Endorphin Deficiency Syndrome: Chronic pain, addiction and autoimmune conditions

Tormented by depression and nothing seems to help? You're not alone. Zoloft, Paxil, Lexapro, Prozac, Wellbutrin, Cymbalta... You've tried two or three of these. They were supposed to help you feel better- but you just didn't! Sound familiar? Did you happen to notice that opioids like oxycodone and hydrocodone are the only substances capable of making you feel normal? You already know that every human brain contains "endorphins"... but did you know that endorphins are almost the exact same thing as morphine, only fifty times more potent? Some people have a deficiency of this endogenous (natural) morphine, resulting in miserable, intolerable depression unless this deficiency is somehow compensated for.

Endorphin Deficiency Syndrome: Do I have it?
If you’re suffering from treatment resistant depression, the following criteria should help you to determine whether an endogenous opioid deficiency is at the root of your problem:

W: Weak immune system- You don't know of anyone who catches nasty colds as often as you do. Perhaps you were even diagnosed with an autoimmune condition or two. (Amazingly enough, whenever you’re on opiates/opioids, your immune system seems to drastically strengthen)
R: No Runner's High. You've never in your life experienced the so-called 'runner's high'.
A: Allergies. Pollen allergy/Hay fever- This often comes with a chronic runny nose and possibly other allergies as well.
T: Tears. You're easy to bring to tears, or at least you were that way through your teenage years.
H: Hypersensitivity/sensory defensiveness- This could be hypersensitivity to touch, sound, light, temperature, etc. You're easily made uncomfortable by slight disturbances in your surroundings.

Did you answer ‘Yes’ to at least four of the above five criteria? Did reading this stunningly accurate description of yourself just make your heart just skip a beat? I’ve been told that happens quite often to readers of this site. The above five traits are not an authoritative diagnostic criteria for Endorphin Deficiency Syndrome, since no such criteria exist. While medical orthodoxy freely admits the fact that endorphins (naturally occurring opiate-like peptides in the human body) are responsible for both emotional well being and stimulating the body to produce disease-fighting antibodies, they’ve yet to draw the obvious conclusion that endorphin deficient individuals are therefore highly vulnerable to depression and sickness.

Here are three more common traits of EDS. These three traits aren’t quite as common as the first five, yet appear frequently enough to warrant mentioning:
* You're introverted, and annoyed by crowds. This may have something to do with the hypersensitivity trait, mentioned above.
* Your motor coordination skills developed slowly as a child. Your training wheels stayed on your bike for longer than normal. You were also lousy at sports.
* You have a 'Cluster B' personality disorder. These are Narcissistic personality disorder, Histrionic personality disorder, Borderline personality disorder, and Antisocial personality disorder.

Click to expand...

Are you too sensitive to life’s pain?
If your endorphin levels are low, you’re one of many people who were born low in the joy department or have run low after expending too many of your endorphins coping with too much of life’s pain. Some people have learned to hide this well by having a protective veneer of toughness or joviality. Others avoid emotional intimacy or confrontation and comfort themselves with chocolate or other foods, alcohol, painkilling drugs or other compulsive behaviors (shopping, sex, etc.) is also released which allows us to conquer and withstand adversity.

What happens when you don’t have enough endorphins?
For most people, thinking about something they love and tuning in to how they feel can stimulate enjoyment, contentment, and euphoria. A massage, certain pleasant fragrances, or soaking up some sunshine, can also do it. However, if you don’t have enough endorphins to boost in the first place, you will find it hard to locate enough natural enjoyment or comfort in your life and even major treats will give you only brief or dim pleasure.

How did You become Endorphin Deficient?
Genetics: Some people are born with low levels of endorphins which makes them more vulnerable to emotional injury. Did people call you a “crybaby” or say your were “just too darned sensitive” even as a child or teenager? Then you may have been deficient from the get go.
Too Much Stress: Every time you get upset, injured, sick, scared, or even excited, you wear down your endorphin levels. Whether your in labor and pushing past the strain or pushing to finish your workout or long distance run, you’re subtracting from your painkilling resources.
Too Much Pain: Emotional and physical pain, as well as abuse and neglect can zap your endorphin supply. Even keeping up the denial or avoidance of the painful memories expends a constant amount of endorphins until people resort to sugar, alcohol or drugs to help them deal with the trauma.
Gender: Adult men have higher endorphin levels than woman unless the woman is doing regular vigorous exercise. Endorphin levels should peak for women during ovulation but if you have PMS, your levels likely don’t rise and are probably low throughout your cycle. Estrogen rules the release of endorphins (and serotonin) so levels are usually low for women in menopause.
Not enough Exercise: If you have a stagnant lifestyle, your levels are likely lower. Moderate exercise can help stimulate endorphin production. {Unless it's genetic or things are already depleted! Then exercise leaves you in massive amounts of pain for days. Catch 22}

Click to expand...

