Ornithine

L-Ornithine is one of three amino acids found in the urea cycle and similar to its partner L-Citrulline, but not L-Arginine, L-Ornithine is a nonprotein amino acid (not used in creating enzymes and protein structures) nor is it coded by DNA or a dietary essential amino acid.

Dietary L-Arginine, which is a conditionally essential amino acid, provides the substrate for circulating levels of L-Ornithine and L-Citrulline (among other pathways, glutamate and glutamine can also contribute) to maintain a basal circulating concentration of approximately 50nmol/mL L-Ornithine.^[1]

L-Ornithine can be produced directly from L-Arginine via the arginase enzyme (conferring urea as a byproduct).^[2][3]

L-Ornithine is a nonprotein amino acid that is produced from other amino acids, most notably the two other amino acids in the urea cycle alongside it known as L-Arginine and L-Citrulline

Ornithine is not related to the nitric oxide cycle, but is the intermediate after urea production that combines with ammonia (via carbamoyl phosphate) to create citrulline

The urea cycle is a cycle involving five enzymes and three amino acids (Arginine, Ornithine, and Citrulline) and one other intermediate which is used to regulate urea and ammonia concentrations in the body;^[4] this cycle is sometimes seen as a nitrogen detoxifying pathway (as it prevents elevated toxic concentrations of ammonia, a small nitrogen containing compound), and Ornithine provision appears to be the rate-limiting step.^[5]

L-Arginine is converted into L-Ornithine via the arginase enzyme (giving off urea as a cofactor)^[2][3] and from there ornithine (using carbamoyl phosphate as a cofactor) is subject to the Ornithine carbamoyltransferase enzyme to produce L-Citrulline. In this sense, the metabolic pathway from arginine towards citrulline (via ornithine) causes an increase in urea and a concomitant decrease in ammonia, which was used by the Carbamoyl phosphate synthase enzyme to create carbamoyl phosphate^[6] and a deficiency of this enzyme results in high blood ammonia concentrations^[7][8] which appears to be the most common genetic fault of the urea cycle.^[9] If need be, arginine can directly be converted into L-citrulline via a Arginine deiminase enzyme to increase, rather than reduce, ammonia concentrations.^[10]

The cycle is formed as citrulline then binds with L-aspartate (related to D-Aspartic acid as its isomer) to form arginosuccinate via the arginosuccinate synthase enzyme, and then the arginosuccinate lysase enzyme degrades arginosuccinate into free arginine and fumarate; arginine then reenters the urea cycle anew.^[6] Fumarate can simply enter the TCA (Krebs) cycle as an energy intermediate.^[10]

The urea cycle involves Ornithine, Citrulline, and Arginine in an interchangeable cycle to regulate ammonia concentrations

Ornithine, out of the three amino acids of the urea cycle (alongside L-Arginine and L-Citrulline) is the primary parent molecule for production of the polyamines putrescine, spermidine, and spermine.^[11][12]

Ornithine is a precursor for production of polyamine compounds

L-Ornithine can also be converted into a metabolite known as l-glutamyl-c-semialdehyde which can be further converted into the neurotransmitter glutamate via P5C dehydrogenase.^[13] This pathway uses pyrroline-5-carboxylate as an intermediate, and is somewhat (indirectly) reversible.^[13]

The urea cycle amino acids are connected to neurology, in part, due to ornithine being converted into glutamate (which can then be converted into GABA, and the glutamate:GABA axis is highly important in neurology)

Ornithine has its transportation mediated by the same transporter systems as L-Arginine (and L-Cysteine)^[14] but a different mechanism than that of L-Citrulline.

Ornithine is taken up by the same transporters as Arginine. Although the research into an oral dose-response is not as extensive with ornithine as it is with arginine, it is plausible that they share similar motifs (fairly good bioavailability at low oral doses of around 2-6g and then progressively getting lower at higher doses and thus being less efficiently absorbed)

Oral ingestion of 40-170mg/kg Ornithine (as hydrochloride; for a 70kg person this is 3-12g) is able to dose-dependently increase serum ornithine concentrations within 45 minutes, which holds stable until 90 minutes.^[15] The exact increases in serum ornithine were not quantified.

