Beneficial or Supportive Interaction, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Preliminary

Effect and Mechanism of Action

Both adrenergic stimulants and tyrosine have been used in the treatment of narcolepsy and attention deficit disorder (ADD) with hyperactivity. An increase in the availability of tyrosine, under certain conditions, may influence the synthesis and release of dopamine.

Research

Animal research indicates that tyrosine depletion attenuates the release of dopamine produced by amphetamine but not the release of noradrenaline. In a rodent model, Geis et al. ¹ observed that rats exposed to amphetamines for 4 to 6 months, but not 35 days or less, reduced amphetamine self-administration after receiving tyrosine. These investigators hypothesized that tyrosine may be useful in certain individuals depending on their history of substance abuse. In an experiment using male rats, Woods and Meyer ² reported that exogenous tyrosine potentiates the methylphenidate-induced increase in extracellular dopamine in the nucleus accumbens.

A dietary deficiency of tyrosine may impair the therapeutic activity of amphetamines by depleting the available reserves of neurotransmitters. In an experiment involving 15 healthy volunteers, McTavish et al. ³ administered D-amphetamine (20 mg orally) 2 hours after they had ingested either a nutritionally balanced amino acid mixture or one lacking tyrosine and phenylalanine, the catecholamine precursors. These researchers observed that plasma tyrosine levels were significantly lower in subjects who received the nutrient-depleted mixture, but that mean plasma amphetamine levels were higher. Nevertheless, subjects reported that the nutrient-depleted mixture decreased the subjective psychostimulant effects of amphetamine, as indicated by visual analog scales. However, the nutrient-depleted mixture failed to reduce the subjective anorectic effect of amphetamine. This attenuation of some subjective effects of amphetamine after tyrosine depletion suggests that adequate tyrosine intake from dietary protein or nutraceuticals is essential to achieve full therapeutic effect in individuals administered amphetamines. Further research through large, well-designed clinical trials may be warranted.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Physicians prescribing mixed amphetamines or related stimulants may consider coadministering L-tyrosine as part of an integrative therapeutic strategy. The potential therapeutic efficacy of either therapy may be enhanced by concomitant use, especially in individuals susceptible to or exhibiting a tyrosine deficiency. Prudent clinical management warrants supervision and regular monitoring within the context of collaborative care by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics.

Beneficial or Supportive Interaction, with Professional Management

Preliminary

Effect and Mechanism of Action:

L-Tyrosine functions as a precursor to L-dopa, dopamine, norepinephrine, and epinephrine, the brain concentrations of which depend on intake of tyrosine. Augmenting tyrosine intake may produce an additive effect.

Research

Chronic cocaine use is believed to cause catecholamine depletion, and similarities exist between cocaine withdrawal and major depression. Tyrosine is the dietary precursor to catecholamines, and administration has produced positive outcomes in small trials of its antidepressant efficacy. The synaptic loss of dopamine with cocaine abuse increases demands for dopamine synthesis, as evidenced by the increase in tyrosine hydroxylase activity after cocaine administration. Consequently, a dopamine deficiency develops when precursor reserves are exhausted. Administration of the precursors of the depleted monoamine neurotransmitters L-tyrosine and L-tryptophan is postulated to promote their biosynthesis and thus restore neurotransmitter function. Precursors use a naturally regulated pathway in which the precursor is converted to the neurotransmitter only when needed, and then the body distributes the product on the basis of need. As dopamine is synthesized from precursors such as L-tyrosine, dopamine reserves are rebuilt, thus overcoming the dopamine depletion problem. Thus, a benefit in treating drug dependence has been hypothesized based on these premises as well as the possibility of reducing the severe depression that typically accompanies withdrawal. Acute and chronic amphetamine abuse presents a situation analogous to that associated with cocaine abuse.

Human studies investigating the use of tyrosine, alone or with tryptophan, in the treatment of cocaine addiction and withdrawal have arrived at mixed conclusions. ^4-7 However, in one small study the combination of imipramine, tyrosine, and tryptophan was associated with a success rate greater than 74% in the treatment of chronic cocaine abuse. ⁸ Verebey and Gold ⁹ proposed a regimen involving concomitant administration of L-tyrosine, L-tryptophan, thiamine, riboflavin, niacin, pantothenic acid, pyridoxamine, ascorbic acid, folic acid, and cyanocobalamin for the treatment of cocaine addiction. Further research through large, well-designed clinical trials may be warranted.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Health care professionals treating individuals for cocaine abuse may consider supporting the withdrawal process through administration of key neurotransmitter precursors such as tyrosine and tryptophan, possibly in concert with imipramine. Although not yet validated by mature research or conclusive evidence, such concomitant administration of these agents may be therapeutically appropriate within the context of collaborative care by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics and with close supervision and regular monitoring. Titration of medication dosage may be appropriate with significant therapeutic response to tyrosine; a tyrosine-induced excess is improbable.

