Medical Hypotheses 72 (2009) 333337

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Medical Hypotheses
journal homepage: www.elsevier.com/locate/mehy

Low-dose naltrexone for disease prevention and quality of life

Norman Brown a,*, Jaak Panksepp b
a
Department of Humanities and Social Sciences, Embry-Riddle Aeronautical University, Daytona Beach, FL 32114, United States
b
Department of VCAPP, College of Veterinary Medicine, Washington State University, P.O. Box 646520, Pullman, WA 99164-6520, United States

a r t i c l e i n f o s u m m a r y

Article history: The use of low-dose naltrexone (LDN) for the treatment and prophylaxis of various bodily disorders is
Received 3 June 2008 discussed. Accumulating evidence suggests that LDN can promote health supporting immune-modula-
Accepted 12 June 2008 tion which may reduce various oncogenic and inammatory autoimmune processes. Since LDN can
upregulate endogenous opioid activity, it may also have a role in promoting stress resilience, exercise,
social bonding, and emotional well-being, as well as amelioration of psychiatric problems such a autism
and depression. It is proposed that LDN can be used effectively as a buffer for a large variety of bodily and
mental ailments through its ability to benecially modulate both the immune system and the brain neu-
rochemistries that regulate positive affect.
2008 Published by Elsevier Ltd.

Introduction health, especially along the dimension of reduced likelihood of

cancers and autoimmune problems. Intermediate levels of LDN
Preventive medicine has excelled in reducing the risk factors of (at 0.25 mg/kg given every other day) were initially found to have
high cholesterol with various statins, and accruing cardiac damage some benets in the treatment of a subset of autistic children [4,5].
with baby aspirin blood thinners. There is considerable contro- One of the clinical impressions was an increased social initiative
versy about general health sustaining effects of adequate vitamins, and cheerfulness, especially on the non-medication days, as if a re-
minerals, herbals and specic puried nutritionals, but there is rel- bound effect of positive social chemistries (e.g., opioids) was occur-
atively little medical research on discrete biochemical supple- ring. There is now increasing data that would suggest that a
ments to facilitate general health and well-being. In this essay temporary blockade of opioid receptors with LDN may lead to an
we introduce low-dose naltrexone (LDN) as a potential way to upregulation of mood enhancing endogenous opioids, and hence
strengthen brain and bodily resources to facilitate emotional perhaps dopamine activity, which may further promote positive
homeostasis and also provide background prophylaxis against frames of mind. As importantly, endogenous opioids have robust
and potential treatment of various cancers and autoimmune disor- immune modulatory properties, which may be harnessed through
ders an idea that has already been extensively discussed on the LDN to facilitate body resources to retard and combat oncogenic
web (e.g., www.Lowdosenaltrexone.org). and autoimmune processes and reduce the impact of allostatic
Naltrexone, an orally effective, long-lasting opiate receptor load on the body.
antagonist, was approved by the FDA for treating alcohol and opi- Although the data is only now emerging for benecial endoge-
ate addiction in 1984, but its general patent expired the following nous brain and body opioid rebound effects from LDN supplemen-
year. It is a non-selective antagonist, with robust effects on plea- tation, indirect evidence does exist for such effects, including the
sure promoting mu opioid receptors (MOR) and delta opioid recep- ability of ultra-low LDN to facilitate the analgesic effects of opioids
tors (DOR) [1], with less antagonism of aversion-mediating kappa [6], and the ability of LDN to facilitate maintenance of drug absti-
opioid receptors (KOR) [2] but substantial effect on the more re- nence in former opiate addicts [7]. In this essay we will focus on
cently discovered orphanin FQ or nociceptin [N/OFQ] opioid family the potential ability of LDN to serve as a facilitator of immunocom-
[3]. The benets of high dose naltrexone in narcotic addiction are petence that may provide prophylaxis for a variety of disorders,
explained by blockade of all pleasure producing effects of opioids, from oncogenesis to neurological disorders, where a compromised
and similar mechanisms may explain the ability of naltrexone to immune system hastens bodily decline.
reduce binging on alcohol.
Here we will consider the potential benets of low-dose nal- Hypotheses
trexone (LDN) as a way to strengthen both brain and bodily re-
sources to promote psychological well-being as well as bodily When administered in low-doses of 34.5 mg daily, naltrexone
increases the expression of mu, delta, and epsilon opioid receptors
* Corresponding author. Tel.: +1 386 226 6631; fax: +1 386 226 7210. as well as central and circulating met-enkephalin (ME) and beta-
E-mail address: [email protected] (N. Brown). endorphin (BE), which may improve psychological well-being.

