Lifting Depression With "Bio-identical" Mood Enhancers
by Leslie J. Farer

Depression affects millions worldwide, regardless of nationality, race, socio-economic status, age or gender. Insufficient activity of key neurotransmitters, such as the monoamines serotonin, norepinephrine, and dopamine, is the leading theory of depression held by neurobiologists today.

Yet despite the wide array of pharmaceuticals currently available — monoamine oxidase inhibitors (MAOI’s), tricyclic antidepressants (TCA’s), and selective serotonin reuptake inhibitors (SSRI’s) — depression remains difficult to treat. In fact, conventional antidepressants are ineffective in an estimated 10% to 30% of depression cases. (1) These so-called “xenobiotic” (foreign to the body) compounds also carry the risk of troublesome and potentially dangerous side effects and delayed onset of action. The good news is that a sizable body of clinical data has established the efficacy of certain physiologically occurring compounds in treating this disease.

Conventional drugs manipulate brain chemistry in a roundabout way because instead of boosting neurotransmitter synthesis, they increase synaptic serotonin levels by hindering usual enzymatic degradation (MAOI’s), or preventing customary re-uptake following nerve transmission (SSRI’s and TCA’s). “Bio-identical” agents (exact replicates of substances occurring naturally in the body), on the other hand, directly correct chemical deficiencies by providing raw materials that spark key metabolic processes leading to neurotransmitter production, thus restoring proper brain chemistry. In addition, they display a quicker onset of action, higher safety level (lower toxicity) and fewer side effects. This article describes a few of these neurotherapeutic substances clinically indicated to combat depression.

S-Adenosylmethionine (SAMe)

SAMe is a metabolite present in all living cells, formed from the amino acid methionine and adenosine triphosphate (ATP), the major energy source necessary for cellular reactions. Since its discovery in 1952, SAMe’s biochemical actions and therapeutic potential have been extensively investigated.

This amino acid derivative plays an integral role in three important mechanisms — as a methyl (CH3) donor in a broad array of cellular reactions involving proteins, phospholipids, DNA and neurotransmitter synthesis (3,4) and as a precursor molecule to both the aminopropylation (4,5) and transulfuration (4,6) pathways, leading to the production of polyamines and glutathione. In order for these pathways to function efficiently, an adequate physiological supply of SAMe is essential; illness and aging may deplete the body’s stores of this crucial biochemical.

Dozens of clinical studies performed since the 1970’s have demonstrated SAMe’s mood-lifting properties. When compared to conventional antidepressants, SAMe has been shown to be as effective as TCA’s (such as imipramine and chlorimipramine), with fewer side effects and faster onset of action. (4,7,8) When taken in combination with TCA’s, SAMe was shown to potentiate and hasten their effect. (8,9)

Perhaps it is the stimulatory effect of SAMe on monoamine neurotransmitters, or its role in phospholipid methylation, or both, which underlies its antidepressant effect.

In addition to relieving symptoms in otherwise healthy people, SAMe has also been shown to ease depression in those suffering from AIDS (10) and Parkinson’s (11). Besides depression, SAMe’s therapeutic value in treating Alzheimer’s (4), liver disease (4,12), and osteoarthritis (4,13) has been demonstrated.

SAMe is an unstable compound; however, stable salts (such as the butanedisulfonate and toluenesulfonate forms) have been developed. SAMe is available as enteric-coated tablets (and as an injectable), the dosage for tablets is typically 400 – 1600 mg daily in divided doses, on an empty stomach; if gastrointestinal problems occur, increase dosage slowly and take with food. Include a daily B-complex supplement or multi-vitamin with folic acid, B6 and B12

L-Tryptophan (LT)

LT is an amino acid precursor to serotonin, one of the monoamine neurotransmitters implicated in depression. Data suggest that lack of this essential amino acid in the diet can potentially cause or exacerbate depression in some people. (14, 15)

LT is present in foods in relatively small quantities and must compete with five other amino acids for entry into the brain via a transport molecule (i.e., a biochemical “vehicle” that “carries” amino acids across the blood-brain barrier). Getting adequate LT into the grey matter is a challenge, considering that as little as one percent of dietary LT may actually enter the brain (16). Although it is possible to increase LT levels through a carefully devised nutritional strategy, it would be extremely difficult, or nearly impossible, to reach or maintain adequate therapeutic levels (gram quantities) through diet alone.

Supplemental LT has been used since the 1970’s for its purported antidepressive effects. However, it’s difficult to draw firm conclusions on its efficacy due to the mixed outcomes punctuating the medical literature, which perhaps stem from poor or inconsistent study design. Even so, LT may be of therapeutic value for those with mild or moderate depression. (17)

It seems that more unequivocal results have been obtained when LT is used as an adjunct to conventional antidepressants. In one such study, when 20 mg of fluoxetine (Prozacâ) was administered with two grams of LT to a group of depressive patients over eight weeks, positive effects were seen sooner compared to a group that took fluoxetine and placebo. (Interestingly, slow wave sleep, which was decreased in the fluoxetine /placebo group, was maintained in the fluoxetine/LT patients.) (18)

In 1989, a single batch of tainted LT caused an epidemic of eosinophilia-myalgia syndrome (EMS), which resulted in its removal from the U.S. market by the FDA. The EMS-induced fatalities and illnesses were attributed not to any toxicity on the part of the supplement itself, but to contamination during the manufacture of this particular batch.

Dosage: One to three grams with a carbohydrate snack or on an empty stomach; do not consume with protein foods.

