Intro

Addiction is the curse of the human condition, we seem to almost be preprogrammed to latch onto anything that makes us feel good. For many our enjoyment of certain activities are manageable but for others it can lead to a downward spiral. Take work for example, many are able to leave their job at the door when it’s time to clock off but for others one's career can become an obsession where all they do and think of is their occupation. The daily cup of coffee may seem harmless but the headaches and grumpy demeanor would beg to differ when you don’t get your caffeine fix. Because we as a species are so susceptible to addiction, scientists have sought out to find out why. one such study towards the end of a very drug influenced 1960s would seek out to find out why we seem to fall so hard when it comes to substance abuse. Afterall we are faced very regularly with the risks of drug use and addiction, and yet so many don’t heed the warnings. The experiment, rather than studying human addiction, would focus on the animal kingdom, and would make use of a bizarre contraption that allowed monkeys to self administer highly addictive substances such as cocaine, meth and opiates. The experiment would result in terror for its subjects, where overdose bodily disfigurement and mental anguish were just some of the outcomes. But the results would only end up proving the obvious that addictive drugs are addictive, and as such the study would go down in infamy for its unethical use of its test subjects. My name is John and today we are looking at the 1969 Self-Administration Of Psychoactive Substances by Monkey study better known as the 1969 monkey drug trials, you are watching the dark side of science. ///////// It is 16th June 1969 and 3 scientists release a controversial research paper, the trio have set out to delve into the darkest depths of addiction. The reception of the wider scientific community is frosty to say the least. The GERALDDI~NEAU***, TOMOJI YANAGITA+, and M. H. SEEVERS study rather proudly showcases a device that allows their animal test subject to self administer drugs intravenously . But our story starts many years before the controversial study with the budding career of Maurice Seevers.

Background

Background years of studying addiction. Maurice servers was studying for his doctorate in Pharmacology in 1928 under the tutelage of Arthur Lawrie Tatum, At the university of Chicago. During this time his interest was sparked in the study of addiction and its psychological and physiological impact. His professor moved to the university of wisconsin in late 1928, and SEEVERS would follow 2 years later after completing his phd and md. During his time with Tatum, the two studied opiates,cocaine and novel barbiturate sedatives. During the late 1920s seevers would release several papers supporting a new theory of opiate addiction. His experiments to support his theory involved testing on dogs, cats and monkeys to explore The phenomenon of psychological tolerance and how it is linked with physical dependence. This was coined as dual action theory Knowing that human addiction is linked to the high of the drug and the aversion from withdrawal. Seevers took on the suggestion from Harry Harlow that addiction in animals is a delayed conditioned response where animals learn to associate the administering of the drug with positive sensations. Seevers combined harlow's suggestion with his own theory of addiction as euphoria from the drug combined with relief from withdrawal. In order to create addicts in his experiments seevers employed a 7 day dosage schedule with only a large enough dose to create a small reaction from the subject. The dose was incrementally increased and it was found that after a month noticeable behaviours were exhibited by the subjects including visual effects, such as excitement when it was injection time. The subjects would even show subdominant body language towards the drug administer. During this period of the 1930s seevers developed a scale to quantify the effects of withdrawal in his subjects which by now included dogs, rats and monkeys. This included noting certain behavioural traits such as clutching at the stomach and chasing the hand holding of the hypodermic needle before administration. During the 1930s the national research council set out to try and find a non addictive morphine derivative, which pushed seevers studies to the forefront and also helped with funding. But as the 1930s drew to an end and the decade gave way to the 40s this search would be put on the back burner due to the 2nd world war, and as such this affected seevers. During the 1950s seevers research was becoming less relevant and as such he sought out to revamp his experiments to try and simulate the more behaviour driven model of addiction. Instead of a regimented single daily dose model, seevers set out to mimic a more human form of dosage for example multiple doses in one day. Seevers would further modify his experiments to allow the animals to self administer and that leads us onto the infamous monkey drug trial.