0306-9877/$ - see front matter 2008 Published by Elsevier Ltd.

doi:10.1016/j.mehy.2008.06.048
334 N. Brown, J. Panksepp / Medical Hypotheses 72 (2009) 333337

The associated bodily changes result in enhanced immune func- no benecial effect and actually facilitated tumor growth. In con-
tions that may stop inammation and the progression of rheuma- trast, a low-dose [0.1 mg/kg] decreased oncogenesis signicantly
toid, gastrointestinal and neurological autoimmune disorders. [23]. Zagon and McLaughlin concluded that LDN increased opiate
These hypothesized disease-modifying effects of enhanced im- receptors and elevated circulating BE and ME after a 46 h period
mune functions contradict current medical opinion that immune of receptor blockade. This rebound phase may release the in-
functions must be globally suppressed to retard the progression creased density of mu and delta opioid receptors for endogenous
of autoimmune diseases. Yet evidence is mounting that LDN may opioid stimulation with the increasingly available BE and ME.
have substantial therapeutic effects in such disorders. Further- The general principle operative here may be that the increased
more, naltrexones enhancement of the immune system is a novel concentrations of BE and ME that gain access to increased density
approach to arresting or preventing a variety of cancers. Resistance of MOR and DOR receptors may functionally supersensitize [24]
to viral diseases may also be enhanced, with a trial currently in endogenous opioid functions throughout the body with benecial
progress to evaluate efcacy of LDN for treating AIDS. downstream effects on various body parameters, especially
Background evidence: Since naltrexone entered the public do- immunocompetence.
main in1984, little funding has been available for researching
treatment for any diseases except alcoholism and opiate addiction, The beta-endorphin pathway in immune regulation
both heavily supported by federal grants. Now, however, there
have been widespread anecdotal reports of successful treatments To grasp potential LDN paths of action, let us consider the fol-
of various cancers, AIDS [8,9], and Multiple Sclerosis [10], and lowing well articulated opioid antagonists pathways for treating
autoimmune diseases such as lupus, arthritis, and bromyalgia autoimmune disease. The potential action of BE in ameliorating
[11]. If chronic LDN could potentiate and regulate the immune sys- autoimmune disease is sketched below.

Rheumatoid inflammation
Beta-Endorphin RF, SED
Naltrexone Crohns disease
MOR, DOR, KOR TH1 TH2
Myelin inflamed

