D, Bingaman SI ym. Safety and tolerability of low-dose naltrexone therapy in children with moderate to severe Crohn's disease: a pilot study. J Clin Gastroenterol. J Clin Gastroenterol. 2013 Apr;47(4):339-45. PMID: 23188075

Ramanathan S, Panksepp J, Johnson B. Is fibromyalgia an endocrine/endorphin deficit disorder? Is low dose naltrexone a new treatment option? Psychosomatics. 2012 Nov-Dec;53(6):591-4. PMID: 22480625

Traore AK, Thiero O, Dao S ym. Single cohort study of the effect of low dose naltrexone on the evolution of immunological, virological and clinical state of HIV+ adults in Mali. J AIDS HIV Res. 2011 Oct;3(10):180-8. linkki

Traore AK, Thiero O, Dao S ym. Impact of low dose naltrexone (LDN) on antiretroviral therapy (ART) treated HIV+ adults in Mali: A single blind randomized clinical trial. J AIDS HIV Res. 2011 Oct;3(10):189-98. linkki

[Ei merkittyjä tekijöitä]. Low-dose naltrexone: tricking the body to heal itself. Exp Biol Med (Maywood). 2011 Sep 1;236(9):vii-viii. PMID: 21991594 (linkki)

Frech T, Novak K, Revelo MP ym. Low-dose naltrexone for pruritus in systemic sclerosis. Int J Rheumatol. 2011;2011:804296. PMID: 21918649

[Ei merkittyjä tekijöitä]. Low-dose naltrexone: harnessing the body's own chemistry to treat human ovarian cancer. Exp Biol Med (Maywood). 2011 Jul 1;236(7):viii. PMID: 21887861

Donahue RN, McLaughlin PJ, Zagon IS. Low-dose naltrexone targets the opioid growth factor-opioid growth factor receptor pathway to inhibit cell proliferation: mechanistic evidence from a tissue culture model. Exp Biol Med (Maywood). 2011 Sep 1;236(9):1036-50. PMID: 21807817

Raknes G, Giverhaug T. [Low dosage naltrexone]. Tidsskr Nor Laegeforen. 2011 Aug 9;131(15):1415-6. PMID: 21844938

Holmoy T. [Research on low dosage naltrexone]. Tidsskr Nor Laegeforen. 2011 Jul 1;131(13-14):1277-8. PMID: 21725378

Raknes G, Giverhaug T. [Naltrexone--high expectations to low dosages]. Tidsskr Nor Laegeforen. 2011 May 6;131(8):844-6. PMID: 21556092

Donahue RN, McLaughlin PJ, Zagon IS. Low-dose naltrexone suppresses ovarian cancer and exhibits enhanced inhibition in combination with cisplatin. Exp Biol Med (Maywood). 2011 Jul 1;236(7):883-95. Epub 2011 Jun 17. PMID: 21685240

McLaughlin PJ, Stucki JK, Zagon IS. Modulation of the opioid growth factor ([Met(5)]-enkephalin)-opioid growth factor receptor axis: novel therapies for squamous cell carcinoma of the head and neck. Head Neck. 2012 Apr;34(4):513-9. PMID: 21584896

Raknes G, Giverhaug T. [Low dosage naltrexone]. Tidsskr Nor Laegeforen. 2011 Aug 9;131(15):1415-6. PMID: 21844938

Donahue RN, McLaughlin PJ, Zagon IS. The opioid growth factor (OGF) and low dose naltrexone (LDN) suppress human ovarian cancer progression in mice. Gynecol Oncol. 2011 Aug;122(2):382-8. PMID: 21531450

Smith JP, Bingaman SI, Ruggiero F ym. Therapy with the opioid antagonist naltrexone promotes mucosal healing in active Crohn's disease: a randomized placebo-controlled trial. Dig Dis Sci. 2011 Jul;56(7):2088-97. PMID: 21380937

Hesselink JM, Kopsky DJ. Enhancing acupuncture by low dose naltrexone. Acupunct Med. 2011 Jun;29(2):127-30. PMID: 21415049

Rahn KA, McLaughlin PJ, Zagon IS. Prevention and diminished expression of experimental autoimmune encephalomyelitis by low dose naltrexone (LDN) or opioid growth factor (OGF) for an extended period: Therapeutic implications for multiple sclerosis. Brain Res. 2011 Mar 24;1381:243-53. PMID: 21256121