	Impaired Drug Absorption and Bioavailability, Precautions Appropriate
	Bimodal or Variable Interaction, with Professional Management
	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect
	Beneficial or Supportive Interaction, with Professional Management

Inadequate

Effect and Mechanism of Action

L-Tyrosine is a semi-essential amino acid that converts to L-dopa (levodopa), and administration of tyrosine can increase dopamine levels. However, levodopa may interfere with the absorption of tyrosine by competitively inhibiting the transport system. ¹⁰ Furthermore, levodopa and aromatic amino acids such as tyrosine and tryptophan can compete for brain uptake, and simultaneous administration may decrease levels of both nutrients and the medication. ¹¹

Research

Tyrosine has been considered a potential tool in the treatment of Parkinson's disease, depression, and other related conditions based on its role as a neurotransmitter precursor. Rodent and human studies have demonstrated that L-tyrosine administration can enhance dopamine synthesis. Growdon et al. ¹² measured levels of tyrosine and homovanillic acid, the major dopamine metabolite, in lumbar cerebrospinal fluid (CSF) of 23 patients with Parkinson's disease before and during ingestion of 100 mg/kg/day of tyrosine; nine subjects were coadministered 100 mg/kg/day of probenecid (to prolong half-life of tyrosine by slowing renal elimination) in six divided doses for 24 hours before each spinal tap, whereas the other 14 did not receive probenecid. These researchers observed that CSF tyrosine levels significantly increased in both groups after oral L-tyrosine administration, and that homovanillic acid levels significantly increased in the group of patients pretreated with probenecid. These findings indicate that “ L-tyrosine administration can increase dopamine turnover in patients with disorders in which physicians wish to enhance dopaminergic neurotransmission.” ¹²

In a small preliminary trial, Lemoine et al. ¹³ prescribed L-tyrosine (45 mg/lb body weight) to five naive patients diagnosed after sleep polygraphy criteria and five patients receiving L-dopa and/or dopamine agonist as long-term treatment of Parkinson's disease. After 3 years of L-tyrosine treatment, several patients demonstrated better clinical results and significantly fewer adverse effects than subjects treated with L-dopa or dopamine agonists. These authors cautioned that further research would be required to determine the “theoretical long-term sparing neurons potentiality” of this approach.

Riederer ¹¹ spectrofluorometrically assayed tyrosine and tryptophan in postmortem human brain areas of patients with Parkinson's disease treated orally with or without L-dopa plus the peripherally acting decarboxylase inhibitor benserazide. He observed that both tyrosine and tryptophan were significantly decreased after treatment with L-dopa and interpreted these findings as demonstrating a competitive action of L-dopa to other aromatic amino acids on human brain uptake. No research has been conducted to determine whether such depletion is clinically significant. Furthermore, evidence is lacking as to whether concomitant L-tryosine could prevent or reverse adverse effects, if any, and whether such coadministration would be safe and effective. Well-designed clinical trials are warranted.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

Administration of L-tyrosine, or its precursor phenylalanine, may serve as a valuable adjunctive therapy in the treatment of Parkinson's disease or similar conditions. Coadministration of tyrosine may prevent or reverse nutrient depletion resulting from levodopa therapy. However, concomitant use of levodopa and L-tyrosine could introduce several complications and should be avoided except under close supervision, regular monitoring, and coordinated care by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics. Although concomitant administration might enhance effectiveness and reduce adverse effects of levodopa therapy, it carries an attendant risk of inducing adverse effects by excessively elevating dopamine levels. In cases where tyrosine is indicated, ingestion of the two agents should be separated (e.g., at least 4 hours apart) to reduce interference with absorption and CNS uptake.

Beneficial or Supportive Interaction, with Professional Management

Inadequate, but considered Consensus

Effect and Mechanism of Action

L-Tyrosine is a direct precursor to thyroxine. Coadministration of tyrosine and exogenous thyroid hormone(s) may produce an additive interaction.

Research

Evidence from clinical trials directly investigating coadministration of tyrosine and thyroid hormone is lacking. Nevertheless, the effect of tyrosine levels on thyroid function is considered axiomatic within conventional pharmacology. Physicians experienced in nutritional therapeutics report beneficial effects after administering tyrosine to support thyroid function and coadministering tyrosine with various forms of exogenous thyroid hormone in treating individuals with hypothyroidism.