tem in health promoting ways, it may serve to combat AIDS and Naltrexone modulation of immune regulation and treatment of
some cancers and reduce autoimmunological self-destructive ac- autoimmune disease
tions in various disorders.
The rst successful clinical trials were for Crohns disease in Recent studies have shown BE concentration in circulating
2006 [12] and in late 2007 for Multiple Sclerosis [13]. Trials for blood cells to be dramatically low in rheumatic diseases such as
MS and bromyalgia are underway at medical centers in California arthritis, lupus and gout, with signicant inverse correlations be-
and Cleveland, along with an AIDS trial in Mali. tween BE and both rheumatoid factor and erythrocyte sedimenta-
The normal 50 mg naltrexone dose that blocks opioid receptors tion rate and hence the likelihood of inammation [25]. Levels of
24 h per day is commonly prescribed for alcoholics and heroin ad- BE were as low as 1/8 to 1/4 normal in other autoimmune-related
dicts who wish to resist a relapse. This typically amounts to more diseases, including bromyalgia [26], Crohns disease [27], multi-
than 0.5 mg/kg for most adults. In contrast, the most common LDN ple sclerosis [28], chronic migraine [29] and cluster headaches
use is typically 4.5 mg, which generally means most adults get no [30] and endometriosis [31].
more than 0.08 mg/kg per day, which can block mu opioid receptors A preliminary pilot trial of 4.5 mg naltrexone for Crohns Dis-
for only a few hours, perhaps up to 6 h. If taken at bedtime, this ease, completed at Penn State in 2005, yielded promising results.
would mean that an individual might wake up the next morning In 3 months 89% of the patients achieved signicant reduction in
with a homeostatic rebound-induced over-activity of their own symptoms and improvement in quality of life measures, and 67%
endogenous opioid systems. It is this type of bodily change in opioid went into remission. These results were maintained after 4 weeks
dynamics that we focus on here. Until recently signicant increases of no naltrexone [12].
in mu, delta and perhaps epsilon opiate receptor expression have Recent work on collagen-induced arthritis in rats have found BE
only been documented in animal models for chronic opiate blockade treatment to reduce clinical arthritis manifestations by shifting the
with high dose naltrexone [14,15], which leads to elevated morphine balance of TH-1 and TH-2 cells toward TH-2. This comes from
analgesia [16]. However, a recent animal study conrmed that a low- down-regulating the NF-kappa2 pathway, including tumor necro-
dose (0.1 mg/kg of naloxone) could elevate mu opioid receptor den- sis factor alpha, Interleukin-1beta, Interleukin-6, inducible nitric
sity as well [17]. More signicantly, the recently completed Italian oxide synthase, and mRNA for matrix metalloproteinase-2 and
Multiple Sclerosis trial utilizing 5 mg of naltrexone daily found sig- mmp-9 [32]. Dr. Sacerdote and her colleagues in Milan have
nicant increases in circulating beta-endorphin, along with wide- reached the same conclusion that BE increases ameliorate autoim-
spread reports of symptom relief [13]. mune diseases by suppressing TH-1 and augmenting TH-2 cells
[33].
Chronic naltrexone affects both immune and endorphin
systems Low-dose naltrexone may work through methione-enkephalin
as well
While high dose naltrexone can counteract the reduction of im-
mune system activity caused by opiate analgesics [18,19], when gi- The scientic case for LDNs positive effect on immune param-
ven alone, it can facilitate immune system parameters [20,21]. eters is strengthened by studies that have evaluated infused ME
Zagon and McLaughlin [22] clearly delineated differences between in the treatment of cancers. Plotnikoff et al. [34] report that ME
high and low-dose naltrexone while studying mice with trans- stimulates expression of interleukin-2 receptors and blood levels
planted neuroblastoma tumors. The full dose of naltrexone of interleukin-2, along with increases in white blood cells, natural
[10 mg/kg] producing constant blockade of opiate receptors had killer cell activity, gamma-interferon, active T-cells and other ele-
 N. Brown, J. Panksepp / Medical Hypotheses 72 (2009) 333337 335

ments of the immune system. These results were obtained both Thus, LDN, through its enhancement of immune functions [21]
in vitro and in vivo and with normal volunteers as well as people and specically of natural killer cell activity [49] may promote pre-
suffering from a variety of cancers, including Kaposis sarcoma, vention and treatment of viral diseases and bacterial infections.
lung cancer, melanoma, and hypernephroma. These benets might Evidence from animal models suggests that naltrexones path to
be sketched as follows: supporting immune defenses against viral disease begins by

T-cells AIDS, opportunistic diseases

Met-Enkephalin
Naltrexone NK cells Cancer (colon, prostate, lung,
MOR, DOR, KOR
IL-2, TH-2 pancreatic, squamus-cell)