[..]
I recently was asked to write an article about low dose naltrexone for a USA magazine called Natural Solutions. The editor planned it to be a response to a person with an autoimmune disease, who is wondering about possibly using LDN. Here is that piece, with a few minor modifications. It contains the sort of information that might be useful for any new potential user of LDN:
“Low-dose naltrexone (LDN) is just an off-label use of the FDA-approved drug naltrexone. Any physician can write the prescription for you. Rather than the original 50mg daily of naltrexone for those addicted to narcotics or alcohol, LDN is used at doses no higher than 4.5mg (nor lower than 1.5mg) and is generally taken at bedtime.
The major mechanism of action of LDN involves blocking the body’s opioid/narcotic receptors for just a very few hours (rather than the all-day blockade caused by the 50mg dosage). Those are the same receptors used by the body’s endorphins. The body responds to this by greatly increasing its endorphin production, and those higher levels last all day -- far after the blockade by LDN has ended. Endorphins turn out to be the major normalizer/upregulator of one’s immune system.
This is of critical importance to anyone who has an autoimmune disease. Published studies have demonstrated that all autoimmune disorders thus far tested are marked by weak, dysfunctional immune systems (in contrast to the common belief that they are probably too strong). This makes good sense, because the first commandment of the immune system is “Thou shalt not attack self!” Only a dysfunctional immune system attacks self. When the LDN normalizes one’s immune system, it halts the further progression of any autoimmune disease. When one takes LDN, one is regaining a normalized immune system – and it is the immune system that has such a positive effect on such a wide variety of conditions.
We have already noted positive benefits from LDN in those with HIV, any autoimmune disorder, many cancers, Parkinson’s disease, motor neuron diseases (such as ALS), COPD, and in childhood autism.
LDN has been especially popular for a great number of people who suffer from MS because it is beneficial in a high percentage of patients and it is the antithesis of the spectrum of “approved” anti-MS medications, which are questionably effective, often painful and problematic to use, are sometimes dangerous, and are always expensive. LDN, in contrast, is almost always effective, easy to use, non-toxic, easily affordable and it has virtually no significant side effects.
Because naltrexone has been a generic drug for many years now, no large pharmaceutical company will invest any money in the large research costs needed to gain FDA approval of these special new off-label uses of the medication. No one makes any significant money from sales of LDN! Nonetheless, there have been many small clinical studies of LDN performed at outstanding medical centers, all showing it to be safe and effective. Check my website for detailed information on the research [www.ldninfo.org/ldn_trials.htm].
In MS alone, there have been two very promising studies. One, out of a group of hospitals in Milan, Italy, showed that of some 40 patients with Primary Progressive MS (for which there is NO recognized treatment) who were treated with LDN over a period of 6 months, only one patient showed any sign of progression! The other study, performed by one of the best neurology departments in the USA, at UCSF, was very brief, but showed that within 8 weeks of LDN treatment there were already statistically positive improvements.
There are only two substantial contraindications to LDN’s use. The first is that the potential user must not be dependent on daily narcotic-containing pain medications. Remember that naltrexone is a pure opioid antagonist, so even one little capsule of LDN taken by such a person might well lead to a prompt and dangerous withdrawal reaction. The other contraindication is based on a supposition: we believe that anyone who has had an organ transplant, and thus must take daily immunosuppressant medications, ought not start using LDN, which reliably strengthens one’s immune system.
Use of LDN is generally compatible with all other treatments or medications, with these few caveats:
Use of any narcotic-containing pain medication during the same few hours (about 5 hours) of LDN’s activity is unwise because LDN will block that drug’s effect.
Use of immunosuppressant medications for any length of time will act to counter LDN’s benefits, most of which are based on its ability to normalize the immune system.
Because LDN is a prescription drug that is made by compounding pharmacies, and because there is a rather high rate of error in compounding the occasional drug, I strongly recommend using only compounders that are recognized for their expertise in compounding effective supplies of LDN. On my website’s home page [www.ldninfo.org], there is a list of pharmacies in the USA, Canada, and the UK, highly recommended for LDN, which have proven themselves over many years. They all ship it to you promptly and are inexpensive

Click to expand...

