Modern medicine has neglected pleasure. With major depressive disorder being the leading cause of disability in the United States for people between the ages of 15 and 44, there is an urgent need to treat depression and, arguably, a somewhat less urgent need to better the lives of already well people. How could the medicinal chemist think of something so gauche as pleasure in a world plagued by suicidality and unremitting despair? And aside from the need to triage affective disorders, there is the unpleasant fact that pleasure, for all its apparent virtues, has a long track record of creating problems. The pleasure of euphoriant drugs can result in habituation and dependence, the pleasure of food in obesity, the pleasure of money in greed and the pleasure of sex in virtually every type of mess known to man. Of these I am most interested in drugs, for the specific reason that they induce pleasure more reliably than almost anything else in life, which otherwise provides no guarantee of joy or satisfaction. Academic, professional and artistic achievement may elicit nothing more than a moment of somber self-reflection, pangs of perfectionist anxiety or the sensation that more could have been done and better. This, however, is not the case with methamphetamine.
Scientists have long understood euphoriant drugs as indispensable tools for exploring the neurological wells of pleasure that exist in our brains. A researcher can reward a mouse with a food pellet or a sucrose solution, but these treats pale in comparison to the glow produced by certain drugs, which, assuming they are sufficiently reinforcing, the mouse will choose over food every time. The point of these scientific investigations is not to create new drugs that will promote human pleasure—though there are exceptions that I'll get to in a minute—but to research the mechanisms of addiction and the nature of dopamine, the mind's chemical of reward. It's pure serendipity that many illegal and semilegal euphoriant drugs were the accidental products of orthodox scientific experiments. LSD was the result of efforts to produce drugs that would increase blood circulation in the elderly. Amphetamine was discovered by Gordon Alles in the course of investigating nasal decongestants. Methaqualone (commonly known as Quaalude) was synthesized in India as a prospective antimalarial treatment. Viagra was initially trialed as a treatment for angina pectoris. The list goes on and on. But outside of therapies aimed at treating various forms of sexual dysfunction, there are no pharmaceuticals intended primarily to induce pleasure. At the same time, billions of dollars are spent annually on the development of drugs that prevent pleasure in order to assist addicts. Antabuse, naltrexone, methadone, Chantix––these are all pharmaceutical efforts to attenuate the pleasure humans derive from the already abundant but ever-growing array of euphoriant drugs.
It would seem that an obvious strategy would be to simply give pleasure-inducing drugs to the depressed people who might benefit from them most. But the aim of pharmaceutical treatments for depression has rarely been to cause joy (clinically, euphoria is sometimes even classified as an "adverse effect") but to help the patient find and remain on the narrow isthmus between happiness and sadness. A 1986 trial employing 15-milligram intravenous doses of methamphetamine found it to be a superbly effective antidepressant in almost half of all female patients tested, though it isn't a drug that most would even consider a realistic therapeutic intervention for depressed patients. (It is, however, currently approved for the treatment of both ADHD and obesity.) Methamphetamine users have earned a reputation for tending to overshoot the mark when left to their own devices, choosing feelings of manic, transcendent euphoria over euthymia (a nice, general positivity) and increased productivity, perhaps limiting the scope of methamphetamine's pharmaceutical application. Meth addicts have given meth a bad name.
During routine investigations of novel tricyclics, then the most prominent class of antidepressants, chemists at the French pharmaceutical company Servier discovered a new drug that exerted not only an antidepressant but also a pronounced stimulant effect. They called it amineptine. Mice given the drug exhibited increased locomotion and slept less when injected with barbiturates. In the 1970s, amineptine was introduced as a pharmaceutical antidepressant in Europe to much fanfare. Its stimulating effects rapidly jolted lethargic depressives out of their malaise and allowed them to resume normal lives without the multiweek therapeutic lag present in other pharmaceutical solutions. And while other antidepressants resulted in reduced libido, amineptine actually induced spontaneous orgasms in many females who consumed it—taking that dangerous next step, beyond treating depression, into the checkered realm of pleasure. It's not surprising that some patients began to take large doses of the drug in order to revel in the high it produced. Medical case reports began to emerge, and among the heaviest users amineptine was found to produce cystic acne on the face, earlobes and genitals with such severity that one dermatologist characterized the addicts' appearance as "monstrous." A governmental warning was issued and amineptine was summarily withdrawn from the international pharmaceutical market, leaving a lacuna in the synapses of many responsible users who had benefited from the drug.
