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Low Dose Naltrexone: A Review


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Research in the area of naltrexone has shown both promise and controversy for cancer treatment. Ongoing validation regarding the differing mechanisms of action, the dosage, and the timing of the dose is required. In reviewing the mechanism of action for low-dose naltrexone, more were identified than originally anticipated, which range from a vague endogenous immune response to a complex mechanism involving LDN affecting a blockade at the OGF-OGFr axis. This article presents the historical use of naltrexone, the current information about the low-dose options and use recommendations, the receptors involved with some controversial effects on cancer with respect to mechanisms of action, and calls for more evidence in the form of phase 3 clinical trials.
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Page Tag: Feature Low Dose Naltrexone
Head: Low Dose Naltrexone
Deck: Role as adjunct cancer treatment
By Line: Heidi Kussmann, ND, FABNO
Heidi Kussmann, ND, FABNO
Manager, Naturopathic Medicine Department and Staff Naturopathic Physician
Cancer Treatment Centers of America at Atlanta/Southeastern Regional Medical Center
600 Parkway North, Newnan, GA 30265
Research in the area of naltrexone has shown both promise and controversy for cancer
treatment. Ongoing validation regarding the differing mechanisms of action, the dosage, and the
timing of the dose is required. In reviewing the mechanism of action for low-dose naltrexone,
more were identified than originally anticipated, which range from a vague endogenous immune
response to a complex mechanism involving LDN affecting a blockade at the OGF-OGFr axis.
This article presents the historical use of naltrexone, the current information about the low-dose
options and use recommendations, the receptors involved with some controversial effects on
cancer with respect to mechanisms of action, and calls for more evidence in the form of phase 3
clinical trials.
Naltrexone Mechanism of Action in Treatment of Cancer
The task of bringing together single dimension information from laboratory research examining
cellular, vascular, and endocrine events to understand the three dimensional mechanisms of
disease in the human body is daunting. The reliance upon research and scientific principles
weighs heavy in cancer where much is unknown about disease progression, especially in the
form of metastasis or recurrence. Currently information is elucidated about mechanisms of
action, from which arise more questions and theories, which in turn provokes the critically-
thinking reader to utilize the available information to the best of their abilities. An example of
the evolution of a treatment that was first presented as novel and which is now entering the realm
of evidence-based medicine is that of low dose Naltrexone (LDN) for use in autoimmune disease
and cancer. For the purpose of this article, LDN and its effects in cancer will be the primary
There is little clinical or research evidence beyond the level of dramatic reports from Dr.’s
Bihari, Berkson and Rubin (Berkson 2009) to support the use of LDN in treatment of cancer. The
authors present case reports of three people diagnosed with pancreatic cancer, treated
successfully with the use of Alpha Lipoic Acid and LDN, and call for clinical trials for further
investigation of their protocol. In elucidating the mechanism of action for this success they
suggested an endogenous immune response. Suffice to say it is a start, and a proposed
mechanism of action may eventually create further research to prove or disprove. Further, there
is recent evidence in cell studies elucidating more than one anti-cancer mechanism of LDN.
Low-dose Naltrexone (LDN) presents itself with complexity: there are different receptors
involved, and the resulting effects of LDN on cancer have varied widely. This article reviews
the recent data regarding the mechanisms of action and the proposed resulting effects of LDN in
treatment of cancer.
Naltrexone History in Brief
Naltrexone is used to treat opioid substance abuse and acts by blocking opioid receptors in the
brain. It was approved by the US FDA in 1984 in 50 mg dose increments as a competitive
narcotic antagonist, for the purpose of stopping or reducing the effects of a heroin or opium
overdose and/or for the reduction of opioid withdrawal symptoms ( May
4 2010). For the purposes of opioid blockade this 50mg ‘high dose’ Naltrexone is in tablet form
for oral consumption away from meals. Depending upon the type of addiction there are different
prescription regimens ranging from daily to every other day schedules (PubMed Health 2011).
