Pier-Vincenzo Piazza floats in his fitted blue tuxedo. He provokes, even boasts, proud as he is. That day, in front of the hundred scientists and decision-makers observing him at the Ministry of Health, the researcher, a self-proclaimed iconoclast, had fun presenting the culmination of his years of research on drugs. “This is sick work,” he says from the top of his platform, pointing to one of his articles.
Accustomed to more reserve, the audience applauded, all smiles. Those who know Pier-Vincenzo Piazza know that he is not exactly daring. In thirty years of career, this luminary of addictology and neurology, author of numerous reference studies, has risen to the top of his discipline. This clever cocktail of imprudence and work means that we are fighting for it, from conference to conference, like at the beginning of June at the Ministry of Health, for the National Day of Translational Research on Addictions.
Coming down from his desk, the guest of honor nevertheless warns, worried about doing too much: “I’m joking, but don’t make a joke out of me.” In the eyes of his peers, the precaution seems unnecessary. The seriousness of the researcher, who discovered several molecular mechanisms linked to addiction, no longer needs to be proven. Impossible to talk about drug addiction without mentioning it. “He did a remarkable job,” summarizes Nicolas Ramoz, neuropsychiatrist at Paris Cité University. So much so that in 2015, Inserm and the Academy of Sciences, two of the highest scientific institutions in the country, each honored him with a prize.
The start of a revolution
Nothing, compared to what awaits him if the “sick” work he praises to the ministry succeeds. Published in the scientific journal nature medicine Last year, his latest work aroused much anticipation in scientific circles. He presents the effects of AEF0117, a molecule of his own, which he is testing in humans in a phase II trial. A potential first treatment for cannabis dependence. And, perhaps, the start of a revolution.
The AEF0117 still needs to pass a whole series of checks. Pier-Vincenzo Piazza says it himself, suddenly stepping out of his somewhat whimsical character to take on the hat of the authoritative clinician: “Failure can still happen.” But the first results displayed behind him at each of his conferences are remarkable: once the molecule has been ingested, the volunteers gradually reduce their cannabis consumption. Without reporting any significant toxicity.
No laboratory in the world has achieved such a feat. All previously tested molecules have been abandoned. They completely blocked THC receptors, one of the active ingredients in cannabis. Which caused forced withdrawal. Consumers ultimately increased their consumption to avoid getting sick, and to compensate for the reduced effects. These dams prevented the activity of a whole bunch of neurotransmitters, chemical signals such as endocannabinoids produced naturally by the body. Such obstruction made them difficult to bear.
A radically different approach
With AEF0117, no such withdrawal symptoms are triggered. And volunteers who took it during clinical trials but who did not smoke did not feel anything. No effect, positive or negative. And for good reason: “The molecule only acts in the presence of THC. Without it, the targeted mechanisms remain dormant, not very active.” Cannabis users reported fewer memory problems, social difficulties or paranoia, a sign that the body had countered THC.
Pier-Vincenzo Piazza’s approach is radically different from what has been done until now. Its molecule copies the natural self-regulation mechanisms of neurons. In the presence of a specific hormone, these cells can modulate their action and thus avoid becoming disrupted, or even suffering damage linked to a form of “overactivation” generated by THC. “We do not prevent all the actions of the drug, but we increase the body’s resilience to its effects,” summarizes the person concerned.
Completely new, the method could inspire other therapies. And ultimately advance the treatment of addiction, which is still very poor. Today’s medicine has many substitutes that replace nicotine and opioids. But they serve to compensate for the lack, and none can directly combat addiction.
“Extraordinarily inventive”
“I have never met a more creative person. He has only pushed the boundaries of addiction,” says Margaret Haney, a biologist at Columbia University in the United States. The two scientists have known each other since the 1990s, when Pier-Vincenzo Piazza, a naturalized Italian of Sicilian origin, arrived in France with a medical degree in hand. The boy he was? “Extremely cultured, with extraordinary energy and inventiveness,” recalls Michel Le Moal, his mentor at the time, a great specialist in dopamine, one of the molecules involved in addiction.
At the time, the young doctor had sent him around ten letters to convince him to choose him in his unit at the Bordeaux hospital. Brazen, already: “He has a voice. And when he decides something, it’s hard to resist him.” Passionate about philosophy and chemistry, he dreamed of explaining the mind through biology. His obstinacy, coupled with great independence of mind, earned him his first discovery in 1989. “No one wanted my intuitions. So I waited for the holidays to carry out my experiments on my own,” says the specialist. Its results are printed in Science. Already a great review.
It is thanks to his experiences, among others, that we know that there are biological weaknesses leading to addiction. With the same quantity of drug, some mice are able to spontaneously restrain themselves. Others, around 20%, return without limit. These differences can be explained by genes, but also by life experiences, such as repeated exposure to stress. “This observation marks a turning point in my career, it changed the way I see things,” he recalls. Where many have chosen to study addictsthis inveterate antidogmatist then convinces himself that the solution lies with those who resist.
Be interested in those who don’t get addicted
It will take him more than a decade to prove that his intuition is correct, that it is possible to exploit what makes some people resist the call of drugs. And another ten years before finding the right substances, among a large number of potential formulas. Initially focused on cocaine, he gradually turned away from it. “The body’s self-regulatory mechanisms were much more intense on cannabis, so we thought there was more room to exploit them,” he explains.
He sees AEF0117 as the advent of a new class of medicine. And hopes to find, tomorrow, ways of action against other drugs and other brain diseases. He protests when people say that cannabis is the mildest of them: “You become addicted a little less often. But then, it’s anything but mild.” It is the only substance, with alcohol, to cause brain damage visible on imaging and profound cognitive deficits, comparable to Down syndrome. And contrary to popular belief, sudden cessation causes d significant physical repercussions, from insomnia to eating disorders: “It’s not just psychological”
The French authorities turned their backs on it for a long time, convinced that cannabis addiction did not really exist. It was in the United States that he found his first funding, to embark on the process of developing his discoveries, with the company he created, Aelis Farma. These same Americans tried for a long time to recruit him when he was still in public research. Without success: “At the time, France had the best infrastructure and the best research funding system. And now, I love my adopted country too much to leave it.” To the point of saying good things about French coffee.
A gigantic market
From now on, its progress is closely followed. There is no question of seeing a potential pharmaceutical flagship leave the France ship. It must be said that the market is colossal. In the United States alone, 19 million people are diagnosed with cannabis addiction. Each year, healthcare services record 250,000 substance-related psychoses. So in December 2023, when it inaugurated its new premises in Bordeaux, Alain Rousset, president of the regional council – one of the main supporters – came in person.
In parallel with this research, Pier-Vincenzo Piazza sometimes intervenes in high schools. Instead of telling young people not to take drugs, he explains to them that some of them will become seriously ill: “Put like that, smoking seems much less subversive.” He is surprised that in France, anti-drug policies are based so much on repression, that they are so out of step with science. And as Sicilian as he is, he loathes the influence of the Church on the subject, largely responsible for making consumers feel guilty, “sinners” who should be punished.
Pier-Vincenzo Piazza would like us to follow consumers, to “detect” addiction before it takes hold. “At present, we are trying to prevent people from taking drugs, while no society has ever achieved such a feat. And we only take care of the most addicted. To treat cancer, we cannot Don’t wait for metastases.” To hear him, one would almost believe that the big name of addiction is in favor of legalization. He won’t say a word about it, the subject is too controversial. There are sometimes, however, limits that should not be exceeded.
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