The winners of Open Lab 2008 are finally out! Thanks to all of you that submitted entries on our behalf, we actually had seven entries up! And it turns out, one got in! It’s that post of mine that never seems to go away “Uber Coca, by Sigmund Freud“. I’m completely thrilled that I made it in, though from the press this post gets, I get the feeling I burned out my best blogging sometime back in May, and since I STARTED in May, this cannot bode well. But really, I’m honored that I made it into the company of such great posts. It makes me feel all warm and fuzzy inside.
Since the post is over at the old site, I will be reposting it here, to give a new link, and so people who don’t tend to follow my links (you know who you are) will be able to see it in all its glory (and here’s hoping all the html makes it over ok, if it doesn’t severe edits are on the horizon).
“Uber Coca, by Sigmund Freud”
Most people know Sigmund Freud as the founder of psychoanalysis, as well as originating the idea of the role of the unconscious in conscious thought, and of course for “sometimes a cigar, is just a cigar.” But were you also aware that Freud was one of the pioneers of research into the properties of cocaine? His review on the properties of cocaine, published in 1884,is described as “the definitive description of the effects of cocaine in humans” (Dyke, 1981). It’s amazing how few people actually know this. The people in my own laboratory, which focuses on the study of stimulants, had no idea that Freud was one of the first to publish on it. So I dug up his original 1884 publication (republished in 1984 in the Journal of Substance Abuse Treatment), and now I’m taking a whack at it, for the edification of anyone who wants to read it (I did a previous post on the modern pharmacology of cocaine, how it works, and the addiction process). And besides, who doesn’t think cocaine is interesting?
Note: There are some problems with citations, as with my previous post on Phineas Gage, it’s hard to find online citations from 1881!
“Über Coca” Von Dr. Sigm. Freud, house officer of the General Hospital of Vienna. Centrallblatt für die ges. Therapie. 2, 289-314, July 1884.
Freud begins with a description of the cocaine plant, erythroxylon coca, which is a bush that’s between four and six feet tall, with egg-shaped leaves (I imagine that there are a lot more important and cool plant properties than that, but unfortunately I am no kind of botanist and wouldn’t even know where to start). It is the leaves of the coca plant that contain the stimulant cocaine, which was first isolated into a crystal and powder by Gardeke in 1855. Gardeke called the active ingredient erythroxylon, but luckily, Niemann also isolated it in 1860, and called it cocaine, and that’s the name that stuck.
Cocaine, established by Lossen as C(17)H(24)NO(4), crystallized into 4-6 sided prisms. It dissolves easily in water when it is formed into an HCl salt, and that is what is used most often these days in the laboratory. It is also the common form of powdered cocaine which people taking intranasally (“intranasal” sounds so much better than “snorting”, huh?), and which can be injected when mixed with saline. Crack cocaine is the cheaper form that is smoked (they take out the filtration process and the removal of the ammonium salt, you end up with a lot more bicarbonate in the mixture).
(image via 3dchem.com)
It appears that by the time Europeans got to the Andes, there was an entire population of cocaine addicts already extant, and Freud estimates that, in his time, the stimulant was used habitually by about 10 million people (in 1981 the number of people in the Andes chewing cocaine was estimated to be about 4 million). The conquistadors called the coca-chewing South Americans “coqueros“, but, believing the effects of the coca plant to come from the devil, banned it immediately. They quickly realized their mistake. According to the explorer and scientist Mantegazza, without cocaine the South Americans could not perform the heavy labor (usually mine work) forced upon them if they weren’t allowed to take cocaine. So the government began to ration out cocaine leaves and allow the mine worked breaks in which to chew.
Coca wasn’t just something you could put in your mouth. South Americans carried coca leaves with them, along with either a bottle of plant ash, or a kind of native clay, and punctured the coca leaves with the ashes or clay before chewing. It turns out that this is essential for the gastrointestinal absorption of cocaine. Although cocaine can be absorbed easily through the mucosal membranes of the cheek when chewed, it breaks down very quickly in the acid environment of the stomach. By combining it with highly alkaline substances such as ash or clay, the South Americans balanced out their stomach acidity, allowing more cocaine to be absorbed into the stomach once the coca leaves were swallowed.
Many of the explorers noticed the incredible effects of coca chewing. An average coquero was known to chew 3-4 ounces of leaves per day, and commonly increased the dose “when he is faced with a difficult journey, when he takes a women, or…whenever his strength is more than usually taxed”. The explorer Tschudi reported a man who
“carried out laborious excavation work for five days and nights, without sleeping more than two hours each night, and consumed nothing but coca. After the work was completed he accompanied Tschudi on a two-day ride, running alongside his mule. He gave every assurance that he would gladly perform the same work again, without eating, if he were given he enough coca. The man was 62…”
Obviously this is the report of a highly functional cocaine addict, but still the feats that people observed under the influence of cocaine were pretty amazing. Freud relates many reports of people using coca instead of food, in particular the story of the siege of La Paz in 1781, where the only inhabitants who survived were those chewing coca in the absence of food.