Elsewhere, 100mg/kg has been noted to increase serum ornithine from approximately 50nmol/mL to around 300nmol/mL within one hour which persisted elevated to a similar degree after some exhaustive exercise (15 minutes or so) and a 15 minute break^[1] and another study using a structure where 3g ornithine was given in the morning and another dose 2 hours later noted that, even 380 minute later, plasma ornithine was elevated beyond placebo (65.8% higher) although it appeared to be on the decline (measurement after 240 minutes was 314% higher).^[16]

Ornithine is fairly well absorbed and peaks about 45 minutes after oral dosing (or perhaps a tad earlier) and then seems to maintain afterwards for up to around 4 hours (somewhere between 4 hours and 6 hours it starts to decline)

Ornithine supplementation (2,000mg) has been noted to not increase serum citrulline nor arginine concentrations by itself or as hydrochloride^[16][16] and only has been noted to increase plasma arginine once as ornithine α-ketoglutarate (as a specific nutrient interaction).^[17]

Supplementation of Ornithine (100mg/kg as hydrochloride) before exhaustive exercise has been noted to increase plasma glutamate concentrations at both rest and after exhaustive exercise (to a small degree, around 50nmol/mL or 9%).^[1]

One study has noted a transient increase in the three branched chain amino acids after 4 hours of exhaustive exercise that was preloaded with 6g ornithine (two doses of 3g separated by 2 hours) in the range of 4.4-9%.^[16]

A slight increase in glutamate may occur after exhaustive exercise, and Ornithine at low doses does not appear to significantly influence concentrations of Arginine nor citrulline

The accumulation of ammonia in skeletal muscle is able to induce muscular fatigue secondary to inhibiting muscle protein contractility,^[18][19] and normally accumulates in serum^[20] and the brain^[21] during exercise, where accumulation into the brain promotes the sensation of fatigue.^[21]

Ammonia has been found to, at 100mg/kg L-Ornithine, be increased after exhaustive exercise (15 minutes or so) while not significantly affected at rest prior to exercise^[1] although in more prolonged exercise (2 hours at 80% VO2 max) the increase in serum ammonia seen with exercise is attenuated.^[16]

Theoretically should reduce ammonia, but has oddly been noted to both increase and decrease ammonia concentrations. Requires more studies to investigate this topic

Skeletal muscle itself can directly buffer ammonia somewhat (both alanine and glutamine can directly buffer ammonia)^[22] while ammonia can be converted to urea in the liver;^[23] however, supplementation of 100mg/kg ornithine does not appear to influence urea concentrations after exhausitve exercise lasting around 15 minutes^[1] but urea has been noted to be increased relative to placebo in a trial using 2 hours of cycling (2g ornithine daily and 6g day of testing), which appeared to be due to preventing the exercise-induced reduction (was 8.9% in placebo, no change in ornithine).^[16]

Although enhancement of the urea cycle follows ornithine supplementation, serum urea concentrations do not appear significantly altered following supplementation of ornithine

One study using 1g or 2g of L-ornithine alongside an equal amount of L-arginine (to total 2g or 4g) has been noted to, over the course of 5 weeks in adult men subject to a strength training program, increase both lean mass and power accrual.^[24]

A lone study to support increases in muscle mass, but the conclusions that can be drawn from this are highly limited; plus, it is confounded with the inclusion of arginine

A cycle ergometer test following 100mg/kg L-ornithine as hydrochloride failed to significantly affect exercise performance (time to exhaustion, heart rate, oxygen consumption) in a short duration cycle to exhaustion lasting about 15 minutes.^[1] A longer trial of 2 hours (80% VO2 max) after taking 2g ornithine daily for 6 days following by a single dose of 6g prior to testing noted that the fatigue rating seen with ornithine was 52% that of placebo and an anti-fatigue effect was noted in a 10 second sprint (similar at baseline, with the decline in performance being less with ornithine relative to placebo after testing); mean speed overall was unaffected.^[16]

There is possible an anti-fatigue effect associated with ornithine supplementation and prolonged exercise. The antifatigue effect only appears to occur during prolonged exercise, which correlates with the time when ammonia would normally cause problems. That being said, there are not many interventions overall to draw conclusions from

Hepatic encephalopathy is a liver condition (affecting up to 84% of those with liver cirrhosis^[25]) which, due to excess ammonia concentrations in the blood and brain,^[26] adversely affects cognitive functioning; in a sense, it is ammonia toxicity.^[27][28] Therapy of hepatic encephalopathy tends to be focused on reducing blood ammonia concentrations.^[27][29]