Choices leaflet: Low Dose Naltrexone (LDN)
Naltrexone is drug developed initially to treat addiction to opiate-based drugs, such as heroin or morphine. It belongs to a class of medications called opiate antagonists.

Naltrexone delivered in lower doses – Low Dose Naltrexone (LDN) – has been used in the USA to treat the symptoms of autoimmune conditions, such as multiple sclerosis, since 1985, and more recently has been used in Europe and the UK.

The low dose method of taking naltrexone was devised and developed by the late Dr Bernard Bihari, from New York. Dr Bihari was qualified in Internal Medicine, Psychiatry and Neurology.

LDN is advocated as a treatment for the symptoms of many conditions including Crohn’s disease, fibromyalgia, Chronic Fatigue Syndrome and coeliac disease –conditions with an autoimmune origin, or potential autoimmune origin.

How naltrexone works

As an opiate antagonist, naltrexone is thought to inhibit endorphins – the body’s natural painkiller. It is believed that by inhibiting endorphins, the body reacts by producing more. This increase in endorphins reduces pain and increases a sense of wellbeing.

Dr Bihari’s initial research showed that increased levels of endorphins stimulated the immune system and promoted an increase in a type of white blood cells – T-lymphocytes. Although not proven, it is believed people with autoimmune conditions have low levels of T-cells, so an increase in T-cells balances the immune system.

Many people with MS report significant improvements in their symptoms – particularly fatigue, pain, mood and spasm – after they start taking LDN.

LDN must be prescribed by a doctor and is safe to take under medical supervision for the treatment of MS symptoms.

Research into LDN

There have been many studies into the safety and effectiveness of LDN as a treatment for MS, and other conditions.

A pilot trial of 40 people with primary progressive MS conducted by Dr M Gironi found naltrexone to be well-tolerated by the patients, who reported an improvement of their symptoms – especially in relation to spasticity.

The study was published in September 2008 in the Multiple Sclerosis Journal.

In 2011, Dr Rahn looked at experimental autoimmune encephalomyelitis (EAE) – an animal model for MS in mice – and the effect of LDN. Published in Brain Research, the study proved that after 60 days, the progression of EAE was halted in mice treated with LDN, and neurological deficits reversed.

Another 17-week randomised trial, where some people were given LDN, and some a placebo, looked into the effects of LDN in relation to quality of life. Ninety-six people were enrolled in the trial – some with relapsing-remitting MS and some with secondary progressive MS. This trial, conducted in 2010 by Dr N Sharafaddinzadeh published in the Multiple Sclerosis Journal, demonstrated the safety of LDN.

However, the results on LDN’s effect on quality of life (as measured by physical and mental health) was not clearly proven, with no statistically significant differences shown between the LDN-dosed group and the placebo group.

Research into LDN is also taking place for other conditions. In 2007, a 12-week trial into LDN’s effectiveness in the treatment of Crohn’s disease, conducted by Prof. J Smith and published in the American Journal of Gastroenterology, reported that 86 per cent of the 17 people enrolled in the trial showed a reduction in the activity of their condition as demonstrated by endoscopic examination.

In 2009, a study conducted by Dr Younger from Stamford University, and published in Pain Medicine, looked at LDN as a treatment for the pain associated with fibromyalgia. The study showed a thirty percent reduction in pain symptoms in people treated with LDN, compared to the placebo.

Click to expand...

What is Naltrexone?

Naltrexone (generic name) is a pharmacologically active opioid antagonist, conventionally used to treat drug- and alcohol addiction – normally at doses of 50mg to 300mg. As such, it’s been an FDA approved drug for over two decades.

However, researchers have found that at very low dosages (3 to 4.5 mg), naltrexone has immunomodulating properties that may be able to successfully treat cancer malignancies and a wide range of autoimmune diseases like rheumatoid arthritis, multiple sclerosis (MS), Parkinson’s, fibromyalgia, and Crohn’s disease, just to name a few.