Most historians believe that people in the Andes began chewing coca leaves around the year 600. There is historical evidence that they were given as offerings and used in religious ceremony, and sometimes placed in the mouths of the dead for acceptance in the afterlife. Freud describes the legend of coca as descending from Manco Capac, who descended from the cliffs of Lake Titicaca (I never knew that “lake Titicaca” was a real place, shows what an ignoramus I am), bringing fire, religion, and coca. The deep ties between coca and religion were the reason the Spanish government tried to ban it at first. South Americans also knew about the local anesthetic properties of cocaine, and may have used it topically for a local anesthetic in the process of trepanation (for more on trepanation, there’s a great series of articles over at Neurophilosophy).
At the time, most people believed that the use of coca in moderation (“moderation” being about 3-4 oz per day of leaves, though with oral ingestion you’d only get about 1/3 of the full dose in the leaf) promoted health, and noted that many coqueros lived a very long time. However, they were already noticing the effects of immoderate use:
– digestive problems (probably from the fact that the leaves were chewed, when cocaine is snorted chronically there are problems with the nasal mucosa, while if it is smoked chronically it can lead to lung problems)
– emaciation: cocaine is an anorectic, and chronic use of coca instead of food would certainly lead to starvation eventually.
– Moral depravity: described as “a complete apathy toward anything not concerned with [coca]”, which is one of the DSM-IV criteria for cocaine addiction.
Freud was the first to note that these effects “[bear] a great similarity to the symptoms of chronic alcoholism and morphine addiction.” But he did not seem to see a similarity between cocaine and morphine in terms of addictive potential. That’s actually not surprising, considering what was known about addiction at the time. For a very long time, people believed that only depressants were addictive, such as morphine, alcohol, or laudanum (which is morphine IN alcohol, talk about the best of both worlds!). Only Scroff characterized cocaine as belonging in the class of narcotics with opium and cannabis. Everyone else ranked it with caffeine.
As soon as cocaine was isolated in 1855, and again in 1860, people began experimenting with it, testing the effects on different animals and, more importantly, the extraordinary effects on humans. Most scientists had to be convinced that the effects of coca were not “confined to the Indian race”, but it was soon very clear that everyone felt something, though what you felt exactly depended on what you were taking and how. Scientists quickly determined that cocaine worked on the central nervous system by observing the effects after severing various parts of the spinal cord, though at the time they localized the area to “the vital area of the medulla oblongata.” Studies of the effects of cocaine on animals were being carried out as early as 1861, and the general consensus was that, in small doses cocaine was stimulating, while in large doses it was paralyzing. They must have been giving enormous doses, and Scroff certainly gave enough to produce convulsions and death in rabbits. A Dr. von Anrep (1880) was Freud’s go to source on the effects of cocaine in animals. He gave 0.01g/kg to dogs, and noticed both motor stimulation and stereotypy (notes as head swinging). That’s an awfully high dose for a dog (a lethal dose in a cat is something like 0.02g/kg), but is the normal dose used in mice, which have much faster metabolisms. Von Anrep also gave cocaine to animals for up to 30 days in a row, and noted no effects on the bodies of the animals (though if he could have looked at their brains and cocaine-related behaviors, he might have told a very different story).
The best part of Freud’s review on the effects of cocaine is his section on cocaine and the human body. Freud took cocaine himself, he estimated about 12 times, to study the effects, and asserting afterward that he had no real craving for it after the experiments were over. He took about 50 mg of it orally (for a 160lb. man, that’s about 0.7 mg/kg, but since it is oral we can say that his blood concentration probably never got higher than 0.2 mg/kg), while he was “feeling slightly out of sorts from fatigue.” Freud described the numbing anesthetic effect on his mouth, as well as exhilaration and euphoria, and “cooling eructations” (those would be burps). He did notice an increase in pulse rate, but said the most constant symptom was burping. I myself have never taken cocaine, but I’d be interested to know if this was common, since I’ve never heard of this particular side effect. Probably it’s a result of taking cocaine orally, which is something that pretty much no one does any more (except for Native Americans in the Andes who still chew the leaves, in which case the “eructations” might be mitigated by the presence of the leaves in the stomach as well). Freud also noted that the “toxic effects” of coca (such as eructations, a “feeling of heat in the head”, dry mouth, and dizziness) don’t last very long, and because weaker with repeated use of cocaine (possibly due to tolerance).