There is very little understood about Naltrexone beyond opioid blockade as the patent expiry led
to it becoming dormant as a prescription item for a number of years. For the treatment of
addiction, ‘high-dose’ Naltrexone exerts opposite effects on the Mu Opioid Protein (MOP)
receptor at the plasma membrane, and can inhibit secretion of opioids in both brain and adrenal
glands via beta endorphins and enkephalins (Figure 1). Naltrexone has been used to treat opioid
overdose, opioid addiction (Gonzalez 2004) and addictions to other substances such as alcohol
(Chick 2000, Davidson 1999). Naltrexone is conventionally dosed up to a maximum of 350 mg
QD. This high-dose use is limited by the adverse effects which are similar to opioid withdrawal
and these effects can even occur in patients without previous exposure to opioids (Hollister
In contrast the Low-dose naltrexone (LDN) dose ranges from 0.1-4.5 mg QD and has not
produced adverse effects. The off-label use of low-dose Naltrexone started with Dr. Bihari and
has been in use since the 1980’s, subsequently described via case report as an anti-cancer
strategy in 2009 by Berkson and Rubin. LDN has been used off-patent for treatment of auto-
immune illnesses and cancer since the late 1980’s. It is compounded into tablets or a powder
which is mixed with water for oral consumption. Comparative absorption data and information
on suppository or injectable doses is limited and unreliable at this time. LDN interacts with
opioid analgesics such as Hydrocodone, Oxycodone, Oxymorphone and other opiate/opioid
narcotics and thus should be avoided in such instances. It is recommended to gradually reduce
the intake and then eliminate the use of any opioid narcotic for 10-12 days before starting LDN.
The compounded powder for oral consumption of LDN has a shorter, temperature-sensitive
shelf-life and a bitter taste when taken on its own, in comparison to the compounded LDN tablet
for oral consumption (Figure 2) (Fawcett 1997).
Receptor Review
Transmembrane receptors in the human body regulate the majority of cellular metabolism and
physiology. The largest group of receptors belongs to a group coupled to G-proteins (G-Protein-
Coupled Receptors, or GPCRs) (Lefkowitz 2007). The super-family of GPCRs regulates
metabolism, including cellular replication, they are the targets for drug therapy in treatment of
cancer and autoimmune disease (Jacoby 2006, Pierce 2002). The genes encoding µ-, δ-, κ-, ζ-
and nociceptin Opioid Proteins (MOP- Figure 1, DOP, KOP, OGFr, NOP respectively) belong in
the super-family of the GPCRs (Brown 2008, Corbett 2006, Wang 2001) are the transmembrane
receptors targeted in the treatment of narcotic abuse (Wang 2001), and are suggested to be the
target in the treatment of autoimmune disease (Zagon 2009) and cancer with LDN (Brown
2008). However, more recent research has indicated that the regulatory effect on cancer cell
growth extends beyond that of the MOP and to an endogenous opioid factor also referred to as
Met5-Enkephalin or Opioid Growth Factor (OGF, Figure 3), and its receptor the ζ-opioid
receptor or Opioid Growth Factor Receptor (OGFr). OGF has a role in growth inhibition and
OGFr determines the properties of cell proliferation (Zagon 2003). Ongoing phase 1 and 2 trials
on squamous cell carcinoma of the head and neck and hepatocellular cancer respectively are
investigating how OGF binds and activates the OGFr to inhibit angiogenesis and tumor cell
growth ( 2010A, 2010B).
Figure 1. The µ-Opioid Receptor
Figure 2. Chemical structure of Naltrexone (PubChem 2010)
Figure 3. Chemical structure of 5’Met-enkaphalin
Naltrexone Past, Present and Future
Naltrexone (Figure 2) was approved by the US FDA in 1984 in 50mg doses (max dose 350mg)
and acts as a narcotic antagonist. It is used to treat and stop heroin or opium overdoses and
withdrawal (Gonzalez 2004), and to treat substance addiction such as alcoholism (Chick 2000,
Davidson 1999). Since the patent expired other uses have thus been investigated. In the 1990’s
Dr. Bihari first used LDN to treat people with AIDS and then later on to treat people with cancer
(Bihari 1995, May 18 2010). There have been reports of successful
treatment of various cancers (Berkson 2009, Dagleish 2005, Hytrek 1996, Zagon 2000), AIDS
(Bihari 1995, Gekker 2001), Multiple Sclerosis (Cree 2010) Autism (Panskepp 1991) and
autoimmune disorders such as Crohn’s Disease (Smith 2007), and fibromyalgia (Brown 2008).
Sustained release naltrexone (32mg) has now completed investigation in Phase 2 trials with
bupropion for the treatment of obesity ( 2010B).
