How synthetic amphetamines made their mark

In an interview published on April 18, 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

© Couperfield- stock.adobe.com

Yet 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), documented for over a century, should not be excluded from this new awareness. Indeed, theemergence of new forms of addiction associated with amphetamines of the cathinone family is now a worrying phenomenon in France.

A brief (medical) history of synthetic amphetamines

The first chemical purification of an amphetamine (ephedrine) is attributed to Nagai Nagayoshi, a Japanese pharmacist, and dates back to 1885. The synthesis of ecstasy (or MDMA, for 3,4-methylenedioxy-N-methylamphetamine) by the Merck laboratories dates back to 1912, and the first synthesis of a cathinone (β-keto-amphetamine) 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 USA (an amphetamine sulfate), an appetite suppressant with Obetrol® from the 1950s, also in the USA (a combination of amphetamine salts), and an energizer with Pervitin® (a methamphetamine) in Germany in the late 1930s.

A powerful methamphetamine, this molecule was sold over the counter in pharmacies 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 start of the conflict in the success of theblitzkrieg strategy, enabling 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 such as Ordinator® (discontinued in 1997) were prescribed to combat attention deficit disorders, as were appetite suppressants such as Isoméride® and Mediator® (prescribed for metabolic disorders, particularly 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 They were withdrawn from the market in 1997 and 2009, respectively, due to serious adverse effects, leading to several convictions of Laboratoires Servier.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, albeit with significant restrictions on prescribing: Zyban®, as a smoking cessation aid, and Ritalin® for attention deficit disorders in children and narcolepsy in adults. Ritalin®, whose medical service has been confirmed by the French National Authority for Health, is probably the most medically useful product to date.

From natural role to first consumption

The use of amphetamines does not date back to their discovery by synthetic chemistry. These compounds occurnaturally in certain plants. Like other plant alkaloids, they constitute defense molecules against herbivores.

Ephedrine has been purified from a plant used in Chinese pharmacopoeia. Ephedra sinica. But the best-known and most socially and economically important plant is khat, from its Latin name Catha eduliswhose freshly harvested leaves contain β-keto-amphetamine or cathinone (which degrades rapidly after harvesting).

Khat is thought to have originated in Ethiopia, where it grows wild in temperate zones at altitudes of over 1,500 metres, benefiting from good rainfall. These cultivation requirements, similar to those of Arabica coffee, have enabled 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 around 60% of the population consumes khat (30% in Ethiopia and Somalia), its cultivation accounts for almost 6% of gross domestic product and mobilizes 14% of the working population.

Seized khat branches
Khat leaves need to be consumed quickly and in large quantities, as the cathinone they contain degrades quickly. This complicates their use.
DEA

For the consumer, access to the psychotropic effects of cathinones is not easy. The first step is to obtain freshly cut twigs, then chew the bitter leaves for a long time to extract the active ingredient. A 500-gram bundle of twigs, i.e. around 150 g of leaves, requires two hours of chewing.

Consuming khat in the traditional way therefore requires time, but also money - to the detriment of children's health and education.

From ecstasy to synthetic cathinones

Compared with khat, synthetic amphetamines offer tenfold psychotropic effects, while being simpler 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 rave parties: ecstasy (MDMA) is used as a party drug, for its doping effect and to facilitate human contact.

The turn of the 2000s saw the emergence of the Internet synthetic drug market - or New Synthetic Products (NPS). These include variations on various psychotropic drugs, mainly cannabinoids, opioid amphetamines, ketamines and, from the 2010s onwards, synthetic cathinones - bodybuilt cousins of the khat alkaloid.

With them, amphetamines moved away from the occasional, marginal use of a small number of experimenters, and reached a large, socially integrated population of regular users.

A drug that activates the reward system

To understand the current dangerous success of cathinones, we need to look at how amphetamines affect 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 behaviors essential to the perpetuation of the species: eating, learning, reproducing, socializing. Cathinones act directly on this system.

After ingestion, inhalation or injection, the small cathinones pass easily through the blood-brain barrier that protects the brain. They then interact with dopamine neurons, preventing their reuptake and promoting their release. Through these mechanisms, cathinones induce a considerable increase in dopamine. In rats, 40 minutes after administration of a standard dose of cathinone, dopamine levels rise by around 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 activates the circuits of the reward system. It is these stimulating and entactogenic effects (altering the desire for physical contact) that users seek, particularly for sexual purposes.

If no further doses are taken, dopamine levels drop rapidly, returning to normal after around 180 minutes. A brief withdrawal syndrome (descent) is frequently reported by users 24 to 48 hours after taking the drug, characterized by fatigue and a general negative feeling (dysphoria).

The use of amphetamines in the 20th century was 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 our 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 - 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.