The Study

I should say that was a very very brief background to seevers work and I thoroughly recommend looking into his studies as they are very interesting albeit sad on the part of his subjects. ////////// The study “self administering animals” Seevers teamed up with another 2 scientists Gerald deaneu and tomoji yanagita, and planned the experiment to take place at Michigan university. The substances to be explored were morphine, codeine, cocaine, d-amphetamine, pentobarbital, ethanol, and caffeine. The experiment set out to explore drug addiction of non physiological substances i.e. drugs that don’t give you physical withdrawal, but can cause psychological addiction. At the time.. being able to model this type of addiction was difficult when working under seevers dual action theory of euphoria of the drug and fear of the pain of withdrawal. As drugs such as cocaine don’t create a physiological addiction, but are very reinforcing in humans, leading to a psychological dependence. In order to test this.... a method of self administration was needed, and this had already been tested on rats in 1962 study by a scientist called weeks. Weeks had pioneered a method of conditioning rats to self administer morphine with use of a lever which delivered a dose intravenously to the animal. Interestingly the animal would continue to self administer the drug maintaining a dependent state, similar to the way a human addict would do so. Another study in 1964 by Thompson and Schuster also employed intravenously delivered morphine but in monkeys that had been restrained. This study set out to see the reinforcing capabilities of morphine versus food, but they didn’t look to see if they could produce an addict from just a spontaneous leveller pull. For the seevers GERALDDI~NEAU, TOMOJI YANAGITA study this method would be used as a basis for a drug delivery method in monkeys, but with a wider variety of drugs. Crucially the new experiment would try to find if after the first injection of any drug by spontaneous lever-press, would the participants continue to seek reinforcement by increasing the number of lever presses and maintain a pattern of self administration over longer periods of time. Thus if a continued behaviour pattern of self administration was observed then a psychological dependency could be demonstrated. Each monkey was housed in a small cubicle 36 inches high, 30 inches wide, and 26 inches deep. The floor had a mesh screen with a pan underneath that facilitated ease of cleaning with it being flushed every 4 hours. There is a panel with two switches mounted on the back wall of the cubicle, these were key to testing the animals drug dependence. The first when activated administered a dose of the drug to the animal, the second made all the same sounds as a dose but just re-delivered the drug back to the reservoir. This was to see if the monkey was seeking the drug or just playing with the switch, both switches would be swapped around at random intervals. There was also a drinking fountain next to the switches for water. The infusion machine could also be programmed to deliver a dose as well as manually controlled on top of the operant control from the switch. The monkeys were intravenously connected to the drug infusion unit via a catheter which terminated at the right atrium of the animal's heart. To hold the animal and catheter together the monkeys were attached to a metal harness which itself was attached to a restraining arm which allowed movement around the cubicle. 25 seconds is required to administer the drug and another 25 seconds is needed to refill the syringe, this helps restrict the number of doses. The machine could administer a dose in 4 different ways 1 by the monkey alone; 2. by automatic timer; 3. by the timer if the monkey fails to press the lever within a predetermined time; 4. by the monkey, with a timer blocking the circuit after in- jection, preventing the monkey from taking the next injection until a predetermined time has elapsed. Each monkey was taken from a pre established breeding colony at the university the experimenters aimed for weights of subjects to be around 3 1⁄2 kg to 4kg. The subject is placed in the harness and restraining arm and on average a acclimation period of around 2-4 days was required for each monkey to get used to their new situation. Then the catheter was to be surgically implanted into the jugular vein under barbiturate anesthesia. Post surgery, saline solution is injected into the catheter every 3//6 hours until the wound has healed. This took roughly 5 days, after which the subject was ready for experimentation. //////// After fully recovered the monkey is introduced to the switches in its cubicle. At this point the active switch that is the switch that can administer through the catheter is only able to give a dose of saline solution. A signal light is placed above the switch to give a visual indication to the monkey that pressing the switch will result in a dose. For the next few days a baseline is recorded of the amount of times the subject presses the switch for a saline dose. After the control period the test drug was introduced for the first time. It was found that most subjects would either keep on pressing the switch for saline or after a few days lose the novelty interest. In the case of the former the introduction of the test drug was easy as the monkey would self dose as it had done with the saline, however the latter would require a little more of an incentive, this was a raisin taped to the switch. After the first dose of drug was received positively then only 2-3 rasin incentives were needed to condition the subject to the level pull = drug mechanism. As multiple monkeys were being employed for looking at various different drugs, understandably not all responses to the drugs were positive. This is where the automatic dose function of the dose machine comes into play. If the monkey didn’t take to the test drug initially... a potential dependence could be made by timed intervals of drug administration, if the animal began to have a positive preference for the drug then an increase in self administration would be seen. However if after 1 month the monkey still didn’t show a preference for the drug then it would be deemed that the animal hadn’t developed a psychological dependence for that particular substance. Now the experiment was really multiple individual experiments with its own group of monkeys for each substance, and as such the length of the study varied by drug. I’ll go through each one in a different order to the 1969 research paper and instead in order of outcome for the participants best to worst. 0 Nalorphine. This study only lasted a month as none of the participants initiated self administration and after automatic doses ended withdrawal only lasted around 2 days. 0 Caffeine. Two of 4 monkeys failed to initiate self-administration of caffeine. One initiated and one failed to initiate self-administration although "priming" with automatic injections caused the latter to begin serf-administration. The pattern of self-administration of caffeine was in all cases sporadic and irregular resulting in no deaths or noticeable withdrawal. 0 Morphine. This experiment lasted a long time and was the substance the experiment team had the most experience with, 11 monkeys were used and 3 failed to self administer but after a little encouragement all became drug dependant. During mechanical failures the monkeys showed withdrawal symptoms and were observed rapidly pushing the lever frantically trying to get another hit. This part of the study lasted for 16 months and apart from being morphine addicts and being Dopey compared to their control counterparts the general health of the participants was good. It was seen that for the first 7-8 weeks the participants increased their dose eventually evening out, although one increased the dosage for 30 weeks! None died during this substance study. O Amthemines. All 5 of the monkeys initiated self administration and not long showed signs of hallucinations plucking the fur off their arms but none died, but by the end of the study period the participants were noticeably. 1 Cocaine. 4 monkeys were used to study the effects of cocaine, initially only half began to self administer. They found that after 30 days one of the monkeys died of an overdose, in order to increase the length of the study limits to amounts of cocaine was implemented. After the 30 day period the monkeys became withdrawn, stopped eating and showed signs of hallucinations. Some bit off their fingers and scratched their skin off. They pressed both levers and were noticeably confused. 2 Ethanol 4 of the 5 monkeys in this experiment Initiated self administration, but for the first few months self administration was interrupted by days of voluntary abstinence. These gaps would reduce as time went on, and the reactions from the animals was similar to what would be experienced in a drunk human, drowsiness, lack of spatial awareness and tiredness. When withdrawal was tested, the animals became sick, experienced tremors and even showed signs of hallucinations. 2 would die not from overdose but asphyxiation during their sleep from respiratory obstruction. 5 Codeine This involved 5 monkeys and only lasted for 8 weeks, 4 started self administration with only 1 needing to be initiated by the use of the automatic doses. The dose rate increased as each subject continued to self administer but after 6 weeks the 1st monkey died due to convulsions because of overdose, by week 8 all were dead after severe convulsions.