At least one physician, Dr. Jacquelyn McCandless, has even found LDN to have a positive effect on children with autism.

Recently I had the pleasure of interviewing Dr. Burton M. Berkson, MD, and he attested to achieving phenomenal results with low-dose naltrexone (LDN) in both cancer patients and those with autoimmune diseases.

Unfortunately, very few physicians are aware of LDN, and none of the pharmaceutical giants back it, meaning there are no friendly sales reps visiting your doctor talking about the potential benefits of this drug in very low doses.

And why would they?

At an average price of $15 to $40 for a month’s supply, the income potential from LDN doesn’t even come off in the rounding. It’s completely insignificant.

How Does Low-Dose Naltrexone (LDN) Work for Autoimmune Diseases and Cancer?

A growing body of research over the past 20 years indicates that your body’s secretion of endorphins (your internal, natural opioids) play an important, if not central, role in the workings of your immune system.

A review article entitled Opioid Therapy for Chronic Pain, published in a 2003 issue of the New England Journal of Medicine, states:

"Opioid-Induced Immune Modulation: .... Preclinical evidence indicates overwhelmingly that opioids alter the development, differentiation, and function of immune cells, and that both innate and adaptive systems are affected.

Bone marrow progenitor cells, macrophages, natural killer cells, immature thymocytes and T cells, and B cells are all involved.

The relatively recent identification of opioid-related receptors on immune cells makes it even more likely that opioids have direct effects on the immune system."

As explained on the informative website www.lowdosenaltrexone.org, when you take LDN at bedtime -- which blocks your opioid receptors for a few hours in the middle of the night -- it is believed to up-regulate vital elements of your immune system by increasing your body’s production of metenkephalin and endorphins (your natural opioids), hence improving immune function.

In addition to increased endorphin production, Dr. Bernard Bihari (who first discovered LDN as a therapeutic agent for AIDS, in 1985), believes LDNs anti-cancer mechanism is likely due to an increase in:

the number and density of opiate receptors on the tumor cell membranes, making them more responsive to the growth-inhibiting effects of the already present levels of endorphins, which in turn induces apoptosis (cell death) in the cancer cells
the absolute numbers of circulating cytotoxic T cells and natural killer cells, as well as killer cell activity

Click to expand...

Dr. Bihari has reportedly treated more than 450 cancer patients with LDN with promising results, including cancers of the bladder, breast, liver, lung, lymph nodes, colon, and rectum.

According to Dr. Bihari, nearly a quarter of his patients had at least a 75 percent reduction in tumor size, and nearly 60 percent of his patients demonstrated disease stability.

Recent Clinical Studies on Safety and Benefits of LDN for Autoimmune Diseases

Although the video above makes it seem as though there are virtually no scientific inquiries into the safety and benefits of LDN, that’s not an entirely accurate assessment. Several studies have been conducted, and more are in the pipeline.

For a more complete list of past and current research, please see the lowdosenaltrexone.org website, but here are a couple of highlights.

LDN for Multiple Sclerosis – Dr. Maira Gironi, an Italian neurological researcher, treated 40 patients affected with Primary Progressive MS (PPMS) with LDN for six months, concluding that LDN was not only safe and well-tolerated, but halted the progression of the disease in all but one patient. The results from this pilot study were published in the journal Multiple Sclerosis in September of last year.

LDN for Crohn’s Disease – The first clinical study of LDN published by a U.S. medical journal was Dr. Jill Smith’s article, Low-Dose Naltrexone Therapy Improves Active Crohn’s Disease, published in the American Journal of Gastroenterology in 2007.

An impressive two-thirds of the patients in her pilot study went into remission, and 89 percent responded to LDN treatment to some degree. She concluded that “LDN therapy appears effective and safe in subjects with active Crohn’s disease.”

Other studies currently underway in various parts of the world, include:

A Phase II placebo-controlled clinical trial on the efficacy of LDN for children and adolescents with Crohn’s disease at Penn State.
A clinical trial of LDN in HIV-infected citizens of Mali—the first scientific study of LDN for HIV/AIDS in Africa—implemented in October 2007.
A study of LDN in the treatment of MS at the University of California, San Francisco, implemented in early 2007.
A clinical trial of LDN in the treatment of fibromyalgia at Stanford Medical Center implemented in October 2007.
A study by the MindBrain Consortium in Akron, Ohio of, especially, the affective changes in MS treated with LDN, begun late 2007.
An animal research study at Penn State of naltrexone in a model of a disease that mimics MS.
Animal research on neurodegeneration at NIEHS, suggesting a protective role for naltrexone.

