Lorenzo’s oil

Gerald Raymond, M.D., Marc Engelen M.D., Ph.D. and Stephan Kemp Ph.D.

VLCFA restricted diet

The biochemical abnormality of ALD was first recognized in 1976 (Igarashi et al. 1976). Affected individuals had elevated levels of saturated very long-chain fatty acids (VLCFA). The demonstration of this abnormality and the realization that a part of these fatty acids were of dietary origin led to early attempts to reduce blood VLCFA levels by dietary modification. This diet was very restrictive in its choices of foods, since VLCFA are present in many plant and animal products. Unfortunately, dietary restriction of C26:O fatty acid intake failed to reduce plasma VLCFA levels in patients with ALD (Brown et al. 1982).

Figure 1: Addition of the monounsaturated fatty acids C18:1 and C22:1 to ALD cells reduces the synthesis of C26:0 because the enzymes responsible for synthesis (elongases) have a higher affinity for monounsaturated fatty acids.

Inhibition of VLCFA synthesis

This lack of dietary effect led to the realization that there must also be a significant production of VLCFA in the body. In fact, the majority of VLCFA are produced from long-chain fatty acids (Tsuji et al. 1981)(see Origin and Metabolism of VLCFA for more information). There have been a number of attempts to interfere with the elongation of long-chain fatty acids. The early focus was on the use of monounsaturated long-chain fatty acids. These monounsaturated long-chain fatty acids are slightly different from the saturated long-chain fatty acids because they have a single double bond in the fat chain. It was predicted that the monounsaturated fatty acids would compete with the enzymes responsible for the elongation of very long-chain fatty acids (elongases) and that their affinity for monounsaturated fatty acids would be higher than for saturated fatty acids. This would reduce the production of saturated VLCFA (Figure 1). Indeed, the addition of monounsaturated fatty acids, especially oleic acid (C18:1), to the tissue culture medium of cultured skin fibroblasts from ALD patients decreased the synthesis of C26:0 by 60% (Rizzo et al. 1984).

Lorenzo’s oil

The introduction of oleic acid (C18:1) followed by erucic acid (C22:1) in combination with a moderately low-fat diet resulted in a reduction of plasma VLCFA levels in 6-8 weeks in patients with ALD (Moser et al. 1987; Rizzo et al. 1989) (Figure 2). This oil, which is a 4:1 mixture of glyceryl trioleate (GTO) and glyceryl trierucate (GTE), has been named Lorenzo’s oil. Lorenzo’s oil is taken orally and is generally well tolerated, although moderate platelet reduction and elevation of liver transaminases have been observed.

From the first studies investigating the role of this mixture in ALD, it was very apparent that it did not alter the progression of the brain disease in affected individuals. This experience has been demonstrated repeatedly. Lorenzo’s oil does not alter the course of childhood or adult cerebral ALD and is never indicated in the cerebral form of the disease. In addition, it has never been studied in preparation for bone marrow transplantation or in the period following such treatment.

Early studies in the adult form of ALD, adrenomyeloneuropathy (AMN), used the treatment in small populations with variable presentations for short periods of time without definitive effect. These very limited clinical trials led to widespread statements of lack of effect and concerns that the compounds were not getting into the brain. In fact, while Lorenzo’s oil lowered levels of C26:0 in plasma and adipose tissue, it failed to alter levels of C26:0 in the brain (Rasmussen et al 1994). The authors concluded: “failure of erucic acid to enter the brain in significant quantity may be a factor in the disappointing results of dietary therapy for ALD”. This may be explained by another study that provided experimental evidence that erucic acid does enter the brain, but is rapidly metabolized (Golovko and Murphy 2006).

In the 1990s, several groups independently began investigating the use of Lorenzo’s oil as a preventive therapy – an agent that would either prevent brain disease in at-risk but unaffected boys or slow the progression in men with AMN. Two studies (Aubourg et al. 1993; Van Geel et al. 1999) showed that Lorenzo’s oil did not alter disease progression in men with AMN. In addition, a few men with AMN developed cerebral involvement despite use of the oil. All of these studies were open-label (Lorenzo’s oil was not tested against a placebo) and thus somewhat limited in their ability to be definitive.

In an effort to provide definitive answers regarding clinical efficacy as a disease-modifying agent in AMN, a Phase III trial of Lorenzo’s oil in AMN was initiated at the Kennedy Krieger Institute in 2007. The 4-year study would include 120 men with AMN without evidence of cerebral involvement and 120 women with ALD with myelopathy. The rate of progression was to be compared in the Lorenzo’s oil and placebo groups using the Kurtzke EDSS score as the primary outcome and a variety of secondary outcomes. Unfortunately, the study was stopped before completion by the Safety Monitoring Board due to suspected side effects of the placebo treatment. Therefore, there is no scientific evidence that Lorenzo’s oil has a disease-modifying effect in AMN.

For cerebral ALD, Moser and colleagues (Moser et al. 2005) reported the experience of a large group of boys who had normal MRI at baseline. In this group, VLCFA were lowered by therapy, and an association was demonstrated between a reduction in the risk of developing cerebral disease and a reduction of VLCFA. However, this study has several limitations, such as the use of historical controls instead of a placebo group, and does not provide definitive evidence of the efficacy of Lorenzo’s oil in preventing the onset of cerebral ALD in boys with ALD. Based on the results of this study, Lorenzo’s oil is therefore offered to boys with ALD in some countries with the aim of reducing the risk of developing cerebral ALD . It should be noted that the use of Lorenzo’s oil is not without side effects and has a significant impact on quality of life.

We recommend that the use of Lorenzo’s oil should only be undertaken by centers that have the ability to provide monitoring with MRI, nutritional guidance, and the ability to measure VLCFA and other essential fatty acids. Other centers consider the efficacy of Lorenzo’s oil unproven and do not recommend its use.

Lorenzo’s oil should never be taken without medical supervision. Although no serious adverse reactions have been observed in the controlled use of the oil and diet, individuals on Lorenzo’s oil must be periodically evaluated for safety. Finally, it must be emphasized that Lorenzo’s oil is indicated only for the biochemical defect of ALD and does not have any role in other demyelinating or progressive neurological conditions, since these individuals have the ability to metabolize very long-chain fatty acids.

Last modified | 2024-06-24