The Story of “Speed” from “Cloud Nine” to Brain Gain

Andrew Lees*,1; Katrin Sikk†; Pille Taba‡    * The National Hospital, Queen Square, London, United Kingdom
† Department of Neurology, North Estonian Regional Hospital, Tallinn, Estonia
‡ Department of Neurology and Neurosurgery, University of Tartu, Tartu, Estonia
1 Corresponding author: email address: andrew.lees@ucl.ac.uk

Long before the advent of medicinal chemistry, Nature's Treasure Chest had revealed a diversity of tonics all of which would now be classified as stimulants. Ma-huang, the yellow hemp (Ephedra sinica) known to contain ephedrine and now banned in the United States was revered in Ancient China for its performance enhancement and used by its practitioners to induce perspiration and treat chest complaints. Quids of betel and khat leaves have been chewed for thousands of years in South East Asia and the Horn of Africa as a way to loosen the tongue and enhance gregariousness. Traces of nicotine from tobacco have been found on a Mayan vase dated 700 AD providing support for its early use as an entheogen by the shamen. The chewing of coca leaves mixed with lime can be traced back at least as far as the Moche period (600 AD). Among the Incas, coca was a divine practice and its leaves were revered by the Andean Indians as a means of assuaging hunger. By the fifteenth century AD, the beans of the coffee plant were being brewed in public places on the Arabian Peninsula as a pick me up for the exhausted. When tea, coffee, and chocolate were brought from the new colonies by the great navigators the elite of Western Europe considered them sacred gifts and profane pleasures.

Following its extraction from Erythroxylum coca in the middle of the nineteenth century cocaine was soon adopted by the medical profession as a local anesthetic, nasal decongestant, and mistakenly as an effective treatment for morphinism. Sigmund Freud observed that it caused exhilaration and lasting euphoria and in 1885 Parke-Davis marketed it in the United States with the sensational but largely truthful slogan that it could, “supply the place of food, make the coward brave, the silent eloquent and render the sufferer insensitive to pain.” At first, it was considered no more addictive than coffee or tea and was included as a vital ingredient in Coca-Cola. Mounting concerns about its addictive potential eventually led in 1914 to the U.S. Government decreeing that its unauthorized possession for recreational purposes was now a criminal offense.

Amphetamine and methylamphetamine were first synthesized around the same time as cocaine but little interest was shown in them until the 1930s when Smith Kline and French looking for a substitute for ephedrine launched Dexedrine inhalers for the relief of hay fever and asthma. During World War 2, amphetamine was widely used by the Allies to combat fatigue and increase bravado but concerns about the increasingly widespread use of “Mother's little helpers” in the 1960s led to its “off label” use being outlawed in Europe and North America. It was hardly surprising that a class of drugs reported to give limitless energy, increase vigilance, and improve sexual performance might prove attractive to human beings. Stockbrokers were able to stay up all night to play the international markets and be in the office the following morning fresh as daisies. Unscrupulous professional sportsmen got an edge on their adversaries broke records and achieved glory. Long distance truck drivers reached ever more demanding deadlines without falling asleep at the wheel. “Speed” offered a short cut to prosperity and bliss and fuelled the capitalist dream.

Advocates of responsible stimulant use pointed to the many well-known artists and intellectuals who attributed their creativity to amphetamine use. Jack Kerouac wrote On The Road in a “creative groove” working day and night for 3 weeks typing on a long roll of paper, chosen deliberately to avoid interrupting his rhythm.

Amphetamines accelerated his thought processes and allowed him to write in “the now.” He had found a new spontaneous way of writing that banished convention and communicated raw physical and emotional experience. “Speed” has also played a role in some of the youth culture movements of Generations X Y, and Z. First used by the Beats in the jazz scene “Bennies” and “Purple Hearts” helped the Mods gain their teenage rite of passage. Bronchipax (ephedrine) and Durophet black bombers (dexamphetamine) helped Northern Soul boys escape bleak post-industrial landscapes while “Ecstasy” brought a sense of emotional connection on the dance floor, increased appreciation of sound, color and touch, and a feeling of closeness to others.

The risk of physical dependence with cocaine and amphetamine is relatively low but heavy regular usage or overdosage can have serious medical consequences leading to accident and emergency hospital referral. Reckless behavior and feelings of invincibility lead to falls, fights, and road traffic accidents, and death can occur from malignant hyperthermia. Profound agitation and acute paranoid psychoses with morbid jealousy require urgent psychiatric referral and drug abstinence after long-term use can unmask chronic depression with suicidal risk. Chorea (crack dancing) abnormal stereotyped movements of the lips, mouth and tongue, and teeth grinding are underreported neurological complications. Complex stereotyped purposeless behaviors (punding) first described in Scandinavian and Californian bikers using high doses of intravenous amphetamine are also now recognized to occur with cocaine and are also seen in patients with Parkinson's disease treated with l-dopa, the natural precursor of dopamine. The sympathomimetic properties of stimulants can also lead to hypertension and an increased risk of stroke and heart failure.

The substituted amphetamines increase brain dopamine, serotonin, and noradrenaline release and inhibit reuptake at axonal synapses. Both cocaine and methamphetamine also act as substrates at vesicular and synaptic storage sites leading to competitive inhibition with monoamine transporters. It would seem reasonable therefore, to expect that they might be useful treatments for both depression and Parkinson's disease but so far the results have been modest at best. The brains of chronic methamphetamine users have been found to have significant (50–60%) reductions in dopamine but in contrast to the findings in Parkinson's disease caudate dopamine deficiency which in some cases approached that seen in Parkinson's disease was always greater than that found in the putamen. None of the methamphetamine addicts had developed Parkinson's disease during life and in contrast to MPTP the unwanted by product of kitchen chemistry manufacture of the narcotic MPPP there was no evidence to suggest that it caused structural damage to dopamine neurones (Moszczynska et al., 2004). Further, evidence for permanent changes in striatal dopamine signaling, however, comes from functional imaging studies in abstinent methamphetamine addicts where dopamine receptor changes have been found (Volkow et al., 2001).

Amphetamine type stimulants comprise the second most widely used class of illicit drugs in the world. According to a national survey of recreational drug use in the United States carried out seventeen years ago 1 in 20 adults aged 35 years or older had used non-prescribed amphetamines at least once (mainly “crystal meths”) (Office of Applied Studies, 1998). At least 4 million people (1.5% of the population) in the United States aged 12 and older have used methylphenidate at least once off label. Increasingly widespread use of “crystal meths” (methylamphetamine) has led to public health concerns that dopamine and serotonergic neurones could be “excited to death” in chronic high-dose users increasing the risk of depression and delayed Parkinson's disease (Guilarte, 2001).

Several retrospective case-control and population studies have provided backing for this notion. A 16-year follow-up cohort study involving California inpatient hospital episodes and death records in patients at least 30 years of age found an increased risk of Parkinson's disease in amphetamine users in an active comparator group of cocaine users and another control group with appendicitis. For every...