Side Effects and Cautionary Warnings

So far, the only adverse events reported in clinical studies have been temporary insomnia and vivid dreaming in some patients. However, there are a few cautionary warnings with this drug, as with most others.

According to lowdosenaltrexone.org, if you fall in any of the categories below, you need to take special precautions:

If you use opioid agonists, i.e. narcotic medications such as Ultram (tramadol), morphine, Percocet, Duragesic patch or codeine-containing medication, should not take LDN until such medicine is completely out of your system.
Patients taking thyroid hormone replacement for a diagnosis of Hashimoto’s thyroiditis with hypothyroidism need to begin LDN at the very lowest range (1.5mg for an adult), as LDN may lead to a prompt decrease in the autoimmune disorder, which then may require a rapid reduction in the dose of thyroid hormone replacement in order to avoid symptoms of hyperthyroidism.
People who have received organ transplants and who therefore are taking immunosuppressive medication on a permanent basis are cautioned against the use of LDN because it may act to counter the effect of those medications.
For more information about low-dose naltrexone, LDNers.org is another good resource.

And, if you or someone you love suffers from any of the autoimmune diseases listed in the article links below, please review them for my personal recommendations on how to resolve the underlying problems of your ailment.

Click to expand...

kalibex said:

But in the end, how do we know if any 'mood issues' we may have are a systemic issue / basic deficiency that no one should be expected to just 'push past'... or us just mechanically trying to avoid conscious suffering?

Click to expand...

luke wilson said:

Don't pharmaceutical grade anti depressants turn you into a zombie?

Click to expand...

Naltrexone (INN, BAN, USAN) is an opioid antagonist used primarily in the management of alcohol dependence and opioid dependence.
[..]

Adverse effects[edit]
The most common side effects reported with naltrexone are non-specific gastrointestinal complaints such as diarrhea and abdominal cramping.

Naltrexone has been reported to cause liver damage (when given at doses higher than recommended). It carries an FDA boxed warning for this rare side effect. Due to these reports, some physicians may check liver function tests prior to starting naltrexone, and periodically thereafter. Concerns for liver toxicity initially arose from a study of non-addicted obese patients receiving 300 mg of naltrexone.[35] Subsequent studies have suggested limited toxicity in other patient populations.

Naltrexone should not be started prior to several (typically 7-10) days of abstinence from opioids. This is due to the risk of acute opioid withdrawal if naltrexone is taken, as naltrexone will displace most opioids from their receptors. The time of abstinence may be shorter than 7 days, depending on the half-life of the specific opioid taken. Some physicians use a naloxone challenge to determine whether an individual has any opioids remaining. The challenge involves giving a test dose of naloxone and monitoring for opioid withdrawal. If withdrawal occurs, naltrexone should not be started.[9]

It is important that one not attempt to use opioids while using naltrexone. Although naltrexone blocks the opioid receptor, it is possible to override this blockade with very high doses of opioids. However this is quite dangerous and may lead to opioid overdose, respiratory depression, and death. Similarly one will not show normal response to opioid pain medications when taking naltrexone. In a supervised medical setting pain relief is possible but may require higher than usual doses, and the individual should be closely monitored for respiratory depression. All individuals taking naltrexone are encouraged to keep a card or a note in their wallet in case of an injury or another medical emergency. This is to let medical personnel know that special procedures are required if opiate-based painkillers are to be used.

There has been some controversy regarding the use of opioid-receptor antagonists, such as naltrexone, in the long-term management of opioid dependence due to the effect of these agents in sensitizing the opioid receptors. That is, after therapy, the opioid receptors continue to have increased sensitivity for a period during which the patient is at increased risk of opioid overdose.[citation needed] This effect reinforces the necessity of monitoring of therapy and provision of patient support measures by medical practitioners.

Contraindications[edit]
Naltrexone (50 mg per day) should not be used by persons with acute hepatitis or liver failure, or those with recent opioid use (typically 7–10 days).

Click to expand...