The Aftermath

The aftermath Now the experiment highlighted some interesting results, because previous experiments had made use of psychologically dependent animals i.e. they had been exposed to the substance via operant conditioning two mechanisms of self administration were thought. The first being avoidance of withdrawal and the other being the animal preferring being under the influence. This followed seevers dual action theory very well. The 1969 study by using non psychologically dependent animals who were naive to the effects of the drugs, showed that addiction in this case was chosen by the subjects to keep themselves under the influence. Much like how humans can continue their dependency even in the face of the negative ramifications such as familial, social and monetary problems stemming from addiction, although of course withdrawal also acts as punishment for not continuing taking the drug. What they also found was that not all monkeys began self administration and needed the automatic doses to become hooked. This shows that there are some more predetermined for addiction than others, much like in humans. By making use of cocaine and amphetamine in the study, it was shown that addiction is more likely caused by a psychological rather than physiological means as both these substances don’t create a physical dependence. Now these results are very interesting and helped provide a greater illumination of drug addiction but it was controversial not in its results but in its method. The experiment isn't cited in multiple most unethical studies lists for a reason. Now I did mention Harry Harlow earlier in the video and the Criticism of this study and Harlows work follow much the same lines. That is the unethical use of animals, where they essentially were torchered and killed during the experiment through the creation of long term drug exposure. Although the experiment hasn’t had as much exposure as say the pit of despair and the monkey mother, the traumer inflicted on the animals is no lesser an affair. Seevers' career wouldn’t be negatively affected by the study and he would continue to use a similar set up to explore the link between nicotine and addiction. The study has become one of the keystones cases in anti animal testing movements as the experiment seemly ignores the Helsinki declaration where “the welfare of animals used for researh must be respeted”. This is especially saddening as the results were essentially in its most simple term drugs known to be addictive are addictive.

Rating

I’m going to rate this subject around a 4 on my ethical scale do you agree? Let me know in the comments! https://deepblue.lib.umich.edu/bitstream/handle/2027.42/46354/213_2004_Article_BF00405254.pdf?sequenc http://garfield.library.upenn.edu/classics1990/A1990CL56100001.pdf https://link.springer.com/article/10.1007/s00213-016-4440-5 https://studylib.net/doc/6655565/unethical%09psychological https://collections.nlm.nih.gov/catalog/nlm:nlmuid-101428804-img https://www.researchgate.net/publication/43014525_Maurice_Seevers_the_Stimulants_and_the_Political_Economy_of_Addiction_in_American_Biomedicine https://deepblue.lib.umich.edu/bitstream/handle/2027.42/46396/213_2004_Article_BF00413045.pdf?sequence=1