In an interview published on 18 April 2021, French President Emmanuel Macron called for "a major national debate on drug use". The interview focused on the repressive aspect of anti-drug policy and the effectiveness of the measures envisaged was immediately the subject of controversy.

Edouard TUAILLON, University of Montpellier

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However, a consensus should emerge from the debate on the recognition of addictions as a major public health risk.

The use of amphetamines (stimulant psychotropic drugs), which has been documented for more than a century, should not be excluded from this awareness. Indeed, theemergence of new forms of drug addiction associated with amphetamines of the cathinone family is now a worrying phenomenon in France.

Brief (medical) history of synthetic amphetamines

The first chemical purification of an amphetamine (ephedrine) is attributed to Nagai Nagayoshi, a Japanese pharmacist, and dates from 1885. The synthesis of ecstasy (or MDMA, for 3,4-methylenedioxy-N-methylamphetamine) by Merck laboratories dates back to 1912, and the first synthesis of a cathinone (β-ketoamphetamine) to 1929.

In the first half of the 20th century, the effects of these synthetic molecules captivated chemists and aroused the interest of the medical world.

Their sympathomimetic (stimulant), anorectic (appetite suppressant) and psychostimulant (doping ) activities led to the marketing of the first amphetamine-based drugs: a bronchodilator with Benzedrine® in 1934 in the United States (an amphetamine sulphate), an appetite suppressant with Obetrol® from the 1950s also in the United States (a combination of amphetamine salts), and an energiser with Pervitin® (a methamphetamine) in Germany in the late 1930s.

A powerful methamphetamine, it was available in pharmacies without a prescription and widely distributed to German troops during the Second World War. Thanks to its long-lasting doping effect, it played a decisive role at the beginning of the conflict in the success of theblitzkrieg strategy, by allowing soldiers to march and fight without sleeping for several days.

The medical use of amphetamine derivatives continued after the war. At the end of the 20th century, psychostimulants were prescribed to combat attention deficits, such as Ordinator® (which ceased to be marketed in 1997), and appetite suppressants such as Isomeride® and Mediator® (prescribed for metabolic disorders, in particular diabetes). They were withdrawn from the market in 1997 and 2009, respectively, due to serious adverse effects leading to several convictions of Laboratoires Servier.

Today, the following drugs are still available but with significant restrictions on prescribing: Zyban® , as an aid to smoking cessation, and Ritalin® for attention deficit disorders in children and narcolepsy in adults. The latter speciality, whose medical service has been confirmed by the French National Authority for Health, is probably the one that has been the most useful in medical terms to date.

From natural role to first consumption

The use of amphetamines does not date from their discovery by synthetic chemistry. These compounds existnaturally in certain plants. They constitute defence molecules against herbivores, like other plant alkaloids.

Thus, ephedrine was purified from a plant used in Chinese pharmacopoeia - Ephedra sinica. But the best known and most important plant in societal and economic terms is the Latin name khat, whose freshly harvested leaves contain ephedrine. Catha edulisThe freshly harvested leaves contain β-ketoamphetamine or cathinone (which degrades rapidly after harvesting).

Khat is thought to have originated in Ethiopia, where it grows wild in temperate areas above 1500 metres with good rainfall. These cultivation requirements, which are similar to those of Arabica coffee, have allowed khat cultivation to spread to certain areas of the Arabian Peninsula, East Africa and Madagascar.

Khat consumption may predate the year 1000, although it seems to have intensified from the 15th century onwards. In Yemen, where about 60% of the population consumes khat (30% in Ethiopia and Somalia), its cultivation accounts for nearly 6% of the gross domestic product and mobilises 14% of the working population.

Seized khat branches
Khat leaves must be consumed in large quantities and quickly, as the cathinone they contain degrades quickly. This makes it difficult to use.
DEA

For the consumer, access to the psychotropic effects of cathinones is not easy. One must first obtain freshly cut twigs and then chew the bitter leaves for a long time to extract the active principle. A bunch of 500 grams of twigs, i.e. about 150 g of leaves, requires two hours of chewing.

Consuming khat in the traditional way therefore requires time, but also money - at the expense of health or children's education.

From ecstasy to synthetic cathinones

Compared to khat, synthetic amphetamines offer a tenfold increase in psychotropic effects, while being easier to produce, transport, store and consume.

In France, amphetamines have been classified as narcotics since 1967. The development of their use as drugs from the 1990s onwards is associated with the advent of electronic music and raves: ecstasy (MDMA) is then used as a party drug, for its doping effect and to facilitate human contact.

The turn of the millennium was marked by the emergence of the synthetic drug market on the Internet - or new synthetic products (NPS). These include variations of various psychotropic drugs, mainly cannabinoids, opioid amphetamines, ketamines and, from the 2010s onwards, synthetic cathinones - the body-built cousins of the khat alkaloid.

With them, amphetamines will move from the occasional and marginal use of a small number of experimenters to a large, socially well-integrated and regular user population.

A drug that activates the reward system

To understand the current dangerous success of cathinones, we need to look at the way amphetamines act on our brains.

The structure of cathinones is similar to that of dopamine, a neurotransmitter that plays a major role in the reward circuit. The reinforcement/reward system is present in many animals (fish, birds, mammals) where it promotes behaviours that are essential for the perpetuation of the species: eating, learning, reproduction, social relations. Cathinones act directly on this system.

After ingestion, inhalation or injection, the small cathinones easily pass the blood-brain barrier that protects the brain. They then interact with the dopamine neurons, preventing its reuptake and promoting its release. Through these mechanisms, cathinones induce a considerable increase in dopamine. In rats, 40 minutes after the administration of a standard dose of cathinone, the increase in dopamine levels is of the order of 500%.

Diagram describing the mode of action of cathinones
Cathinones influence the reward system by interacting with dopamine neurons, a neurotransmitter involved in the sensation of pleasure.
E. Tuaillon, Provided by the author

This influx of dopamine will activate the circuits of the reward system. It is these stimulating and entactogenic effects (altering the desire for physical contact) that users will seek in particular for sexual purposes.

In the absence of further use, dopamine levels drop rapidly and return to normal after about 180 minutes. A brief withdrawal syndrome (descent) is frequently reported by users 24-48 hours after taking the drug, characterised by fatigue and a general negative feeling (dysphoria).

The use of amphetamines in the 20th century was thus marked not only by easier access, thanks to chemical synthesis, but also by the temptation to improve one's physiological capacities - often in a festive context.

In this age of augmented reality and instant gratification, cathinones have become the bearers of a deceptive promise to easily satisfy our desires...The Conversation

Edouard TUAILLON, University Professor and Hospital Practitioner. Areas of expertise: infectious diseases, virology, sexual health, University of Montpellier

This article is republished from The Conversation under a Creative Commons license. Read theoriginal article.