Nutritional Therapeutics, Clinical Concerns, and Adaptations

With proper clinical management, coadministration of tyrosine with natural or synthetic thyroid medications represents a potentially valuable synergy in the treatment of individuals with subclinical or frank hypothyroid conditions. The administration of tyrosine, alone or in combination with synergistic agents such as iodine, is common within the professional practice of nutritional therapeutics. Concomitant administration of tyrosine may be therapeutically appropriate but requires supervision and regular monitoring within the context of collaborative care by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics. Titration of medication dosage may be appropriate with significant therapeutic response to tyrosine; a tyrosine-induced hyperthyroid state is improbable. Conversely, any additive effect of augmented tyrosine intake may be minimal in individuals whose thyroid gland has atrophied because of chronic use of synthetic thyroid medication and subsequent decline in endogenous hormone synthesis.

Potentially Harmful or Serious Adverse Interaction—Avoid

Preliminary

Effect and Mechanism of Action

The MAO inhibitors act by inhibiting the activity of the enzyme monoamine oxidase, which normally breaks down central monoamine neurotransmitters to render them inactive. The potentiation of sympathomimetic substances and related compounds by MAO inhibitors may result in hypertensive crisis and potential risk of heart attack or stroke. Tyramine in foods (e.g., red wine, aged cheeses) is the pressor amine most often implicated in these reactions. Tyrosine is converted into tyramine through decarboxylation by bacteria in the bowel. Therefore, elevated levels of tyrosine could induce an increase in tyramine capable of causing a clinically significant interaction.

Research

Concomitant intake of an MAO inhibitor (including selegiline) and foods containing certain pressor amines, particularly tyramine, or pharmacological agents containing sympathomimetic agents, has been associated with potentially serious hyperadrenergic states. ¹⁴ Besides tyramine, other amines and amine precursors, such as tyrosine, dopamine, levodopa, and histamine, may also precipitate such interactions. ¹⁵ This interaction is severe but infrequent and is characterized by severe occipital and temporal headache, elevation of both systolic and diastolic blood pressures, neuromuscular excitation, neck stiffness, diaphoresis, and mydriasis, generally occurring within 2 hours of ingestion of the substances. Cardiac dysrhythmias, heart failure, or intracerebral hemorrhage can occur, but rarely do. Meperidine (Demerol) and dextromethorphan (in many OTC cough medicines) have both been associated with fatal interactions with the type A MAO inhibitors.

Reports

No case reports have been published documenting adverse interactions involving tyrosine and MAO inhibitors. However, several reports have described delirium, hypomania, myoclonus, hyperreflexia, and diaphoresis attributed to the combination of L-tryptophan and a MAO inhibitor. ^16-18

Clinical Implications and Adaptations

Physicians prescribing phenelzine and related MAO inhibitors need to advise patients to avoid concomitant intake of L-tyrosine, sympathomimetic drugs (including amphetamines, cocaine, methylphenidate, dopamine, epinephrine, and norepinephrine), or related compounds (including methyldopa, L-dopa, L-tryptophan, 5-HTP, and phenylalanine), as well as foods high in tyramine. Concomitant administration of tyrosine may be appropriate in the treatment of some individuals but requires close supervision and regular monitoring within the context of collaborative care by health care professionals trained and experienced in both conventional pharmacology and nutritional therapeutics.

	Drug-Induced Adverse Effect on Nutrient Function, Coadministration Therapeutic, with Professional Management
	Drug-Induced Nutrient Depletion, Supplementation Therapeutic, with Professional Management
	Prevention or Reduction of Drug Adverse Effect

Emerging

Effect and Mechanism of Action

The formation of brain noradrenaline depends on brain tyrosine levels, associated with the ratio in plasma of tyrosine to other large, neutral amino acids (LNAAs). The combination of estrogen and progestins in oral contraceptives (OCs) can decrease plasma levels of tyrosine so as to contribute to adverse effects of the medications (e.g., depression).