You tend to socially isolate yourself, and turn all negative emotions inwards.
You feel others don't "understand your pain/suffering".
Anger/hate gets directed inwards, and you form a "I'm un-savable, un-worthy monster who deserves to suffer" identity. This is especially true when you notice how 'different' you are to everyone else.

Click to expand...

Gaby said:

Julia Ross said:

Are you too sensitive to life's pain?

3 Do you consider yourself or do thers consider you to be very sensitive? Does emotional pain or perhaps physical pain really get to you?
2 Do you tear up or cry easily-for instance, even during TV commercials?
2 Do you tend to avoid dealing with painful issues?
3 Do you find it hard to get over losses or get through grieving?
2 Have you been through a great deal of physical or emotional pain?
3 Do you crave pleasure, comfort, reward, enjoyment, or numbing from treats like chocolate, bread, wine, romance, novels, marijuana, tobacco, or lattes?

If you score more than 6...

Endorphins levels are low.

Estrogen rules the release of endorphin, as well as serotonin, in the brain. If estrogen or DHEA is low, taking estrogen or DHEA supplements can raise endorphin levels substantially, among other benefits.

Supplement: a combination of the D and L forms of the amino acid phenylalanine. Synergistic in the pain prevention department. The L one, helps amplify pleasure indirectly by increasing catecholamines and it forms PEA (phenylethylamine) found in chocolate which is energizing and related to euphoria.

Low endorphin is associated with pain, low PEA with depression, and LPA (the L one) increase both. The D one, DPA is a potent endorphin booster. It neutralizes enzymes (endorphinase and enkephalinase) in the brain that destroy endorphins.

DLPA is an exc anti-depressant.

If DLPA is wiring or sleepless inducing, then DPA. If you have sleep problems at night but need energy in the morning, 1 or 2 DLPA capsules first thing in the morning and in the midmorning. If they need endorphin boost in the afternoon, for example if they are 3pm chocolate nibblers, then DPA at that time. Rarely DPA can convert into LPA and PEA, so can also be energizing in the afternoon, usually it is well tolerated though.

A supplement blend of the essential amino acids: histidine, isoleucine, leucine, lysine, methionine, phenylalanine, threonine, tryptophan, valine (make sure it has all of them, if it doesn't have tryptophan, you have to take 5HTP). In addition to DLPA and protein rich meals and snacks, can help your endorphin building off to a strong start.

5HTP can also increase endorphins, it takes a month though.

More than half of our low-endorphin clients also show clear signs of being low in serotonin and respond beautifully to the combination of DLPA in the morning and midmorning and 5HTP or tryptophan in the afternoon and evening.

B vitamins help restore endorphin function regenerate damaged nerves. Mg neutralizes most pain-provoking chemicals. Migraine and PMS respond to mg

Vit D and calcium can stop the pain from osteoporosis, PMS, and bone cancer, since the pain of these condiions is caused by a calcium and vitamin D deficiency.

Vit C also affects endorphin levels.

Omega 3s block inflammatory pain directly. Promote production and protection of all mood-enhancing brain chemicals, including endorphin. So do vitamins D, E, B complex and zinc.

DPA 500mg if you need to avoid more stimulating DLPA 1 three times a day with meals.

Freeform amino acid blend 700-800mg 1-2 with breakfast and then at midday.

Click to expand...

Click to expand...

Neurotransmitter:
Enkephalin (Opioids)

Amino Acid (Building block):
l-phenylalanine, glycine, methionine {If you have a MTHFR mutation methionine may be low/unavailable}

Deficiency:
A deficiency of glycine can result in: A deep sense of inadequacy, incompleteness. Reduced ability to combat physical pain

Toxicity:
Excessive sedation, can be fatal if combined with other sedating agents.

Genetics or Natural Depletion:
Opioid levels passed from parents to offspring. Trauma reduces availability

External/Chemical Source of Depletion:
All drugs effecting opioid system will eventually reduce natural supply if used for prolonged periods. {chronic pain which stimulates the opiod system will do the same}

Present in Foods:
Glycine can be found in seafood, fowl, lima beans, ham

What is Glycine?

Glycine is both a protein amino acid and a neurotransmitter in the central nervous system.

