LOLA (L-Ornithine L-Aspartate)

What LOLA is

LOLA is a salt of the amino acids L-ornithine and L-aspartate. After absorption it is rapidly split into its two components. In the liver’s urea cycle, ornithine serves as a starting substance and activator; aspartate supplies, among other things, building blocks for binding ammonia as glutamine.

In Germany, LOLA is approved under the name Hepa-Merz as granules and as an infusion solution concentrate, both pharmacy-only, not prescription-only. The drug data come almost exclusively from people with liver cirrhosis and cannot be transferred to healthy people.

How it works

According to the summary of product characteristics, ornithine aspartate acts via two key pathways of ammonia detoxification: urea synthesis in the liver cells around the portal vein and glutamine synthesis in the cells around the hepatic veins. In a diseased liver that no longer detoxifies ammonia sufficiently, this approach is plausible.

The same summary of product characteristics states that, under normal conditions, ornithine and aspartate are not the limiting factor for urea synthesis. So a healthy liver usually does not lack the raw material, and the promise of a “liver detox” for healthy people has no study basis.

What the studies show

Cochrane review 2018: benefit possible, but very uncertain

Goh 2018 analyzed the randomized trials on LOLA in liver cirrhosis. Calculated across all trials, encephalopathy and mortality decreased. In the few trials with low risk of bias, the effect disappeared: for mortality RR 0.47 with a confidence interval of 0.06 to 3.58 (4 trials), for encephalopathy RR 0.96 (1 trial with 63 participants). Compared with lactulose and rifaximin, the standard drugs, no difference was found. Ten completed trials were unpublished.

Infusion and granules versus placebo

Kircheis 1997 gave 126 patients with cirrhosis, elevated ammonia and chronic encephalopathy infusions with 20 g LOLA or placebo for 7 days. Ammonia after a protein meal, the number connection test and mental state improved more under LOLA. Stauch 1998 found similar results with 18 g granules per day over 14 days in 66 patients, with no side effects in either group.

Severe encephalopathy: in addition to standard therapy

Jain 2022 treated 140 patients with grade III to IV encephalopathy with lactulose and rifaximin, plus LOLA infusions or placebo. Under LOLA, the grade improved more often (92.5 versus 66 percent), and after 28 days fewer patients had died (16.4 versus 41.8 percent). It is a single study; confirmation is pending.

Acute liver failure: no benefit

Acharya 2009 randomized 201 patients with acute liver failure to 3 days of LOLA infusions or placebo. Ammonia did not differ between the groups at any time point, and mortality was 42.4 percent under LOLA versus 33.3 percent under placebo, a non-significant difference.

Where the data stop

• The methodologically best trials. There, the benefit in cirrhosis could not be demonstrated, and the Cochrane authors say they are “very uncertain”.
• Healthy people and athletes. There is only one small study with 11 endurance athletes who received LOLA together with branched-chain amino acids; ammonia at the end of the prolonged exercise was even higher than under placebo, but fell faster afterwards (Mikulski 2015).
• Liver detox, hangover aid, fatty liver. For these promises outside cirrhosis, the sources analyzed here contain no controlled evidence.
• Acute liver failure. Here LOLA did not help in a large trial (Acharya 2009).

Status, approval and legal

In Germany, L-ornithine L-aspartate is approved as Hepa-Merz Granulat 3000 and as Hepa-Merz infusion solution concentrate, both pharmacy-only, not prescription-only. The indication is latent and manifest hepatic encephalopathy. For the granules, the approved intake is up to 1 to 2 sachets of 3.0 g ornithine aspartate 3 times daily; for the concentrate, up to 4 ampoules daily. Whether LOLA may additionally be marketed as a food supplement has not been officially clarified: no general ruling (Allgemeinverfügung) by the BVL for this is known, and the substance is the active ingredient of an approved medicine. For pure L-ornithine as a food supplement, such a general ruling exists, see L-ornithine. Food supplements are not permitted to advertise the treatment of liver diseases. Ornithine and aspartate are not on the World Anti-Doping Agency’s prohibited list.

Safety

The summary of product characteristics lists occasional nausea, vomiting, stomach pain, flatulence and diarrhea, and very rarely pain in the limbs; these complaints are usually transient. LOLA is contraindicated in more severe kidney dysfunction; a serum creatinine above 3 mg/100 ml serves as a guide value. It should be avoided during pregnancy and breastfeeding; there are no data for children. The granules contain fructose and the colorant sunset yellow (Gelborange S), which can trigger allergic reactions. Interactions are not known so far, but have not been systematically studied either. Anyone with a liver or kidney disease belongs in medical care with LOLA, not in self-treatment. This text is information and does not replace medical advice.

Sources

• Goh ET et al., Cochrane Database Syst Rev 2018 – L-ornithine L-aspartate in hepatic encephalopathy (PMID 29762873)
• Kircheis G et al., Hepatology 1997 – LOLA infusions versus placebo, 126 patients with cirrhosis (PMID 9185752)
• Stauch S et al., J Hepatol 1998 – oral LOLA versus placebo, 66 patients (PMID 9625322)
• Jain A et al., Hepatology 2022 – LOLA in severe encephalopathy, 140 patients (PMID 34822189)
• Acharya SK et al., Gastroenterology 2009 – LOLA in acute liver failure, 201 patients (PMID 19505424)
• Mikulski T et al., Folia Neuropathol 2015 – branched-chain amino acids and ornithine aspartate in endurance exercise (PMID 26785372)
• Summary of product characteristics (Fachinformation) Hepa-Merz Granulat 3000
• Summary of product characteristics (Fachinformation) Hepa-Merz infusion solution concentrate