Research

Moller and colleagues have been investigating the effects of OC use on amino acid metabolism for more than 25 years. In 1981, they studied the relationship of this effect on tryptophan and tyrosine, in particular on the association between OC use and depression. They found that, compared to controls, the “estrogen-progestogen users showed elevated plasma levels of total tryptophan and decreased levels of tyrosine,” and that there “was a clear trend that the incidence of adverse reactions was related to the decrease in tyrosine levels.” Furthermore, “the plasma ratio of tryptophan to competing amino acids was increased in the estrogen-progestogen users, whereas the ratio of tyrosine to competitors was severely decreased suggesting a decreased brain tyrosine concentration.” They noted that ethinyl estradiol was more potent than mestranol in its effect on plasma tyrosine. ¹⁹ In a subsequent series of published human studies, they demonstrated significantly increased plasma tyrosine transaminase activity, and significantly decreased plasma tyrosine and tyrosine/LNAA levels at midcycle and luteal phase, relative to the follicular phase, in women administered new-generation combined OCs compared with comparable controls. They observed that, after an oral protein load, the area under the curve in plasma of tyrosine and tyrosine/LNAA in OC users at the luteal phase were 43% and 29%, respectively, of control levels. These results “suggest that the decreased tyrosine availability to the brain in OC users may result in a substrate-limited reduction of brain noradrenaline formation, which, secondarily, may contribute to disturbances of mood, coping mechanisms, and appetite in susceptible subjects.” ²⁰ These researchers interpreted the findings of their third study to “suggest that the metabolic effects of the new-generation combined OCs on neutral amino acids and cholesterol are only modest to slight, except for the effect on tyrosine, the brain noradrenaline precursor, which may cause disturbances of various noradrenaline-mediated central functions in susceptible individuals.” ²¹

Clinical Implications and Adaptations

Physicians prescribing OCs may find it prudent to suggest that patients supplement with L-tyrosine and B-complex vitamins, particularly if they are susceptible to or have experienced depression or other emotional adverse effects in relation to medication use. Botanical and nutrient support of liver conjugation may also be beneficial within the context of collaborative care by health care professionals trained and experienced in both conventional pharmacology and nutritional/botanical therapeutics. Such coadministration is generally considered safe and does not require regular monitoring.

See also Amphetamines and Related Stimulant Medications.

As a precursor of many neurotransmitters, tyrosine may increase the activity of exogenous sympathomimetic agents. In an animal model using hyperphagic rats, Hull and Maher ²² observed that L-tyrosine (200 and 400 mg/kg) potentiated the anorectic activity of amphetamine/AMPH (0.75, 1.25, or 1.75 mg/kg), ephedrine/EPH (5, 10, or 20 mg/kg), and phenylpropanolamine/PPA (5, 10, or 20 mg/kg) in a dose-dependent manner. This response pattern suggested increased catecholamine synthesis in stimulated neurons. Notably, the potentiation by L-tyrosine was attenuated when L-valine was coadministered. However, in a subsequent experiment, they found that L-tyrosine fails to potentiate several peripheral actions of the sympathomimetics, particularly peripherally mediated PPA-, EPH-, and AMPH-induced increases in gastrointestinal transit time and retention and intrascapular brown adipose tissue thermogenesis. Lastly, these researchers demonstrated that although each of the mixed-acting sympathomimetics significantly increased mean arterial, systolic, and diastolic blood pressures when administered alone, the coadministration of L-tyrosine failed to potentiate the pressor responses of PPA, EPH, or AMPH in urethane-anesthetized rats. Thus, Hull and Maher ²³ concluded that the potentiation of the mixed-acting sympathomimetics by L-tyrosine is “largely restricted to centrally mediated responses.”

Research through well-designed clinical trials would be necessary to determine whether coadministration of L-tyrosine and sympathomimetic appetite-suppressant agents would produce similar results in humans. Even though pharmacologically plausible, the combined use of these agents cannot be supported by the available evidence.

Butorphanol (Stadol, Stadol NS), codeine sulfate, fentanyl (Actiq Oral Transmucosal, Duragesic Transdermal, Fentanyl Oralet, Sublimaze Injection), hydrocodone, hydromorphone (Dilaudid), levorphanol (Levo-Dromoran), meperidine (Demerol), methadone (Dolophine; Methadose), methadone hydrochloride (Dolophine, Methadose), morphine sulfate (Astramorph PF, Avinza, Duramorph, Infumorph, Kadian, MS Contin, MSIR, Oramorph SR, RMS; Roxanol, Roxanol Rescudose, Roxanol T), opium tincture, oxycodone (Endocodone, OxyContin, OxyIR, Percolone, Roxicodone), oxymorphone (Numorphan), paregoric, pentazocine (Talwin, Talwin NX), propoxyphene (Darvon; Darvon-N).