Naltrexone Mechanisms of Action
As an opioid antagonist, high dose (50mg 350mg) naltrexone blocks secretion of opioids in the
brain and adrenal glands via the MOP. At low dose (3-4.5mg) nocturnal dose-timing of
naltrexone is hypothesized to block opioid receptor expression (MOP, DOP, KOP) and increases
circulation of met-enkephalin (Figure 3) and beta-endorphin for up to 6 hours. The MOP is
hypothesized to play a role in the various responses of the immune system to stress, infection and
malignant transformation (Makman 1994). LDN has several proposed theoretical mechanisms of
action depending on whether the treatment is targeted for cancer or autoimmune disease. A
recent cell study investigation revealed controversy. In the anti-cancer role of LDN the
OGF/OGFr axis can be allosterically modulated to created multi-dimensional effects on
signaling pathways for cellular replication. Allosteric modulation is also demonstrated by the
human immune system and readers will recall that the subtypes of Th cells are allosterically
modulated to create immune functionality. According to the investigator Dr. Ian Zagon at Penn
State University (e-mail communication May 12, 2010): “All human cancers are equipped with
the OGF/OGFr axis and depend on it for regulation of cell proliferation. NTX (naltrexone)
works by blocking the OGF-OGFr axis. It causes an up-regulation. If the dose is low enough,
you allow time for OGF to interact with OGFr to cause a depression in cell proliferation. If you
give repeated low doses or a high dose you get up-regulation but no interaction between peptide
and receptor. Since the OGF-OGFr axis is tonically active - it is on all the time and watching
over the pace of cell proliferation by inhibitory pathways, blockade of OGF-OGFr by naltrexone
continuously allows cells to be unregulated in cell division and you have more cells produced.”
For the purpose of illustrating further the complexity of this drug there are several mechanisms
of action proposed in treatment of the following different types of cancer:
In neuroblastoma, the low (3-4.5mg) and high dose (100 mg) naltrexone administered
demonstrated a direct modulating effect on oncogenesis. The low dose naltrexone
elevated opiate receptors and circulating beta endorphin and met-enkephalin through the
4-6 hour receptor blockade (McLaughlin 1987) and resulted in decreased oncogenesis.
A small study of 14 patients with untreatable metastatic solid tumors treated with
melatonin (20mg hs) and naltrexone(100mgQD) to augment Interleukin-2 therapy
demonstrated that lymphocyte production is amplified compared with melatonin and IL-2
therapy alone (Lissoni 2002)
In Nude mice with colon cancer (HT-29) treated with 0.1mg/kg naltrexone demonstrated
that tumorigenicity was inhibited by opioids via a 2.5 increase in plasma met5-enkephalin
in naltrexone-treated mice and an 85% reduction of binding capacity of 3H-Met5-
enkephalin in tumor tissue when compared to the control group (Hytrek 1996).
In pancreatic cancer MIA PaCa-2 clonal cell lines the single-low-dose naltrexone-
induced amplification of the OGFr axis delayed the G1/S inter-phase of the cell cycle via
CDK inhibition of p16 or p21, causing a decrease in CDK4/CDK2 activity and RB
protein phosphorylation, thus halting DNA synthesis and subsequent cell growth (Zagon
It remains to be determined how LDN exerts its effects via either an independent or combined
extracellular or cytoplasmic effect on cancer cell replication. These give rise to the confirmation
that often LDN is not a single therapy provided in isolation of other cancer treatment, and that
there are pharmacokinetic properties to LDN which affect enkephalin production, lymphocyte
production, and cyclin dependent kinases on control of the cell cycle.
The number of cancer survivors alive compared to those seeking a cure is can be described as an
inverse relationship. There is a distinct lack of cancer survivors, in spite of all the enormity of
efforts ongoing to seek a cure. Research in the area of naltrexone has shown both promise and
controversy for cancer treatment and requires ongoing validation regarding the differing
mechanisms of action, the dosage, and the timing of the dose and the type of cancer. In
reviewing the mechanism of action for low-dose naltrexone, more were identified than originally
elucidated by historical data and case reports. An endogenous immune response has been
suggested via case report as one possible theory, as well as an increase in enkephalins,
lymphocytes, and allosteric blockade at the OGF-OGFr axis. It is a daily challenge to understand
the intended and untoward influences of naltrexone upon tumor cell growth because of the
differing receptors involved and to tailor a specific protocol based upon the current evidence for
people with cancer. In looking to the future use of LDN, there is a need for collaborative effort
between the research bench and the patient that may provide more information regarding the
mechanisms of tumor initiation, progression and promotion to help extend the limit of one’s
knowledge, skills and judgment when treating the complex disease of cancer.
