A randomized controlled double-blind clinical trial comparing versus placebo the effect of an edible algal extract (Ulva Lactuca) on the component of depression in healthy volunteers with anhedonia

Anhedonia, defined as a loss of sensitivity when it comes to feeling pleasure, is observed in various personality disorders but also commonly and to a lesser extent in healthy subjects for whom it is a personality trait [1‐7]. It may be attributable to a minor disturbance of the mesocorticolimbic reward system involving serotoininergic and dopaminergic mediators [8‐10] that are expressed as ill-being by contrast with the term well-being and characterized notably by a decline in morale with a component of depression. Anhedonia is an isolated symptom and not a psychopathological state unlike depression of which it may a component but which requires the association of numerous other components to meet the DSM V (Diagnostic and statistical Manual of Mental Disorders) definition.

Faced with this symptom, psychotropic substances and especially antidepressants have been and still are used too often in particular because of the danger of addiction and dependence that continued intake may entail [3]. Faced with overconsumption, especially in France, and the need to reduce it (Government scheme for combatting drugs and addictive conduct 2013–2017. La documentation Française) many studies have been directed at research into nutriments or plant extracts that might have a similar action to antidepressants, acting on the same physiological mechanisms, but without inducing pharmacological dependence. They would supposedly provide a solution to the ill-being felt by people experiencing low morale with a component of depression but with no major depressive episode (MDE) as per the DSM V [11], which covers a very large proportion of people to whom antidepressants are still prescribed for want of a satisfactory scientifically-proven alternative.

The seaweed extract tested in this study and developed by OLMIX SA is part of this search for a non-medicinal alternative to combat low morale and its component of depression. Research has isolated a concentrated lyophilized and ground fraction of a water-soluble extract of an edible alga [12] named Ulva lactuca Linnaeus and more commonly known as sea lettuce. The extract obtained is rich in oligo-elements (up to 50%) and proteins (10–20%). A pre-clinical study has evaluated the antidepressant effect of the algal extract administered orally as a preventive treatment in three doses (10, 20 and 40 mg/kg/day) in Wistar adult male rats [13]. The effects of the seaweed extract were evaluated on the animal model equivalent of depression compared with a control group treated with the carrier (spring water) and a reference group treated with Imipramine in doses of 10 mg/kg/day. After 15 days of intake of the study products, the results show superior and comparable effects of Imipramine and seaweed extract at 20 and 40 mg/kg/day compared with the control. Moreover, a dose-dependent effect was observed in animals treated with the extract at doses of 10, 20 and 40 mg/kg/day [13]. To confirm in humans the potential efficacy of the product identified in animals, we conducted a randomized controlled double-blind clinical trial on the component of depression in healthy volunteers with anhedonia.

The major finding of this double-blind randomized control trial is to show the positive effect of the seaweed extract on the component of depression of anhedonic patients measured by the QIDS-SR benchmark despite a substantial placebo effect in the control group. By D84, the total QIDS-SR score. Significantly decreased more in the Ulva.L.L. group than in the placebo group (p: 0.0389). This difference is essentially linked to an improvement of the sleep disorders (p: 0.0219), of the psychomotor consequences (p: 0.002) and of the nutrition behaviour (p: 0.0694).. Some 90.1% of subjects said they felt an improvement with Ulva L.L. versus 72.5% in the placebo group (p: 0.0114) and similarly 90.9% of doctors judged the subjects to have improved versus 70.8% (p: 0.021). It should be pointed out that this effect shows up despite a substantial placebo effect that continued practically until D28 and then declined whereas the depressive symptoms continued to improve in subjects taking the water-soluble extract of Ulva L.L. This gradual improvement perceived by subjects and physicians is consistent with the gradual effect observed in the change in the QIDS-SR total depressive symptom inventory score and three of its subsections. The results attest to the effect of a dietary supplement that requires a relatively long intake period to produce a gradual physiologically significant change and of a placebo whose effect gradually declines with time. The size of the effect is also worth pointing out. In a phase II a trial on the efficacy of a combination of dextromethorphane and quinidine (Q), the observed improvement was − 5.9 ± 6.6 [23] and in a trial comparing Quetiapine against a placebo the difference in the QIDS-SR effect was 3.7 [24].