Infusions of L-Ornithine appear to be able to reduce circulating ammonia concentrations in clinical settings^[30][31][32] while oral supplementation of L-Ornithine-L-Aspartate at 6g thrice a day (18g total) for 14 days was able to effectively reduce blood ammonia in both postprandial and fasted states.^[33]

The reviews that investigate this topic (one review^[34] assessing four interventions^{[33][30][35][31]} and meta-analysis^[36]) noted some degree of promise, but limitations include study size^[34] and benefits may be limited to those with overt encephalopathy rather than those merely at risk thereof.^[36]

Hepatic Encephalopathy is a condition of the liver characterized by high ammonia concentrations in the blood and brain with cognitive side-effects. Ornithine supplementation may be able to reduce ammonia concentrations following oral ingestion in persons with encephalopathy associated with cirrhosis, but there is limited evidence using oral dosing (most studies conducted with intravenous ornithine in clinical settings)

Ornithine infusions (injections) have been noted to increase circulating growth hormone concentrations which is dependent on the hypothalamus.^[37]

2,200mg ornithine paired with 3,000mg arginine and 12mg B12 for 3 weeks has been noted to increase plasma growth hormone concentrations by 35.7% (measured immediately after exercise), an increase which attenuated an hour later but was still greater than placebo.^[38]

A study conducted in 12 bodybuilders who received an acute dose of 40, 100, or 170mg/kg Ornithine hydrochloride noted that only the highest dose (170mg/kg, or 12g for a 70kg man) was able to increase GH concentrations after 90 minutes to 318% above baseline with no significant effect at 45 minutes.^[15] Despite the percentage increase, the authors suggest it may not be overly relevant as the increase was from 2.2+/-1.4ng/mL to 9.2+/-3.0ng/mL^[15] while normal diurnal variations in growth hormone fluctuate between nondetectable and 16ng/mL.^[39]

Ornithine supplementation is able to cause an acute increase in growth hormone secretion following supplementation. However, due to the interactions between Arginine and growth hormone (specifically, the idea that an acute increase does not confer day-long benefit) applies to ornithine as well. These results may not be practically relevant

A combination supplement of Ornithine and Arginine has failed to significantly influence testosterone concentrations in resistance trained adults given 2,200mg Ornithine and 3,000mg Arginine for 3 weeks.^[38]

No known positive influences of ornithine supplementation on testosterone levels

There are various effects of ornithine on cortisol, with an intravenous infusion or ornithine being able to stimulate ACTH and subsequently cortisol^[37] yet another study using 400mg ornithine prior to alcohol consumption noting a relative decrease the next morning (thought to be secondary to accelerating alcohol metabolism).^[40]

Beyond that, one study using both L-Ornithine and L-Arginine (2,200mg and 3,000mg) for 3 weeks with exercise has failed to significantly influence cortisol.^[38]

Various different effects of ornithine on cortisol. An increase has been noted with infusions (somewhat tied into the growth hormone increase, so practical relevance of such an increase in not sure) while it can attenuate a hangover-induced rise in cortisol. In the most practical situation of just taking ornithine as a preworkout, it did not do anything

Ornithine is sometimes supplemented as L-Ornithine α-ketoglurate with the two molecules in a 1:2 stoichiometric ratio.^[41] These two molecules (Ornithine and α-ketoglutarate) are metabolically related, as ornithine can convert into α-ketoglurate via conversion into glutamate semi-aldehyde, glutamylphosphate, glutamate, and finally α-ketoglutarate;^[41] the pathway is fully reversible, and it is thought that providing supplemental α-ketoglurate alongside ornithine reduces the amount of flux from ornithine to α-ketoglurate and instead encourages production of other products of ornithine.^[41] This has been noted in a study using either Ornithine (6.4g as hydrochloride), α-ketoglurate (3.6g as calcium salt), or the combination with equal amounts (10g) where only combination therapy increased plasma levels of arginine and proline (all treatments increased glutamate).^[17]

The supplementation of ornithine alongside α-ketoglurate is able to suppress the conversion of ornithine into α-ketoglurate (normally occurs anyways) and indirectly promote conversion of ornithine into other metabolites such as arginine