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Full-text available
The authors, in a previous article, described the long-term survival of a man with pancreatic cancer and metastases to the liver, treated with intravenous alpha-lipoic acid and oral low-dose naltrexone (ALA/N) without any adverse effects. He is alive and well 78 months after initial presentation. Three additional pancreatic cancer case studies are presented in this article. At the time of this writing, the first patient, GB, is alive and well 39 months after presenting with adenocarcinoma of the pancreas with metastases to the liver. The second patient, JK, who presented to the clinic with the same diagnosis was treated with the ALA/N protocol and after 5 months of therapy, PET scan demonstrated no evidence of disease. The third patient, RC, in addition to his pancreatic cancer with liver and retroperitoneal metastases, has a history of B-cell lymphoma and prostate adenocarcinoma. After 4 months of the ALA/N protocol his PET scan demonstrated no signs of cancer. In this article, the authors discuss the poly activity of ALA: as an agent that reduces oxidative stress, its ability to stabilize NF(k)B, its ability to stimulate pro-oxidant apoptosic activity, and its discriminative ability to discourage the proliferation of malignant cells. In addition, the ability of lowdose naltrexone to modulate an endogenous immune response is discussed. This is the second article published on the ALA/N protocol and the authors believe the protocol warrants clinical trial.
Full-text available
The use of low-dose naltrexone (LDN) for the treatment and prophylaxis of various bodily disorders is discussed. Accumulating evidence suggests that LDN can promote health supporting immune-modulation which may reduce various oncogenic and inflammatory 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 beneficially modulate both the immune system and the brain neurochemistries that regulate positive affect.
Pharmacotherapies for heroin addiction may target opiate withdrawal symptoms, facilitate initiation of abstinence and/or reduce relapse to heroin use either by maintenance on an agonist or antagonist agent. Available agents include opioid agonists, partial opioid agonists, opioid antagonists and alpha(2)-agonists for use during managed withdrawal and long-term maintenance. Experimental approaches combine alpha(2)-agonists with naltrexone to reduce the time of opiate withdrawal and to accelerate the transition to abstinence. Recently, buprenorphine has been introduced in the US for off ice-based maintenance, with the hope of replicating the success of this treatment in Europe and Australia. Naloxone has been added to buprenorphine in order to reduce its potential diversion to intravenous use, whilst facilitating the expansion of treatment. Although comprehensive substance abuse treatment is not limited to pharmacotherapy, this review will focus on the rationale, indications and limitations of the range of existing medications for detoxification and relapse prevention treatments. The two major goals of pharmacotherapy are to relieve the severity of opiate withdrawal symptoms during the managed withdrawal of the opioid and to prevent relapse to heroin use either after abstinence initiation or after being stabilised on a long-acting opiate agonist, such as methadone.
Summarizes results from a series of open and double-blind trials that have yielded positive therapeutic effects with low doses of naltrexone (NTX), including reductions in autistic stereotypes, aggressiveness, and self-injurious behaviors, and the production of heightened prosocial emotional attitudes that are accompanied by increased smiling, eye contact, attention, and attempts to communicate. The positive behavioral change seems to be enhanced by social support, and how such features of therapeutic situations can be maximized to optimize clinical benefits from NTX is discussed. Since "serenic" drugs (e.g., eltoprazine) have strong antiaggressive effects in other preclinical models while leaving prosocial activities intact or elevated, they may be useful agents for the treatment of various autistic symptoms. (PsycINFO Database Record (c) 2012 APA, all rights reserved)
The µ opioid receptor, MOR, displays spontaneous agonist-independent (basal) G protein coupling in vitro. To determine whether basal MOR signaling contributes to narcotic dependence, antagonists were tested for intrinsic effects on basal MOR signaling in vitro and in vivo, before and after morphine pretreatment. Intrinsic effects of MOR ligands were tested by measuring GTPγS binding to cell membranes and cAMP levels in intact cells. β-CNA, C-CAM, BNTX, and nalmefene were identified as inverse agonists (suppressing basal MOR signaling). Naloxone and naltrexone were neutral antagonists (not affecting basal signaling) in untreated cells, whereas inverse agonistic effects became apparent only after morphine pretreatment. In contrast, 6α- and 6β-naltrexol and -naloxol, and 6β-naltrexamine were neutral antagonists regardless of morphine pretreatment. In an acute and chronic mouse model of morphine-induced dependence, 6β-naltrexol caused significantly reduced withdrawal jumping compared to naloxone and naltrexone, at doses effective in blocking morphine antinociception. This supports the hypothesis that naloxone-induced withdrawal symptoms result at least in part from suppression of basal signaling activity of MOR in morphine-dependent animals. Neutral antagonists have promise in treatment of narcotic addiction.