Glycine as a Supplement

Supplemental glycine has anti-spastic activity, as well as antioxidant and anti-inflammatory activities. Supplemental glycine works by inhibiting the messages from the spinal cord that cause abnormal responses such as jerky, exaggerated, spastic, or uncoordinated muscular movements, especially those that are often magnified during intense anxiety or in association with some withdrawal situations.
{I use to have all of those 'jerky, exaggerated, spastic, or uncoordinated muscular movements' responses, especially to excitement/anxiety as a kid. This may be another thing to consider for those with MS}

Glycine readily crosses the blood-brain barrier.

Always remember, before taking glycine or any other nutritional supplement, consult your health care professional first.

Click to expand...

Low-Dose Naltrexone and Met-Enkephalin Improve EAE Mice
Widely touted in multiple sclerosis patient communities, low-dose naltrexone does appear to improve disease scores in about half of mice with an experimentally induced version of MS. Researchers found a similar pattern of results with met-enkephalin.
STEPHANI SUTHERLAND, PH.D.

SAN DIEGO—A growing subculture of MS patients and clinicians has been touting low-dose naltrexone (LDN) as a wonder treatment for multiple sclerosis, despite scanty scientific evidence. But researchers at Pennsylvania State University, Hershey, have taken the drug back to the lab and shown that the opioid-receptor antagonist modifies established disease in a mouse model of relapsing-remitting MS. Met-enkephalin, an endogenous opioid peptide the authors call opioid growth factor (OGF), similarly dampened disease.

Graduate student Leslie Hammer presented the work from Patricia McLaughlin, Ph.D., and Ian Zagon, Ph.D., in two posters at Experimental Biology 2014 on Sunday, April 27.

Jarred Younger, Ph.D., a clinical researcher at Stanford University, studies LDN for chronic pain but was not involved in the studies presented at the meeting. “LDN (in particular) and OGF are the center of groundswell movements in the U.S. and U.K. that are rarely seen with pharmaceutical agents, … [but] the circulating claims of LDN have pulled way ahead of the science,” Younger wrote in an email to MSDF. That said, “Zagon and his team have progressed in a disciplined way to support the hypothesis that OGF (and LDN) could reverse the pathophysiological mechanism of multiple sclerosis. Their work is solid.”

Hammer induced relapsing-remitting experimental autoimmune encephalomyelitis (RR-EAE) by injecting mice with proteolipid protein followed by pertussis toxin. The group had previously shown that OGF could slow disease progression when delivered alongside the pathogenic injections (Hammer et al., 2013), but the new work tested the treatments 10 days later, once motor signs of disease had set in.

For 40 days, Hammer assessed the mice daily for tail tonicity, gait, righting reflex, and limb strength, and assigned a point value to each behavior. Those points were then summed to determine each mouse's daily disease score on a 10-point scale.

About half the mice treated with either OGF or LDN responded to treatment, displaying significantly lower disease scores over the course of 40 days than did control mice that received saline. Disease scores in the nonresponding mice worsened similar to those of controls. The responders also spent fewer days with moderate to severe disease scores, had fewer relapses, and spent more time in remission than did controls or nonresponders. By 40 days, over 70% of the responders to LDN had gone into total remission—with a disease score of 0.5 or lower—lasting an average of 11 days, whereas only one of nine saline-treated mice saw a total remission lasting 4 days.

Hammer then examined sections from the mouse spinal cords stained with Luxol fast blue, a marker of myelin, and neutral red, a nonselective cellular stain. At 14 days, all the mice treated with either OGF or LDN showed significantly less demyelination than controls. After 40 days, mice in the responder group showed very little demyelination compared to controls and nonresponders.

The authors believe that the beneficial effects of both naltrexone and of Met-enkephalin were achieved through the OGF receptor (OGFr), which they identified and sequenced in 1999 (Zagon et al., 1999). Whereas most opioid receptors sit on the cell surface, the OGFr lives on the nuclear membrane, and its activation by OGF stifles cell proliferation by inhibiting specific kinases required for DNA replication during the cell cycle, McLaughlin told MSDF. But although OGFr is found on all replicating cells, McLaughlin said, activating the receptor “is in no way apoptotic, and it doesn’t alter differentiation or migration of cells. So we’re not killing cells, we are slowing their replication.”

Why block opioid receptors?
Younger told MSDF, “The reception I get when talking about LDN, from basic scientists to clinicians, people say, ‘Naltrexone blocks the μ-opioid receptor; why would you want to do that?’ ” In fact, naltrexone blocks all the opioid receptors, from the classic μ-opioid receptor (MOR) that relieves pain to the more obscure OGFr.