α-ketoglurate may also be an intermediate in amino acid metabolism that combines with ammonia (under the influence of a reducing agent) to form glutamine, which is an ammonia buffering mechanisms independent of the urea cycle. The reducing agent was initially thought to be NADH^[42] or possibly formate (produced in the urea cycle)^[43]

α-ketoglurate may be the intermediate in glutamine metabolism that can buffer ammonia independently of the urea cycle via using ammonia to reform glutamine

The provision of Ornithine to a liver cell appears to be the rate-limiting step in urea syntesis and ammonia detoxification,^[5] and provision of both L-Arginine (218% at 0.36mM)^[44] and the isomer D-Arginine (204% at 1mM)^[45] are able to promote ornithine uptake into cells.

Supplemental arginine and/or citrulline (which provides arginine) also has the ability to reduce ammonia, secondary to increasing uptake of ornithine. That being said, it appears to be an inefficient workaround, and synergism between arginine and ornithine for ammonia detoxification has not yet been thoroughly investigated

L-Aspartate (not to be confused with D-aspartic acid) is commonly used alongside ornithing in the form of L-Ornithine L-aspartate for the purpose of treating hepatic encephalopathy.^[33][46][47] This is thought to be of use since treatment of hepatic encephalopathy requires ammonia detoxification and both ornithine and asparate are involved in the urea cycle (ornithine converts to citrulline to sequester ammonia via carbamoyl phosphate production, and then citrulline starts to be converted back into arginine only with L-asparate as a cofactor).

Due to the ability of ornithine to stimulate the urea cycle and accelerate ammonia excretion^[48][49] and alcohol consumption causing a quick rise in ammonia concentrations^[50][51] (and some evidence that there may be interactions with their metabolic pathways^[52]), it is thought that Ornithine may have a role in reducing symptoms of hangovers or drunkedness.

Ingestion of 400mg L-Ornithine a half hour before drinking alcohol (0.4g/kg 90 minutes before bed) was able improve some measurements taken the next morning (self-reported ratings of anger-hostility, confusion, sleep length, and fatgiue) and a reduction in cortisol in persons defined as 'flushers' (persons, usually asian, with a defect in the aldehyde dehydrogenase gene which metabolizes alcohol; 'flushers' are more sensitive to the effects of alcohol^[53]) but overall ethanol metabolism and the state of drunkedness were unaffected.^[40]

This study^[40] also makes note of a preliminary study (unable to be found online) where 800mg Ornithine L-Asparatate was effective on improving subjective parameters in flushers only, with those not classified as flushers not having any benefit.

Limited evidence, but it may be useful to alleviate the 'morning after' side effects in persons sensitive to alcohol. The preliminary evidence also suggests that this does not apply to those not characterized as 'flushers', so practical relevance of this information for frequent drinkers is not known

L-Ornithine α-ketoglutarate (specifically) is thought to be beneficial for burn healing since it is a precursor for both arginine and for glutamine^[54][17] (also proline,^[55] but this is usually not of concern), both of the former amino acids are known to be helpful as enteral additions during clinical settings (arginine^[56][57] and glutamine^[58][59] respectively).

Several studies have been conducted using L-Ornithine α-ketoglutarate intravenously where it has accelerated the rate of healing from burns.^{[60][61][55][62]}

L-Ornithine α-ketoglutarate appears to accelerate wound healing in clinical instances of burns, but the usage of L-Ornithine α-ketoglutarate as a general healing accelerator is not known (clinical studies may not necessarily apply to real world application of this supplement)

Ornithine shares the same intestinal transporters as L-Arginine supplementation, and due to that large boluses of ornithine may also cause diarrhea.^[14] As this is secondary to the transporter being saturated, the safe upper limit of intake (4-6g rarely causes side-effects) may apply to arginine, ornithine, and other amino acids that share the transporter (L-cysteine) collectively.

The diarrhea is due to these amino acids causing nitric oxide production in the colon, which stimulates water resorption in the colon and osmotic diarrhea.^[63] Elsewhere, intravenous or nasogastric infusions of ornithine at 20g or so have been noted to induce diarrhea.^[64][65]

High oral doses of ornithine can plausibly induce diarrhea, but there appears to be a larger safety buffer between the active dose and the diarrhetic dose with ornithine than there is with arginine (with citrulline being free of known intestinal side-effects)