ALSUntangled Group. ALSUntangled No. 8: Low dose naltrexone for ALS. Amyotroph Lateral Scler. 2011 Jan;12(1):76-8. PMID: 21174518

Sharafaddinzadeh N, Moghtaderi A, Kashipazha D ym. The effect of low-dose naltrexone on quality of life of patients with multiple sclerosis: a randomized placebo-controlled trial. Mult Scler. 2010 Aug;16(8):964-9. PMID: 20534644

Shannon A, Alkhouri N, Mayacy S ym. Low-dose naltrexone for treatment of duodenal Crohn's disease in a pediatric patient. Inflamm Bowel Dis. 2010 Sep;16(9):1457. PMID: 20014017

Cree BA, Kornyeyeva E, Goodin DS. Pilot trial of low-dose naltrexone and quality of life in multiple sclerosis. Ann Neurol. 2010 Aug;68(2):145-50. PMID: 20695007

Guttuso T, Salins N, Lichter D. Abstract #13: Low-Dose Naltrexone's Tolerability and Effects in Fatigued Patients with Parkinson's Disease: An Open-Label Study. Neurotherapeutics. 2010 Jul;7(3):332. link

Berkson BM, Rubin DM, Berkson AJ. Revisiting the ALA/N (alpha-lipoic acid/low-dose naltrexone) protocol for people with metastatic and nonmetastatic pancreatic cancer: a report of 3 new cases. Integr Cancer Ther. 2009 Dec;8(4):416-22. PMID: 20042414

Gilhooly TC. Low dose naltrexone as a treatment for multiple sclerosis. Br J Neurosci Nurs. 2009 Nov 13;5(11):494.

Younger J, Mackey S. Fibromyalgia symptoms are reduced by low-dose naltrexone: a pilot study. Pain Med. 2009 May-Jun;10(4):663-72. PMID: 19453963

Desjardins S, Doyen C, Contejean Y ym. Treatment of a serious autistic disorder in a child with Naltrexone in an oral suspension form. Encephale. 2009 Apr;35(2):168-72. PMID: 19393386

Brown N, Panksepp J. Low-dose naltrexone for disease prevention and quality of life. Med Hypotheses. 2009 Mar;72(3):333-7. PMID: 19041189

Gironi M, Martinelli-Boneschi F ym. A pilot trial of low-dose naltrexone in primary progressive multiple sclerosis. Mult Scler. 2008 Sep;14(8):1076-83. PMID: 18728058

Patel PN. Low-dose naltrexone for treatment of multiple sclerosis: clinical trials are needed. Ann Pharmacother. 2007 Sep;41(9):1549-50. PMID: 17623758

Berkson BM, Rubin DM, Berkson AJ. Reversal of signs and symptoms of a B-cell lymphoma in a patient using only low-dose naltrexone. Integr Cancer Ther. 2007 Sep;6(3):293-6. PMID: 17761642

Mannelli P, Patkar AA, Peindl K ym. Effectiveness of Low-Dose Naltrexone in the Post-Detoxification Treatment of Opioid Dependence. J Clin Psychopharmacol. 2007 Oct;27(5):468-474. PMID: 17873678

Smith JP, Stock H, Bingaman S ym. Low-dose naltrexone therapy improves active Crohn's disease. Am J Gastroenterol. 2007 Apr;102(4):820-8. PMID: 17222320

Matioli F, Ribeiro JC, Fukuhara PS ym. Low dose naltrexone improves the muscular conditions in mdx mice. 2007. linkki

Good P. Low-dose naltrexone for multiple sclerosis and autism: does its benefit reveal a common cause? Med Hypotheses. 2006;67(3):671-2. PMID: 16759815

Berkson BM, Rubin DM, Berkson AJ. The long-term survival of a patient with pancreatic cancer with metastases to the liver after treatment with the intravenous alpha-lipoic acid/low-dose naltrexone protocol. Integr Cancer Ther. 2006 Mar;5(1):83-9. PMID: 16484716

Agrawal YP. Low dose naltrexone therapy in multiple sclerosis. Med Hypotheses. 2005;64(4):721-4. PMID: 15694688