As far as psychic effects, he reported exhilaration and lasting euphoria, which he said were the same as “a normal euphoria of a healthy person.” He felt an increase in a feeling of self-control, and felt “more vigorous and capable of work”, but he said the overall feeling was “simply normal” and he found it hard to believe he was under the influence of a drug at all. Freud hypothesized that the psychic effects of cocaine were not due to stimulating effects, but rather “the disappearance of element in one’s general state…which cause depression”. He felt no need for food or sleep, said he could eat, but didn’t feel that a meal was necessary, and that he could sleep once the cocaine was wearing off, but like food, it didn’t seem necessary.
Freud was not the only person to test the effects of cocaine on themselves. Sir Robert Christison attempted to walk 15 miles in a day without eating, both in control conditions and under the influence of cocaine. He found that consuming 2 drams (1 dram = 1.7 grams, so about 3.4 grams for a 70kg man, about 0.048g/kg orally, which might result in a blood dose of around 16mg/kg) enabled him to walk for more than 9 hours without getting tired, and he still didn’t feel tired or hungry as of the next morning. Several investigators ended up describing cocaine as being “an excellent thing for a long walk” (Mason). More experiments were performed on Bavarian and German soldiers, who were given cocaine when they were at the point of exhaustion, and then asked to perform military maneuvers.
The effect of an oral dose of cocaine faded away very gradually, but Freud described himself as needing an extra dose to cure his fatigue after about 3 hours. The duration of cocaine in the brain following an i.v. dose is around 15-20 minutes, though the highs and duration change depending on how you take it, so the duration Freud got could be because it was an oral dose. He didn’t report any depression after the effects had worn off, which is not too surprising after the first few times of use. The psychological withdrawal effects of cocaine appear to occur mostly in habitual users, when frequent use begins to cause permanent neurobiological changes.
Freud used doses on himself that were pretty low, but others, such as Mantegazza, the explorer, tried higher doses, and experienced stereotypy (a violent urge to move), as well as hyperthermia and hallucinations (due to cocaine’s serotinergic effects). Apparently he took as much as 18 drams of coca leaves at a time, and though he suffered extreme stereotypies, did not seem to suffer any other effects.
Freud was not the first to propose the use of cocaine as a therapeutic; the explorer Pedro Crespo recommended it for medical use as early as 1793. Everyone agreed on the stimulant value of cocaine, proposing it for long journeys, mountain climbing (cocaine can alleviate some of the effects of altitude sickness due to increases in pulse rate and blood pressure), and in wartime. Freud proposed using it in place of alcoholic stimulants (low doses of alcohol have stimulating properties), and said it was much more potent and less harmful. He suggested using low doses and titrating so that the effects of the doses overlapped, so that people were always under the maximum effect of cocaine. Interestingly, self administration studies have shown that rats given cocaine to self administer via i.v. will titrate their dose in the same way.
Another use that Freud thought would be important was the use of cocaine for indigestion. Apparently cocaine makes you feel a lot better when you’ve eaten too much, and Freud noted that he used cocaine in “salicylate of soda” as a preventative for stomach problems. He also mentioned a case student where cocaine was used in the treatment of severe migraine. Although Freud mentions many possibly uses (in asthma, stomach problems, anesthesia, and recovery from wasting diseases), most doctors (Freud included) thought that cocaine’s major therapeutic value would be in psychiatry. Although at the time doctors had many nervous system depressants available (such as laudanum, ether, or morphine), they didn’t have any stimulants. Doctors were already using cocaine for treatment of melancholic inhibition (major depressive disorder), and hypochondria (Antonio Julian, 1787). Studies were already taking place on the chronic effects of subcutaneous cocaine in depressed patients (Morselli and Buccola). The researchers observed a “slight improvement” in mood, but mostly noted the effects on digestion. Freud also noted that cocaine could be a powerful aphrodisiac (though he noted the sexual effects in some of his patients, he did not say whether he experienced any himself), and called for further investigation into the psychiatric effects of cocaine.
What astonishes most people when they read “Uber Coca” is Freud’s hypothesis (based on a case study at the time) that cocaine could be successfully used to intervene in alcoholism and morphine addiction, by slowly replacing the alcohol or morphine with cocaine, and then discontinuing the cocaine. Although we know now that this can’t work (combinations of morphine or heroin with cocaine are usually considered more addictive, and in any case the morphine addict may end up with two addictions rather than one), it was one of the first times that anyone had proposed substitution of one drug for another as therapy for addiction. So this paper paved the way for research into substitution therapies such as methadone maintenance for opiate addiction, as well as ongoing studies looking at long term stimulants such as Adderall or Ritalin for cocaine addiction.
