PUTTING NUTRITION FIRST

by Richard A. Kunin, M.D.

March 2007

Two of the saddest looking faces I have ever seen stared out at me from the pages of the New York Times last week (2/15/07).  Michael and Carolyn Riley of Boston wore a look of despair and bewilderment, even beyond the point of asking “why me?”   Can it get any worse – to lose your baby after four years of struggle with her ADD behavioral problems and then be charged with her murder even before you have gotten over the shock and grief of the death?   How cruel it must seem to these two young parents to find themselves in shackles!  And then we read the legal damage control from Tufts-New England Medical Center, where the child was treated, calling her care “appropriate and within responsible professional standards,” referring to three adult drugs not normally used in children, let alone toddlers.  Rebecca, the child, was treated with valproic acid (Depakote), clonidine (Catapres), and quetiapine (Seroquel).  In addition, the parents had given her over-the-counter “cold pills,” containing dextromethorphan and chlorpheniramine. 

Why is this tragedy of interest to members of the National Health Federation?  Because we stand for medical freedom and better medical treatment too, including the use of non-toxic natural treatments.  In this case, the medical team was trying to find a combination of pharmaceuticals that would safely control anxiety and misbehavior of this 4-year-old problem child.  Not an easy thing to do, and toxicity was evident in that she was often observed to be over-sedated.  Her pre-school teacher even complained about it.  The doctors were making adjustments visit-to-visit, but the parents were evidently losing track of her medications.  Not a good sign, but not uncommon either. 

Is it possible that nutrient supplements could have made a difference in such a case? Would the usual complementary doses of B vitamins, magnesium and Vitamin C have made it possible to lower her medications?  An orthomolecular physician would know that all medications detoxified by means of liver and kidney require enzymes (p450 oxidases) that utilize Vitamin C.  That is why Vitamin C is well known as an aid in detoxification.

Carnitine Essential  

What is not as well known is that children also need supplements of the near-vitamin, carnitine.  Every cell in the human body requires carnitine, it is required for transporting fatty acids across cell membranes so as to feed the cell its energy supply.  Cells starve without carnitine and children are frequently unable to synthesize carnitine adequately – especially in the case of iron deficiency, which is more common in children than adults.  Also, many medications bind to carnitine and interfere with its ability to transport fatty acids.  In particular, aspirin and acetaminophen precipitate Reye’s Syndrome (i.e., liver failure, delirium, and fever), leading to death, probably by interfering with carnitine.

Carnitine is described in textbooks of medical nutrition as a conditional vitamin.[1]  It is present in the diet, especially in meat, and is also synthesized in the human body by methylation of lysine, in reactions requiring methionine, folic acid, B12, and zinc.  It is essential for fat metabolism, serving as a transport agent to carry long-chain fatty acids into the mitochondria, a key step in oxidative metabolism.  Deficiency impairs energy metabolism, thus causing fatigue, muscle weakness and pain, hypoglycemia without ketosis, and lipid accumulation in liver, muscles, and adipose tissue.[2]  Nerve cells also require carnitine and there have been promising results using carnitine in studies of senile dementia.[3]

Malnutrition Induced By Medications

To repeat a very important point, though, because it bears repeating: valproic acid causes carnitine depletion, especially in children and particularly in combination with other medications, which is common in medical practice.  A recent report describes the extra risk of death in elderly patients when they are treated with antipsychotic medications such as Seroquel (quietiapine).  Seroquel was one of the medications prescribed for Rebecca Riley and may have contributed to her demise.  Such antipsychotic medications are not generally regarded as dangerous for adults; yet, the risk of death in the elderly on antipsychotic medications is increased by 56% in the first month alone!  Is the risk likely to be lower for a child?  I would say not.

In 1997, I wrote about a case of carnitine deficiency induced by a combination of valproic acid and aspirin in one of my patients and then submitted it as a case report to the editor of the American Journal of Psychiatry because I knew I was the first, or one of the first, clinicians to make such a diagnosis and accomplish laboratory confirmation in an office-practice setting.  My case report was initially rejected and after some back and forth with the Journal, for a variety of reasons, my case report was never published.