Bihari B. Efficacy of low dose naltrexone as an immune stabilizing agent for the treatment of HIV/AIDS [letter]. AIDS Patient Care. 1995 Feb;9(1):3. PMID: 11361353

Bouvard MP, Leboyer M, Launay JM ym. Low-dose naltrexone effects on plasma chemistries and clinical symptoms in autism: a double-blind, placebo-controlled study. Psychiatry Res. 1995 Oct 16;58(3):191-201. PMID: 8570775

Bihari B, Drury F, Ragone V ym. Low dose naltrexone in the treatment of AIDS: long term follow-up results. V International Conference on AIDS. Poster M. C.P. 62. Montreal, June 1989.

Bihari B, Drury F, Ragone V ym. Low dose naltrexone in the treatment of AIDS. IV International Conference on AIDS. Poster 3056. Stockholm, June 1988. linkki

Muita aiheeseen liittyviä tutkimuksia ja julkaisuita

Syöpä

Sarkar DK, Zhang C. Beta-endorphin neuron regulates stress response and innate immunity to prevent breast cancer growth and progression. Vitam Horm. 2013;93:263-76. PMID: 23810011

Zagon IS, Donahue R, McLaughlin PJ. Targeting the opioid growth factor: opioid growth factor receptor axis for treatment of human ovarian cancer. Exp Biol Med (Maywood). 2013 May;238(5):579-87. PMID: 23856908

Chen W, Liu J, Meng J ym. Macrophage polarization induced by neuropeptide methionine enkephalin (MENK) promotes tumoricidal responses. Cancer Immunol Immunother. 2012 Oct;61(10):1755-68. PMID: 22419372

Sarkar DK, Zhang C, Murugan S ym. Transplantation of {beta}-Endorphin Neurons into the Hypothalamus Promotes Immune Function and Restricts the Growth and Metastasis of Mammary Carcinoma. Cancer Res. 2011 Oct 1;71(19):6282-91. PMID: 21835894

Boehncke S, Hardt K, Schadendorf D ym. Endogenous μ-opioid peptides modulate immune response towards malignant melanoma. Exp Dermatol. 2011 Jan;20(1):24-8. PMID: 20955200

Smith JP, Bingaman SI, Mauger DT ym. Opioid growth factor improves clinical benefit and survival in patients with advanced pancreatic cancer. Open Access J Clin Trials. 2010 Mar 1;2010(2):37-48. PMID: 20890374

Avella DM, Kimchi ET, Donahue RN ym. The opioid growth factor-opioid growth factor receptor axis regulates cell proliferation of human hepatocellular cancer. Am J Physiol Regul Integr Comp Physiol. 2010 Feb;298(2):R459-66. PMID: 19923357

McLaughlin PJ, Zagon IS, Park SS ym. Growth inhibition of thyroid follicular cell-derived cancers by the opioid growth factor (OGF) - opioid growth factor receptor (OGFr) axis. PMID: 19835629

Zagon IS, Donahue RN, McLaughlin PJ. Opioid growth factor-opioid growth factor receptor axis is a physiological determinant of cell proliferation in diverse human cancers.Am J Physiol Regul Integr Comp Physiol. 2009 Oct;297(4):R1154-61. PMID: 19675283

Donahue RN, McLaughlin PJ, Zagon IS. Cell proliferation of human ovarian cancer is regulated by the opioid growth factor-opioid growth factor receptor axis. Am J Physiol Regul Integr Comp Physiol. 2009 Jun;296(6):R1716-25. PMID: 19297547

McLaughlin PJ, Kreiner S, Morgan CR ym. Prevention and delay in progression of human squamous cell carcinoma of the head and neck in nude mice by stable overexpression of the opioid growth factor receptor. Int J Oncol. 2008 Oct;33(4):751-7. PMID: 18813788

Zagon IS, Kreiner S, Heslop JJ ym. Prevention and delay in progression of human pancreatic cancer by stable overexpression of the opioid growth factor receptor. Int J Oncol. 2008 Aug;33(2):317-23. PMID: 18636152

Sarkar DK, Boyadjieva NI, Chen CP ym. Cyclic adenosine monophosphate differentiated beta-endorphin neurons promote immune function and prevent prostate cancer growth. Proc Natl Acad Sci U S A. 2008 Jul 1;105(26):9105-10. PMID: 18562281