Servier responded by replacing amineptine with an antidepressant it hoped would have lower abuse potential. It was named tianeptine, and it behaved more like an opioid, inhibiting the pain response in mice whose tails were singed on hot plates and the coughing of guinea pigs sprayed with citric acid. But, like amineptine, tianeptine had a fast onset and did not interfere with sexual functioning. Slowly, the reports of addiction to its more narcotic effects began to trickle in; a female user in Turkey worked her way up to ingesting 150 12.5-milligram tianeptine tablets each day. Russian and Armenian tianeptine addicts preferred to inject the sugarcoated pills to increase the high, sometimes resulting in severe vascular damage that necessitated the amputation of limbs. Now tianeptine is a controlled substance in those countries. In other countries it's banned entirely. But it should be noted that the abuse of these substances occurred only in a minority of users. The stories of both drugs, to my mind, serve as reminders that the medical establishment believes that pleasure has no place in the treatment of depression.
Popular science is caught up in a juggling act—a state of constant media manipulation—that revolves around the chemicals in our brains. Dopamine is doubtlessly a neurotransmitter of major importance, and it plays a crucial role in reinforcing certain behavioral patterns. But to simply classify it as a "pleasure chemical" betrays the versatile role it plays in nature, where it is involved just as much in encoding aversion, movement, lactation and vomiting as it is in facilitating bliss. Serotonin, the neurochemical target of an immensely lucrative series of pharmaceutical antidepressants such as Prozac, is widely called the "happy chemical"—a characterization based on the simplistic idea that elevating serotonin levels in the brain is all that is required to alleviate depression. But it has yet to be definitively proved that low levels of serotonin in the brain are a cause of depression. The association between serotonin and mood disorders remains poorly understood. Any therapeutic effect attributed to SSRI antidepressants could instead be the result of far more complex effects—the generation of new neurons in the hippocampus, for example. Our old friend tianeptine actually decreases the amount of serotonin available in neural synapses, yet it exerts a therapeutic effect that is every bit as potent—and apparently more enjoyable—than today's most popular antidepressants. Oxytocin, often called the "love hormone," is involved in parent-child bonding and appears to be released as an indirect result of postorgasmic surges in the hormone prolactin, but it is just as much involved in fostering aggression toward outsiders not present during the moments of oxytocin release. Then there are the endorphins, which were once thought to cause runner's high, a feeling now thought to be the product of endocannabinoids—chemicals that originate inside us and activate the same receptors as cannabis. But despite their great potential for pleasure, endocannabinoids are relegated to the dustpan of biogenic pleasure chemicals. A pharmaceutical disaster called rimonabant, an appetite suppressant that blocked the activity of endogenous cannabinoids, induced psychosis and suicidal depression in many users.
So the intentional design of pleasure-inducing drugs is a rare occasion indeed. The scientists who have dedicated their lives to the creation of chemicals that have the sole purpose of inducing good feelings can be counted on a single hand. Most notable among them is Alexander Shulgin, one of MDMA's earliest proponents as well as the inventor of more than 100 novel psychedelics. But the lesson Shulgin learned from his pursuit of chemicals that provide consumers with a sense of transcendent euphoria was a difficult one; there was certainly money to be made from his inventions, which currently support a multimillion-dollar black- and gray-market industry, but the funds did not come back to him. He is currently struggling to pay his medical bills as his career comes to an end. Meanwhile, the manufacturers of dubiously effective yet non-abusable SSRI antidepressants luxuriate in vast pyramids of pharmaceutical wealth.
The avant-garde of intelligent recreational drug design exists in New Zealand in the form of a small pharmaceutical company called Stargate International. It's run by an entrepreneur named Matt Bowden, who has introduced numerous psychoactive drugs that have the explicit purpose of fostering human pleasure. In fact, his company possesses the world's only commercial laboratory operating aboveground in an effort to design new recreational drugs for mass distribution.
And let's not forget transhumanists like David Pearce, an Oxford-trained philosopher who has spent his life in the noble search for eternal unremitting bliss. He refers to his work as "paradise engineering" and speaks of "the hedonistic imperative." Brushing away the quibbles of those who suggest pleasure can be felt only in contrast to the counterweight of pain, Pearce believes that the pain caused by disorders like depression will one day be considered as preventable and unnecessary as the pain one would experience while being operated on without anesthesia. (The two may even converge in the surgical anesthetic ketamine, a.k.a. Special K, which acts as a potent antidepressant.)
While many raise the puritanical objection that the pleasure felt as a result of these drugs is somehow false or artificial, the research of neuroscientist Matthew Baggott on MDMA has actually found the opposite: One of the defining features of MDMA's effect is a feeling of increased authenticity. And Pearce's work has gone past mere speculation. He has successfully found a way to alleviate his own depression with a unique combination of the methamphetamine derivative selegiline and amineptine (a personal supply of which he secured after its pharmaceutical banishment). While it's unclear whether the future of human pleasure will hinge on the administration of small molecules like amineptine or more invasive means like deep brain stimulation, we should feel encouraged by the fact that we've already reached a place where pure euphoria can be reliably induced by chemicals. The question will soon become whether we can accept—and withstand—readily available pleasure.