Like methamphetamine before it, methadone was first explored and used widely by, guess who, the Nazis. In the very late thirties I.G. Farben was looking for non-addictive opioid anesthetics to replace the notoriously addictive morphine on the battlefield. At the time it wasn't known that any unnatural stimulation of the brain's opiate receptors would lead to their desensitization (and thus the person's addiction), so the research seemed perfectly reasonable. At some point during this period the I.G. discovered heroin, which, needless to say, had the opposite of the low addiction rate they were looking for. Other compounds were explored; unsurprisingly, none fitting the criterion were found.

In September of 1941, researchers Max Bockmuhl and Gustav Ehrart from the Hoescht branch of the corporation patented a chemical that they called Polamidon, which would eventually come to be known as methadone. One year later, the I.G. Farben proper sent the first sealed units to the German military for use and testing. Because the dosage ratios weren't well established, use of too much methadone at a time often led to nausea and overdose, so the drug never went into mass production or use.

At the end of the war, all of I.G. Farben's research and patent knowledge went to the United States, and the Eli-Lilly company ended up with control of methadone. They gave the drug the name Dolophine (from dolor, pain, and fin, the end) and began clinical trials. Again, nobody stopped to do proper dosage research, and the 200 mg, four times a day (!) dosages were far too much for most patients. They also noticed the rapid onset of tolerance, and the much lesser strength of euphoria than that caused by morphine. U.S. methadone manufacture was stopped for good in 1947, when a researcher named Isbell published work recommending that "unless the manufacture and use of methadone are controlled, addiction to it will become a serious health problem."

In the mid-to-late 1960's, drug clinics started becoming commonplace in the mainstream, and methadone maintenance treatment (MMT) was discovered for use in heroin addiction. With AMA support it caught on quickly becoming the standard treatment. Methadone lacked the euphoric rush of heroin, and its long half-life in the body meant withdrawals were kept away for more time. Also useful was the fact that methadone could be taken in tablet form, meaning that the patient wouldn't have to see needles or any other accouterments of heroin addiction.

Of course, as is noted above, that long lasting half-life of activation made methadone all the more addictive, and kicking it all the more difficult. Still, long-term maintenance prescriptions of methadone were much safer than heroin use on the street, so prescription and use were not limited by this addictivity. Many a heroin user went on to spend years addicted to methadone, due to a combination of overworked, overprescriptive drug clinics and the chemical's difficulty to stop using.

This pattern continued, and escalated heavily in the 1980's with the rise of HIV AIDS. Sadly, heroin use had been skyrocketing through the early 80's, and for much of that time the transmission route and danger of AIDS was widely unknown. These factors combined to make injecting heroin an order of magnitude more dangerous than it had been in the 60's and 70's, and even greater usage of methadone maintenance prescriptions. Because of the attention paid to HIV, enough money was gradually funneled to MMT clinics that they could afford continuous daily monitoring and regulation of their patients. As of 1992 the United States had over 120,000 of these patients in 800 programs receiving daily methadone maintenance.