Zagon I, Donahue RN, Rogosnitzky M ym. Imiquimod upregulates the opioid growth factor receptor to inhibit cell proliferation independent of immune function. Exp Biol Med (Maywood). 2008 Aug;233(8):968-79. PMID: 18480416

Zagon IS, Rahn KA, McLaughlin PJ. Opioids and migration, chemotaxis, invasion, and adhesion of human cancer cells. Neuropeptides. 2007 Dec;41(6):441-52. PMID: 17910895

Zagon IS, Verderame MF, Hankins J ym. Overexpression of the opioid growth factor receptor potentiates growth inhibition in human pancreatic cancer cells. Int J Oncol. 2007 Apr;30(4):775-83. PMID: 17332915

McLaughlin PJ, Verderame MF, Hankins JL ym. Overexpression of the opioid growth factor receptor downregulates cell proliferation of human squamous carcinoma cells of the head and neck. Int J Mol Med. 2007 Mar;19(3):421-8. PMID: 17273790

McLaughlin PJ, Zagon IS. Progression of squamous cell carcinoma of the head and neck is associated with down-regulation of the opioid growth factor receptor. Int J Oncol. 2006 Jun;28(6):1577-83. PMID: 16685459

Zagon IS, Jaglowski JR, Verderame MF ym. Combination chemotherapy with gemcitabine and biotherapy with opioid growth factor (OGF) enhances the growth inhibition of pancreatic adenocarcinoma. Cancer Chemother Pharmacol. 2005 Nov;56(5):510-20. PMID: 15947928

Zagon IS, McLaughlin PJ. Opioids and differentiation in human cancer cells. Neuropeptides. 2005 Oct;39(5):495-505. PMID: 16169076

Jaglowski JR, Zagon IS, Stack BC ym. Opioid growth factor enhances tumor growth inhibition and increases the survival of paclitaxel-treated mice with squamous cell carcinoma of the head and neck. Cancer Chemother Pharmacol. 2005 Jul;56(1):97-104. PMID: 15791460

McLaughlin PJ, Jaglowski JR, Verderame MF ym. Enhanced growth inhibition of squamous cell carcinoma of the head and neck by combination therapy of paclitaxel and opioid growth factor. Int J Oncol. 2005 Mar;26(3):809-16. PMID: 15703840

Zagon IS, McLaughlin PJ. Opioid growth factor (OGF) inhibits anchorage-independent growth in human cancer cells. Int J Oncol. 2004 Jun;24(6):1443-8. PMID: 15138586

Smith JP, Conter RL, Bingaman SI ym. Treatment of advanced pancreatic cancer with opioid growth factor: phase I. Anticancer Drugs. 2004 Mar;15(3):203-9. PMID: 15014352

McLaughlin PJ, Levin RJ, Zagon IS. Opioid growth factor (OGF) inhibits the progression of human squamous cell carcinoma of the head and neck transplanted into nude mice. Cancer Lett. 2003 Sep 25;199(2):209-17. PMID: 12969794

McLaughlin PJ, Stack BC, Levin RJ ym. Defects in the opioid growth factor receptor in human squamous cell carcinoma of the head and neck. Cancer. 2003 Apr 1;97(7):1701-10. PMID: 12655527

Blebea J, Mazo JE, Kihara TK ym. Opioid growth factor modulates angiogenesis. J Vasc Surg. 2000 Aug;32(2):364-73. PMID: 10917997

McLaughlin PJ, Levin RJ, Zagon IS. The opioid growth factor receptor in human head and neck squamous cell carcinoma. Int J Mol Med. 2000 Feb;5(2):191-6. PMID: 10639600

Bisignani GJ, McLaughlin PJ, Ordille SD ym. Human renal cell cancer proliferation in tissue culture is tonically inhibited by opioid growth factor. J Urol. 1999 Dec;162(6):2186-91. PMID: 10569617

McLaughlin PJ, Levin RJ, Zagon IS. Regulation of human head and neck squamous cell carcinoma growth in tissue culture by opioid growth factor. Int J Oncol. 1999 May;14(5):991-8. PMID: 10200353