Naltrexones potential for cancer prevention and treatment increasing both beta-endorphin and met-enkephalin, which may
then bind to sensitized mu opioid receptors to increase natural kill-
Potential benet for cancer treatment has arisen largely from er cell activity for quelling viral infection [50]. Since we only have
the work of Penn State investigators Ian Zagon and his colleagues. clinical evidence from uncontrolled observations in the many dis-
Zagon published initial evidence that chronic LDN (0.1 mg/kg in orders mentioned above, well-controlled double-blind clinical
mice) reduced neuroblastoma tumor incidence by 66%, retarded studies are warranted, despite the difculty in nancing studies
tumor development by 98% and lengthened survival by 36% over off-patent medicines.
controls [35]. The apparently intermittent receptor blockade via
LDN signicantly reduced cancer cell development, in contrast to Conclusion
a constant blockade that accelerated tumor growth [36]. Further-
more, the specic mu receptor blocker beta-Funaltrexamine did Low-dose naltrexones potential for enhancing the quality of life
not signicantly retard tumor development, yet the nonspecic through both reward and energy functions arises from the well-
blocker naltrexone did [37]. demonstrated links between mu opioid receptors and central
Both ME and BE may enhance NK cell activity via the mu dopamine neurons in the mesencephalon [51,52]. Solid evidence
receptor [38] and also by binding to receptors on cancer cells for safety and tolerability of chronic LDN is present in the recent
themselves [23]. Animal studies have shown full dose naltrex- Crohns trial [12] and MS trial [13], as well as decades of FDA ap-
one to reduce tumor activity in mammary cancer [39]. In hu- proved daily 50 mg doses for alcoholism. There is no published evi-
mans, high dose naltrexone has been involved (along with IL- dence to support the old black box warning about potential liver
2) in arresting 6 of 10 metastasized renal cancers [40] and damage from chronic high doses [53]. This only happened at extre-
[along with IL-2 and melatonin] in retarding metastasized can- mely high doses that were used in some of the early toxicology
cer growth in terminal cases of kidney, stomach, pancreatic, trials.
colorectal, and thymus cancer [41]. In sum, we conclude that low-dose naltrexone presents a safe
While studying the efcacy of ME for neuroblastoma and and promising approach to prevention and/or treatment of many
squamous cell, colon, and pancreatic cancer, Zagon and col- autoimmune diseases and cancer variants, as well as potentially
leagues used full dose naltrexone to block MEs retardation of tu- various viral (e.g., AIDS) and neurological diseases (Multiple Scle-
mor growth [42]. This contrasts with their prior studies which rosis) that are exacerbated by compromised immunity. LDNs po-
have shown low-dose treatments to be effective on colon cancer tential for modulating both opioid and immune systems yields a
[43], and neuroblastoma [35]. Though acute high doses of nal- very wide eld for clinical experimentation as well as novel re-
trexone effectively block opioid retardation of the growth of search directions for strengthening the scientic evidence for
some cancer cells, chronic low-doses foster that retardation. Fur- linkages between opioid and immune systems in the regulation
thermore, LDN has arrested B-cell lymphoma in one published of various disease processes. There are solid reasons to believe
case [44] and, along with alpha-Lipoic Acid, metastasized pan- LDN can also promote positive emotional states through the
creatic cancer for 3 years in another [45]. Anecdotal reports of endogenous opioid amplication of positive affect and energy
LDN causing remission include colorectal, mammary, ovarian, [52]. From a psychiatric perspective, the facilitation of endoge-
small-cell and non-small-cell lung, and prostate cancers, as well nous opioids should alleviate depression since, to some degree,
as Hodgkins and non-Hodgkins lymphoma, multiple myeloma, that multifaceted problem reects reduced ability to experience
and neuroblastoma [46]. Intravenous ME may turn out to be a pleasure. Evidence also exists for resilience against cardiovascu-
better treatment for some cancers, or more effective when com- lar stress [54,55] and for specic enhancement of the reward
bined with LDN. But the paradoxical effect of low-dose generic system for exercise [56], palatable tastes [57,58], laughter
naltrexone of increasing both circulating BE and ME and the den- [59,60], sex [61], social bonding [4,62], and even the placebo ef-
sity of their mu and delta receptors bears further study because fect of positive expectations [63].
of its impressive cost-effectiveness. In a time of imperative health care reform, the prospect of so
LDN also holds promise for prostate cancer prevention and early many novel contributions to both disease suppression and qual-
treatment, since all of the anecdotal prostate cancer cases in one ity of life by a generic pharmaceutical presents signicant chal-
report that had not undergone hormone treatments went into lenges and opportunities for government, the medical research
remission [46]. Independently, medical interest has begun to focus community, the pharmaceutical industry and health care
on the immune system for a rst defense against this cancer [47]. management.
Furthermore, Dr. Bihari, whose experiences with LDN have been
extensively summarized [46], reported success retarding or arrest- Acknowledgement
ing AIDS in 1988 [9]. Low concentrations of naltrexone in vitro
have also been shown to potentiate the effectiveness of the antiret- This work is supported by generous gifts from Skips Pharmacy
roviral drugs zidovudine (AZT) and indinavir, lending support to of Boca Raton, FL, The Compounder Pharmacy of Aurora, IL, and
Biharis claims [48]. Irmat Pharmacy of New York, NY.
336 N. Brown, J. Panksepp / Medical Hypotheses 72 (2009) 333337

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