Combination drugs: Buprenorphine and naloxone (Suboxone); codeine and acetaminophen (Capital and Codeine; Phenaphen with Codeine; Tylenol with Codeine); codeine and acetylsalicylic acid (Empirin with codeine); codeine, acetaminophen, caffeine, and butalbital (Fioricet); codeine, acetylsalicylic acid, caffeine, and butalbital (Fiorinal); hydrocodone and acetaminophen (Anexsia, Anodynos-DHC, Co-Gesic, Dolacet, DuoCet, Hydrocet, Hydrogesic, Hy-Phen, Lorcet 10/650, Lorcet-HD, Lorcet Plus, Lortab, Margesic H, Medipain 5, Norco, Stagesic, T-Gesic, Vicodin, Vicodin ES, Vicodin HP, Zydone); hydrocodone and acetylsalicylic acid (Lortab ASA); hydrocodone and ibuprofen (Reprexain, Vicoprofen); opium and belladonna (B&O Supprettes); oxycodone and acetaminophen (Endocet, Percocet 2.5/325, Percocet 5/325, Percocet 7.5/500, Percocet 10/650, Roxicet 5/500, Roxilox, Tylox); oxycodone and acetylsalicylic acid (Endodan, Percodan, Percodan-Demi); pentazocine and acetaminophen (Talacen); pentazocine and acetylsalicylic acid (Talwin Compound); propoxyphene and acetaminophen (Darvocet-N, Darvocet-N 100, Pronap-100, Propacet 100, Propoxacet-N, Wygesic); propoxyphene and acetylsalicylic acid (Bexophene, Darvon Compound-65 Pulvules, PC-Cap); propoxyphene, acetylsalicylic acid, and caffeine (Darvon Compound).

Research using a rodent model indicates that L-tyrosine may potentiate the analgesic effect of opiate medications. In an experiment exposing rodents to a hot plate, Hull et al. ²⁴ found that the observed potentiation of morphine sulfate (10 mg/kg) and codeine sulfate (30 mg/kg) was positively correlated with increases in brain tyrosine concentrations. The L-tyrosine-induced potentiation was dependent on increased catecholamine synthesis, as determined by alpha-methyl- p-tyrosine pretreatment. Furthermore, blockade of L-tyrosine uptake into the brain by the coadministration of L-valine attenuated this potentiation. No other L-amino acid, except L-tryptophan, was capable of mimicking the potentiating action of L-tyrosine. The authors concluded that these findings demonstrate that L-tyrosine “dose dependently potentiates the analgesic activity of opioids and are consistent with the requirement of the central conversion of L-TYR to catecholamines via TYR hydroxylase for this response.” ²⁴ In a subsequent study, Ali ²⁵ observed that L-tyrosine (25, 50, 100, and 200 mg/kg), administered subcutaneously, dose-dependently potentiated the antinociceptive action of subcutaneous morphine (5 mg/kg).

Well-designed clinical trials would be necessary to determine whether L-tyrosine would potentiate the analgesic activity of opiates in humans.

Tyrosine levels are occasionally low in depressed patients. Several studies in the 1970s published encouraging findings showing potential benefit from the treatment of depression using tyrosine, especially when combined with 5-HTP. ^26-29 However, subsequent research failed to demonstrate significant antidepressant activity on the part of L-tyrosine. ³⁰ Further human trials are warranted to investigate the relative influences of variations in presentations of depression, associated neurotransmitter patterns, and pharmacogenomic variability, as well as practice management principles for shaping individualized and evolving therapeutic interventions.

Branched-chain amino acids (BCAAs: isoleucine, leucine, valine) compete with tyrosine and other aromatic amino acids for absorption and transport across the blood-brain barrier into the brain. Separating intake of tyrosine (by at least 2 hours) from other amino acids and meals high in protein will reduce interference with bioavailability and therapeutic action. Dietary carbohydrates increase the amount of tryptophan, tyrosine, and phenylalanine that reach the brain.

L-Tyrosine is a direct precursor to thyroxine. The combined use of tyrosine and iodine, from dietary or supplemental sources, has been practiced within naturopathic medicine and other traditions of nutritional therapeutics for decades, based on the hypothesis that coordinated intake can support the endogenous synthesis of thyroid hormones. Nevertheless, evidence from clinical trials directly investigating coadministration of tyrosine and iodine is lacking. Long-term, well-designed clinical trials are warranted to determine the safety and efficacy of this therapeutic strategy.

L-Tyrosine is synthesized from L-phenylalanine. Coadministration could theoretically enhance the activity of both nutrients. However, concomitant administration of phenylalanine and tyrosine at high dosage levels should be avoided outside of professional supervision because of potential additive effects. Food sources may contain both nutrients but typically would be considered safe at usual levels of intake.