This effect on the component of depression of anhedonia thus seems to be clearly demonstrated and corroborates the results of the preclinical study evaluating the antidepressant effect of the seaweed extracts administered orally in adult male Wistar rats [13]. That study compared the seaweed extract at doses of 10, 20 and 40 mg/kg/day on groups of 12 rats against a control batch treated with the carrier (springwater) and a reference batch treated with Imipramine at doses of 10 mg/kg/day. The primary objective was to determine the efficacy of the extract on depression after 15 days of treatment on the principle of the Behavioural Despair Test (BDT) that is the benchmark for screening substances with an antidepressent effect. The results showed animals treated with Imiparmine and seaweed extract were less resigned than those treated with the placebo. A dose-dependent effect was observed for the seaweed extract.

Tolerance of the seaweed extracts was good and comparable with that of the placebo. This supports two toxicity studies conducted before the clinical trial: evaluation of acute toxicity and evaluation of sub-chronic toxicity by ingestion [25, 26]. Acute toxicity of the seaweed extract taken orally was evaluated with a single limit dose of 2000 mg/kg in 12 male and female Wistar rats monitored for 15 days. Two experimental series of six rats were studied. No mortality was observed and no abnormal behaviour was observed in the two-experimental series for male and female rats before and 1, 2, 3, 4, 5 and 6 h after administration of the single oral dose until completion of the experiment. No direct or induced significant weight loss was observed [25]. No anomaly of any organ was observed at autopsy. Subchronic toxicity of the seaweed extract was evaluated by oral administration at doses of 250, 500 and 1000 mg/kg/day for 28 days in male and female Wistar rats. No mortality, no abnormal behaviour, no body weight loss, no change in body weight change, no difference in food and water consumption, no opthalmological anomaly, no difference in functional tests and no histopathological anomaly was observed after 28 days of treatment. This good tolerance is an important factor for this product that could be an alternative to benzodiazepines for light to moderate depressive symptoms or at least as first-line treatment so they could be reserved for more severe situations. Further clinical studies must be conducted to confirm this since the registration of products whether as dietary supplements (health claims) or medication (marketing authorization) require at least two convergent clinical trials.

A review of the litterature does not retrieve some similar studies using alga extract. However, it is noticeable that the research of alternative natural products to the benzodiazepines is a growing research way which corresponds to a real patients’ and societal need and that clearly appear in the increasing number of published papers presenting good quality randomised clinical trials on that subject in the reference data bases like Pubmed. Among these research, can be mentioned the works of Mosaffa-Jahromi M [27] on the effectiveness of anise oil for Treatment of Mild to Moderate Depression in Patients With Irritable Bowel Syndrome, of Pasalar M [28] on the efficacy of jollab in the treatment of depression in dyspeptic patients, of Anushiravani M [29] comparing the effectiveness of a combined herbal drug based on Echium amoenum with Citalopram in the treatment of Major Depressive Disorder or those of Lopresti AL [30] on a standardised extract from saffron (Crocus sativus L.) for the treatment of youth anxiety and depressive symptoms. Unfortunately all these works do not use the same criteria that we used to evaluate the effect on depression and do not target the same profile of depressive patients which do not allow real efficacy comparison.

The status of the product is another point of discussion. As this pivotal study has demonstrated the action of Ulva L.L. extracts on depressive symptoms in humans, it now remains to be seen whether to continue with it as a dietary supplement with the difficulty of this positioning for depression or to shift towards a plant-based medicinal status for which the product has potential. Identifying the substance contained in the seawaeed extract and the source of the effect would be an added benefit whether for the dietary supplement case or the plant-based medication case, but is not a mandatory requirement.

This double-blind randomized placebo-controlled trial shows that daily intake for 3 months of a water-soluble extract of Ulva L.L. continues to significantly improve the component of depression of subjects presenting anhedonia compared with a placebo. This opens up perspectives for its potential use in everyday clinical care particularly as it would avoid the undesirable effects of medicinal drugs currently used. It is worth underscoring that this effect is shown despite a substantial placebo effect that persisted up to D28 and then diminished whereas the depressive symptoms continued to improve in subjects taking the water-soluble Ulva L.L. extract.