Six volunteers were taken to hospital last week after taking part in the Phase I trial of the new medication, Health Minister Marisol Touraine revealed Friday.
She said the men, aged between 28 and 49, were part of a group of around 90 people who had taken the drug, while about 30 others had received a placebo.
The volunteers were given varying doses but the six men were in the group who were taking the drug "regularly".
"This is unprecedented" in France, said the health minister, vowing to "shed light" on who was responsible.
"The shock is even greater given the fact that the people taking part in clinical trials are healthy."
Pierre-Gilles Edan, head of the neurology department at the hospital in Rennes where the volunteers were taken, said that, aside from the man who was clinically dead, three others were suffering a "handicap that could be irreversible" and another also had neurological problems.
The sixth volunteer had no symptoms but was being monitored.
Touraine said the drug acted on natural receptors found in the body known as endocannibinoids which regulate mood and appetite but did not contain the compound found in the cannabis plant.
The drug molecule had previously been tested on chimpanzees, she said.
Phase I is when a drug is tested on humans for the first time, after likely tests on animals and in the laboratory to ensure its safety.
France's national drug safety body (ANSM) confirmed it was the worst-ever incident to have taken place in a drug trial in the country.
The trial, which began in July 2015, was being conducted by the privatelyowned Biotrial company on behalf of Portuguese drugmaker Bial. Biotrial has its French headquarters in Rennes.
In a statement, the Portuguese firm Bial insisted it had followed "international best practice" in developing the drug and said it would cooperate with the investigation to "determine in a rigorous and exhaustive manner" what had happened.