Zagon IS, Smith JP, McLaughlin PJ. Human pancreatic cancer cell proliferation in tissue culture is tonically inhibited by opioid growth factor. Int J Oncol. 1999 Mar;14(3):577-84. PMID: 10024694

McLaughlin PJ, Zagon IS, Skitzki J. Human neuroblastoma cell growth in tissue culture is regulated by opioid growth factor. Int J Oncol. 1999 Feb;14(2):373-80. PMID: 917516

Levin RJ, Wu Y, McLaughlin PJ ym. Expression of the opioid growth factor, [Met5]-enkephalin, and the zeta opioid receptor in head and neck squamous cell carcinoma. Laryngoscope. 1997 Mar;107(3):335-9. PMID: 9121309

Zagon IS, Hytrek SD, Smith JP ym. Opioid growth factor (OGF) inhibits human pancreatic cancer transplanted into nude mice. Cancer Lett. 1997 Jan 30;112(2):167-75. PMID: 9066724

Zagon IS, Hytrek SD, McLaughlin PJ. Opioid growth factor tonically inhibits human colon cancer cell proliferation in tissue culture. Am J Physiol. 1996 Sep;271(3 Pt 2):R511-8. PMID: 8853370

Zagon IS, Hytrek SD, Lang CM ym. Opioid growth factor ([Met5]enkephalin) prevents the incidence and retards the growth of human colon cancer. Am J Physiol. 1996 Sep;271(3 Pt 2):R780-6. PMID: 885340

Hytrek SD, McLaughlin PJ, Lang CM ym. Inhibition of human colon cancer by intermittent opioid receptor blockade with naltrexone. Cancer Lett. 1996 Mar 29;101(2):159-64. PMID: 8620464

Murgo AJ. Modulation of murine melanoma growth by naloxone. Cancer Lett. 1989 Feb;44(2):137-42. PMID: 2920373

Zagon IS, McLaughlin PJ. Opioid antagonist modulation of murine neuroblastoma: a profile of cell proliferation and opioid peptides and receptors. Brain Res. 1989 Feb 20;480(1-2):16-28. PMID: 2540873

Zagon IS, McLaughlin P. Endogenous opioids and the growth regulation of a neural tumor. Life Sci. 1988;43(16):1313-8. PMID: 2845218

Faith RE, Murgo AJ. Inhibition of pulmonary metastases and enhancement of natural killer cell activity by methionine-enkephalin. Brain Behav Immun. 1988 Jun;2(2):114-22. PMID: 3233355

Zagon IS, McLaughlin PJ, Goodman SR ym. Opioid receptors and endogenous opioids in diverse human and animal cancers. J Natl Cancer Inst. 1987 Nov;79(5):1059-65. PMID: 2824913

McLaughlin PJ, Zagon IS. Modulation of human neuroblastoma transplanted into nude mice by endogenous opioid systems. Life Sci. 1987 Sep 21;41(12):1465-72. PMID: 3041143

Murgo AJ. Inhibition of B16-BL6 melanoma growth in mice by methionine-enkephalin. J Natl Cancer Inst. 1985 Aug;75(2):341-4. PMID: 3860686

Zagon IS, McLaughlin PJ. Duration of opiate receptor blockade determines tumorigenic response in mice with neuroblastoma: a role for endogenous opioid systems in cancer. Life Sci. 1984 Jul 23;35(4):409-16. PMID: 6087062

Froelich CJ, Bankhurst AD. The effect of beta-endorphin on natural cytotoxicity and antibody dependent cellular cytotoxicity. Life Sci. 1984 Jul 16;35(3):261-5. PMID: 6087056

Zagon IS, McLaughlin PJ. Opioid antagonists inhibit the growth of metastatic murine neuroblastoma. Cancer Lett. 1983 Nov;21(1):89-94. PMID: 6640516

Zagon IS, McLaughlin PJ. Naltrexone modulates tumor response in mice with neuroblastoma. Science. 1983 Aug 12;221(4611):671-3. PMID: 6867737

Mathews PM, Froelich CJ, Sibbitt WL Jr. ym. Enhancement of natural cytotoxicity by beta-endorphin. J Immunol. 1983 Apr;130(4):1658-62. PMID: 6300232

HIV ja muut infektiot

Steele AD, Henderson EE, Rogers TJ. Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication. Virology. 2003 Apr 25;309(1):99-107. PMID: 12726730