It might seem counterintuitive to use an opioid-receptor antagonist to treat pain or immune disease, but the drug paradoxically increases endogenous opioids. “LDN actually blocks opioid receptors for a short time,” McLaughlin told MSDF, “and that causes upregulation of all endogenous opioid peptides and some receptors.”

Naltrexone is approved by the U.S. Food and Drug Administration for treating alcohol and heroin addiction. For addicts, a dose of naltrexone blocks opioid receptors and dampens the euphoric effects of opiate drugs. But the dosages used by some MS patients and in the current experiments are about one-tenth of those used for addiction treatment—high enough to trigger opioid upregulation, but low enough that the receptors are available after a short time.

Opioid receptors may not be the only ones affected by the drug and by endogenous opioids. Growing evidence shows that other receptors may bind naltrexone and endogenous opioids, perhaps with benefits in disease. For example, a study from Linda Watkins and colleagues at the University of Colorado, Boulder, showed that naltrexone inhibited signaling through the toll-like receptor type 4 (TLR4) and reversed chronic pain independent of MOR in a rodent model (Lewis et al., 2012). “Opioid receptors may be but a small part of the story now that we have found other receptors,” Younger said. “I am sure there are effects of Met-enkephalin and LDN that we don’t even know about yet.”

Neurologist Anthony Turel, M.D., treats MS patients at Penn State Hershey Medical Center—over 200 of them with a prescription for LDN, fillable only through a compounding pharmacy. Turel is currently analyzing those patients’ charts in a retrospective study of their response to the drug. For various reasons, some patients chose LDN as their first or only treatment for MS. “I have a few patients that started on naltrexone who, over the years, anecdotally, have done fairly well even without other therapies,” he told MSDF.

Whether OGFr underlies the benefits seen in the current studies remains somewhat unclear, but some studies suggest how OGFr activation might slow MS pathology. McLaughlin and colleagues previously reported that exogenous OGF suppressed proliferation of B cells (Zagon et al., 2011) and T cells (Zagon et al., 2011) in vitro independent of classical opioid receptors. “If that occurs, you would likely see benefit on the actual course of MS,” Turel told MSDF.

Although a couple of clinical trials have attempted to measure those benefits, the results are murky, perhaps because LDN faces some specific hurdles. For example, agencies that fund large trials generally want to see a drug dose-response curve, Turel said, “but that won’t work with naltrexone” because of its peculiar mechanism of block followed by opioid upregulation. “If you block receptors at a higher dose, you just block them for a longer time,” Turel said.

One small clinical trial hinted at benefits for MS, but the small sample size and a significant dropout rate dampened its power (Cree et al., 2010). Another study showed that primary progressive MS patients on LDN showed mild benefits in quality of life, but perhaps even more importantly it showed that the drug elevated subjects’ endogenous endorphins, even weeks after the drug had been discontinued (Gironi et al., 2008). A third study detected no clear benefit of LDN on quality of life in MS patients, but those investigators used a crossover design, in which subjects’ outcomes are compared on and off the drug, sometimes in that order (Sharafaddinzadeh et al., 2010). But according to the findings of lasting elevated endogenous opioids, “you can’t do a crossover study, because you have to wait possibly months before the system readjusts and comes down,” Turel said.

Although clear evidence for benefits of LDN in MS patients—and how it achieves them—is still missing, support is growing for further study of this opioid antagonist. “My gut feeling is that there are people who respond to this and do better,” Turel said. Only time—and large-scale clinical trials coupled with more basic research—will tell.

Key open questions
Could Met-enkephalin be delivered chronically in patients without adversely affecting normal cell replication?
What receptors underlie the benefits of Met-enkephalin and LDN in the mice—the OGFr, classic opioid receptors, TLR4, or others—and what are the downstream molecular consequences?
Met-enkephalin activates OGFr and the δ-opioid receptor. What effects would long-term treatment with Met-enkephalin have in patients?
Is production of endogenous opioids compromised in MS patients?

Click to expand...

Finn said:

I'm considering asking my doctor to prescribe neltrexone for alcohol dependency. I think it may also hope for other issues, such as chronic pain. Is low dose neltrexone more effective than high\er dosage (50mg)?

Click to expand...