A Case Study in Carnitine Deficiency

Here in my office was a 57-year-old divorced woman, with bipolar disorder and frequent spells of insomnia and mania that had gone on for almost 40 years.  More recently, she had been on lithium, haloperidol, clonazepam, and vitamins, including antioxidants and supplemental niacin and pyridoxine, but was still averaging over three manic attacks a year, most requiring hospitalization.  In 1992, valproic acid (Depakote) 250 mg, and lithium 900 mg, twice daily, had stabilized her condition.  Her sleep and mood had improved, too, with 4-8 milligrams of lorazepam (Ativan).

She even moved into a residential hotel and got along well in shared social facilities for the first time in 30 years.  Then, on a chill December day, she appeared for lunch – dressed in her bathing suit.  Obviously confused, she was hospitalized and her dose of valproic acid was doubled to 500 milligrams.  She improved and was discharged after three days; but relapsed within two weeks when her speech became slurred and her gait unsteady.  She looked drunk but had not been drinking.  Self-diagnosing “flu” because of myalgia, she treated herself with aspirin.  Within a few days she worsened and became too weak to stand without assistance.  Her friends, alarmed by her condition, brought her to my office as an emergency case.  They had to carry her because she was too weak to even hold up her head, which hung forward on her chest and shoulders.  Her hands were weak too, but her breathing and heart rate were normal despite mild basal rates.  She was not stuporous or demented; on the contrary, she was talkative and in good humor.

I suspected carnitine depletion because I had read a case report of weakness in an epileptic child treated with valproic acid,[4] which is one of many drugs known to deplete carnitine.  My patient had taken a gram per day of valproic acid for the preceding three weeks, during which time she had poor appetite and ate no meat or dairy products, i.e., a low-carnitine diet.

Valproate inactivates carnitine by binding to it, and further depletes it by inhibiting methylation of lysine, thus interfering with carnitine synthesis.  I obtained blood and urine samples for total carnitine and acyl-carnitine levels and found the results were far below normal.  I immediately gave her a 1000 milligram oral dose of L-carnitine, and she took two additional doses in the next eight hours before bedtime at home.  She improved in about six hours and by the next morning, 16 hours later, she felt well and was able to walk normally.  I also told her to stop taking aspirin. 

Three weeks later she had a high-normal plasma carnitine level, despite continued treatment with valproic acid.  Myasthenia has not reoccurred, and in fact she continued to improve behaviorally in the next two years on carnitine 1000 milligrams daily.  Her serum levels of valproic acid measured 80 mg/L (therapeutic range 50-10) at the time of her myasthenic reaction, while ten days later it measured only 42 mg/L.  It seems likely that carnitine repletion enhanced valproate excretion, thus lowering serum level.

Many drugs and chemicals bind to carnitine and thus displace fatty acids which are its physiologic target.  As a rule, any molecule that contains a benzene ring is likely to bind to carnitine, and this includes salicylic acid and hundreds of organic acids.[5]  For example, depletion is likely in case of Vitamin-B12 deficiency, which increases the excretion of the organic acid, methyl malonic acid.  Biotin deficiency has a similar outcome by provoking the excretion of isovaleric acid.  Thyroid can aggravate carnitine deficiency by increasing oxidative metabolism, which depends on carnitine.  Weight loss and prolonged physical exercise both increase carnitine use and can thus deplete reserves.  Children are at greater risk since their ability to synthesize the vitamin is not fully developed and this may be a factor in aspirin-induced Reye’s Syndrome.  Vegetarians are also at risk because of dietary deficiency of carnitine and its precursors, Vitamin B12, methionine, and zinc.

The Bottomline

In summary, carnitine deficiency must be considered in all sick patients, especially those on valproic acid, aspirin, NSAIDs, tranquilizers (both phenothiazines and benzodiazepines), antibiotics, and cancer chemotherapy agents.[6]  The increased use of valproic acid since 1989 is good reason for all physicians and psychiatrists to be aware of medication-induced carnitine deficiency.[7]

It does still haunt me to think that my unpublished-but-documented case report and research insights into carnitine might have influenced someone and perhaps even saved lives.  But it is a long-shot to expect that.   There was very little sign of readiness by the orthodox medical world to participate in orthomolecular dialogue on such an important issue then.  Is the orthodox medical world ready yet to begin “putting nutrition first?”