Receptors for hormones, neurotransmitters, drugs, sensory stimuli and many other agents represent the gateway to cellular metabolism and activity. They regulate virtually all physiological processes in mammals. Yet as recently as 40 years ago their very existence was still in question. One class of receptors, those coupled to G proteins (also known as GPCRs or seven transmembrane receptors) comprise by far the largest group (approx. 1000), and are the most important target of clinically used drugs. Here I provide a very personal retrospective of research over the past 35 years which ultimately led to the identification, purification, reconstitution and cloning of the adrenergic receptors; the discovery of their homology with the seven transmembrane spanning visual light receptor rhodopsin and the realization that there was a large gene family of G protein coupled receptors; the elucidation of the molecular mechanisms of receptor desensitization and signalling through G protein-coupled receptor kinases and beta-arrestins; and the appreciation that the structure, signalling, and regulatory mechanisms of the receptors are all highly conserved across the large receptor superfamily.
To evaluate the efficacy of 4.5mg nightly naltrexone on the quality of life of multiple sclerosis (MS) patients. This single-center, double-masked, placebo-controlled, crossover study evaluated the efficacy of 8 weeks of treatment with 4.5mg nightly naltrexone (low-dose naltrexone, LDN) on self-reported quality of life of MS patients. Eighty subjects with clinically definite MS were enrolled, and 60 subjects completed the trial. Ten withdrew before completing the first trial period: 8 for personal reasons, 1 for a non-MS-related adverse event, and 1 for perceived benefit. Database management errors occurred in 4 other subjects, and quality of life surveys were incomplete in 6 subjects for unknown reasons. The high rate of subject dropout and data management errors substantially reduced the trial's statistical power. LDN was well tolerated, and serious adverse events did not occur. LDN was associated with significant improvement on the following mental health quality of life measures: a 3.3-point improvement on the Mental Component Summary score of the Short Form-36 General Health Survey (p = 0.04), a 6-point improvement on the Mental Health Inventory (p < 0.01), a 1.6-point improvement on the Pain Effects Scale (p =.04), and a 2.4-point improvement on the Perceived Deficits Questionnaire (p = 0.05). LDN significantly improved mental health quality of life indices. Further studies with LDN in MS are warranted.
Preclinical investigations utilizing murine experimental auto-immune encephalomyelitis (EAE), as well as clinical observations in patients with multiple sclerosis (MS), may suggest alteration of endogenous opioid systems in MS. In this study we used the opioid antagonist naltrexone (NTX) to invoke a continuous (High Dose NTX, HDN) or intermittent (Low Dose NTX, LDN) opioid receptor blockade in order to elucidate the role of native opioid peptides in EAE. A mouse model of myelin oligodendrocyte glycoprotein (MOG)-induced EAE was employed in conjunction with daily treatment of LDN (0.1 mg/kg, NTX), HDN (10 mg/kg NTX), or vehicle (saline). No differences in neurological status (incidence, severity, disease index), or neuropathological assessment (activated astrocytes, demyelination, neuronal injury), were noted between MOG-induced mice receiving HDN or vehicle. Over 33% of the MOG-treated animals receiving LDN did not exhibit behavioral signs of disease, and the severity and disease index of the LDN-treated mice were markedly reduced from cohorts injected with vehicle. Although all LDN animals demonstrated neuropathological signs of EAE, LDN-treated mice without behavioral signs of disease had markedly lower levels of activated astrocytes and demyelination than LDN- or vehicle-treated animals with disease. These results imply that endogenous opioids, evoked by treatment with LDN and acting in the rebound period from drug exposure, are inhibitory to the onset and progression of EAE, and suggest that clinical studies of LDN are merited in MS and possibly in other autoimmune disorders.