5-Hydroxytyptophan (5-HTP)

5-HTP, a metabolite of LT, is the immediate precursor to serotonin.* This amino acid analog is commercially produced by extraction from the seeds of the African plant, Griffonia simplicifolia. Unlike LT, 5-HTP easily crosses the blood-brain barrier — it does not require the presence of a transport molecule or compete with other amino acids to enter the brain. As much as 70% is absorbed into the bloodstream from an oral dose. (16)

Like LT, 5-HTP acts primarily by increasing levels of serotonin within the central nervous system, with the added benefit of augmenting levels of other neurochemicals too, including melatonin, dopamine, norepinephrine and beta-endorphin. (16)

Antidepressant effects and positive clinical outcomes appear to be more consistent with 5-HTP than with LT. (19, 20)

One author undertook the task of attempting to statistically analyze the results of 15 heterogeneous studies evaluating the efficacy of 5-HTP in depression, performed from 1972 to 1991. These investigations varied as far as type of depression, study design (open trial or double-blind vs. placebo), dosage, and duration of treatment, and thus were not suitable for a standard meta-analysis. Nonetheless, the researcher tallied the results and took a grand total: out of 511 patients, 285 showed improvement with 5-HTP (56%); when only the double-blind studies (8 out of the 15 studies) were considered, 94 out of 161 patients demonstrated amelioration of symptoms (58%). (16)

[*An interesting biochemical aside — serotonin can be subsequently metabolized to other products, including the sleep and circadian rhythm hormone, melatonin; a naturally occurring compound we discussed earlier, SAMe, is required for this conversion, underscoring its diverse physiological roles.]

When compared to conventional antidepressants, 5-HTP was shown to be as effective as the SSRI fluvoxamine (21) and the TCA imipramine, (22) with fewer side effects and a faster onset of action (within one to two weeks vs. four or more weeks) (23, 24). And, like LT, 5-HTP has been successfully used in conjunction with MAOI’s and TCA’s to enhance their therapeutic effect. (25, 26)

Medical experts differ over whether 5-HTP should be taken with a drug known as a decarboxylase inhibitor (such as carbidopa) to prevent the metabolism of 5-HTP to serotonin in the bloodstream before it reaches its target destination, the brain. Proponents of co-administration of carbidopa (27) argue that if the conversion takes place in the blood, negligible serotonin will enter the brain, due to the neurotransmitter’s limited access across the blood-brain barrier; others question the need for such an agent, pointing to successful clinical outcomes using 5-HTP alone (16).

Dosage: 50 to 100 mg, two times per day. Some people may experience mild nausea, so start with 50-mg doses, take with meals and increase slowly as needed.

Nicotinamide Adenine Dinucleotide (NADH)

NADH is the coenzyme, or active, form of Vitamin B3 (known as niacin, niacinamide, or nicotinic acid). It is a large and structurally complex molecule that exists both in its oxidized (NAD+) and reduced or electron-rich (NADH) form.

NAD+/NADH plays a critical role in each of the three major cellular energy pathways that generate ATP, the high-energy intermediate necessary to all cellular processes (which we discussed earlier in relation to SAMe). NADH is also involved in neurotransmitter production.

The name Birkmayer has long been associated with NADH — it belongs to two physicians of the Birkmayer Institute in Vienna, Austria who have performed groundbreaking research into the metabolic role of the B3 coenzyme in disease states, and have developed a patented stabilized form.

In several fascinating studies performed by the Birkmayers, successful outcomes were obtained by treating Parkinson’s patients with NADH. It was found that the patients’ reduction of symptoms was related to the coenzyme’s influence on endogenous dopamine production. (28, 29) (The synthesis of dopamine is impaired with the disease.) In the course of this research, the Birkmeyers observed another interesting phenomenon — the Parkinson’s patients’ improvement was also accompanied by a decline in disease-related depressive symptoms. This finding spurred the researchers to conduct further studies on NADH’s effect on various types of depression. In 205 patients treated with the coenzyme (administered orally, intramuscularly, or intravenously), 93% demonstrated improvement, establishing NADH as a neurotherapeutic agent with the “potential capacity to stimulate the biosynthesis of L-Dopa (a precursor to dopamine), dopamine and norepinephrine.” (30)

NADH has also been shown to be effective in treating such diverse conditions as Alzheimer’s (31), chronic fatigue syndrome (32), and even jet lag (33). The double role of NADH in the energy production pathways and neurotransmitter synthesis make it an intriguing subject of medical research and a novel and versatile therapeutic agent.

Dosage: A typical dose is 5-10 mg taken in the morning on an empty stomach (at least 30 minutes before breakfast); some people may find a larger dose of 10-20 mg more effective.

Conclusion

These effective, relatively non-toxic and naturally occurring raw materials for neurotransmitter production are an ideal first course of action in treating many (except the most severe) cases of depression. When necessary, they may also be used as adjuncts to conventional pharmaceuticals to enhance their action and speed their onset.

In the next article, we’ll cover a few more of these fascinating substances, including acetyl-l-carnitine, DHEA, omega-3 fatty acids and others.

References

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Caution

If you are currently taking an antidepressant, do not stop or alter treatment without a physician’s supervision. The natural anti-depressants described here may interact with conventional drugs. If you are not taking medications and would like to try one of these supplements, it would be prudent to inform your physician, and then take one at a time for a course of four to eight weeks to determine its effect. Please note that S-adenosylmethionine, L-tryptophan and 5-hydroxtryptophan (and St. John’s Wort, which is a natural, but not bioidentical agent, and is not covered here) act on the serotinergic system, and if taken together could, potentially, dangerously elevate levels of the neurotransmitter (a condition known as serotonin syndrome, characterized by hypertension, flushing, dizziness, disorientation, and muscle twitching (2)). Dosages listed should be used as guidelines only; consult your health-care professional if you wish to exceed these recommendations.