Gekker G, Lokensgard JR, Peterson PK. Naltrexone potentiates anti-HIV-1 activity of antiretroviral drugs in CD4+ lymphocyte cultures. Drug Alcohol Depend. 2001 Nov 1;64(3):257-63. PMID: 11672940

Sharp BM, Gekker G, Li MD ym. Delta-opioid suppression of human immunodeficiency virus-1 expression in T cells (Jurkat). Biochem Pharmacol. 1998 Aug 1;56(3):289-92. PMID: 9744564

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Autoimmuunisairaudet

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Zagon IS, McLaughlin PJ. Targeting opioid signaling in Crohn's disease: new therapeutic pathways. Expert Rev Gastroenterol Hepatol. 2011 Oct;5(5):555-8. PMID: 21910569

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Zagon IS, Donahue RN, Bonneau RH ym. T lymphocyte proliferation is suppressed by the opioid growth factor ([Met(5)]-enkephalin)-opioid growth factor receptor axis: implication for the treatment of autoimmune diseases. Immunobiology. 2011 May;216(5):579-90. PMID: 20965606

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CFS/ME jne

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Immuunijärjestelmä yleisesti

Lucas K, Maes M. Role of the Toll Like receptor (TLR) radical cycle in chronic inflammation: possible treatments targeting the TLR4 pathway. Mol Neurobiol. 2013 Aug;48(1):190-204. PMID: 23436141

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Haavojen parantuminen

McLaughlin PJ, Pothering CA, Immonen JA ym. Topical treatment with the opioid antagonist naltrexone facilitates closure of full-thickness wounds in diabetic rats. Exp Biol Med (Maywood). 2011 Oct 1;236(10):1122-32. PMID: 21917593

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Neuroprotektiiviset vaikutukset

Cai Z, Ratka A. Opioid system and Alzheimer's disease. Neuromolecular Med. 2012 Jun;14(2):91-111. PMID: 22527793

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Liu B, Hong JS. Neuroprotective effect of naloxone in inflammation-mediated dopaminergic neurodegeneration. Dissociation from the involvement of opioid receptors. Methods Mol Med. 2003;79:43-54. PMID: 12506689

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Psykiatrinen käyttö

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Kipu

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Keskeneräiset ja tulevat LDN-tutkimukset

Lääketehdas TNI Biotech on hankkinut itselleen LDN:n kehittäjän Bernard Biharin LDN-patentit ja aikoo tehdä LDN:llä laajamittaisia tutkimuksia mm. Malawiin perustettavassa syöpä- ja infektiosairaalassa, tavoitteenaan FDA-hyväksyntä. Se on hakenut LDN:lle harvinaislääkkeen (orphan drug) asemaa lasten Crohnin taudissa. Myös LDN:ää fibromyalgiassa tutkinut Jarred Younger yrittää kerätä rahoitusta kolmosvaiheen tutkimukseen, jotta LDN voisi saada FDA-hyväksynnän fibromyalgian hoitoon Yhdysvalloissa. Parhaillaan on käynnissä tutkimus siitä, vähentääkö LDN tulehdusta fibromyalgiassa.

Uusi tutkimus kokeilee LDN:ää sekä Crohnin taudissa että haavaisessa paksusuolentulehduksessa. Myös masennuksen hoidosta on käynnissä mielenkiintoinen tutkimus, tosin annos on jostain syystä vain 2 x 1 mg päivässä. Ian Zagon jatkaa tutkimuksia LDN:n käytöstä eri syöpien hoidossa, mm. pään ja kaulan syövät, mutta näistä ei ole verkossa tarkempia tietoja. Gliooman eli erityisen pahanlaatuisen aivokasvaintyypin hoidosta löytyy kuitenkin tutkimus. Toinen tutkimus oli meneillään LDN:n käytöstä levinneen melanooman, kastraatioresistentin eturauhassyövän ja munuaissyövän hoidossa, mutta se on tuntemattomasta syystä keskeytetty (yleinen syy keskeyttää kliininen tutkimus on, että halukkaita osallistujia ei ole löytynyt tarpeeksi). Tutkimus LDN:n käyttöä lasten fibromyalgiassa näyttää sekin valitettavasti peruuntuneen.