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A Closer Look at the Rat Park Experiment, Part 1

By Kenneth Anderson, MA

Bruce K. Alexander’s rat park experiment series have become a very popular topic among people interested in addiction in recent years. The rat park experiments, published in 1978, 1979, and 1981, showed that albino Wistar rats living in a naturalistic environment with other rats consumed a lot less morphine than rats in solitary confinement in individual cages. In this article, I will give some of the historical background which led up to the rat park studies (Part 1), review the rat park studies themselves ( Part 2 ), and take a look at where we have gone since (Part 3). A huge number of studies have been conducted on the effect of environment on addiction in animal models since the days of the rat park experiment, and we have found that in some cases the results are similar to rat park, but in other cases they are the exact opposite. The effects of genetics, environment, and substances combine in very complex ways indeed.

Rats hate the bitter taste of morphine and consume very little of a morphine solution under ordinary circumstances, hence, they do not develop morphine addiction in nature, although they are quite happy to consume a solution of cocaine. Prior to 1940, all experimenters had managed to do in animal experiments on addictive substances was to induce tolerance and withdrawal by injecting animals with morphine. In 1940, Sidney Durward Shirley Spragg was the first experimenter to teach animals to become addicted to drugs. Spragg injected chimpanzees with morphine until they developed physical dependence, then taught them to open a white box containing a syringe loaded with morphine when they started going into withdrawal and to open a black box containing bananas when they were hungry. Of course, Spragg had to inject the monkeys himself, but they often brought him the syringe from the box.

Psychologist Donald O. Hebb was the first to realize that rats living in solitary confinement in cages might behave differently than rats nurtured in a naturalistic environment. Although classical behaviorism treats the brain as a black box that can connect any stimulus with any response with equal ease, this proposition proved to be false quite early on. In his 1949 book The Organization of Behavior , Hebb describes how he took home two litters of rat pups from his lab and raised them as pets, then compared their performance on a rat intelligence test with rats raised in the lab. The rats raised as pets far outstripped the rats raised in a lab on these tests. Later experiments found that raising rats in an enriched environment affected the emotionality, conditionability, and body weight of adult rats.

Another milestone in the study of addiction in animals occurred in 1962, when James R. Weeks published an article describing a procedure which he had developed whereby rats could inject themselves with drugs by pressing a lever, much the way that rats learned to press a lever for food pellets in a Skinner box , aka operant conditioning chamber. This gave scientists an easy way to model addiction to any drug in any lab animal.

In 1969, Gerald Deneau et al. published a paper on rhesus monkey trials of morphine, codeine, cocaine, amphetamine, pentobarbital, ethanol, caffeine, nalorphine, Thorazine, and mescaline. Deneau was with the Department of Pharmacology at the University of Michigan, which did the animal trials on drugs before the drugs were sent to the Lexington Narcotic Farm for human trials. Trials of both limited and unlimited access were reported. The rhesus monkeys were in solitary confinement and fitted with a harness connected to a cage wall with a hinged arm; the harness housed a catheter to the jugular vein through which the monkeys could self-inject a drug by pressing a lever. The monkeys hated the harness and several managed to break the connecting arm; it took them two days to adapt to the harness and settle down. The harness and arm are illustrated below.

Image of a scientific contraption designed to study animals and addiction before the design of The Rat Park experiment

Still, the harness was an improvement on previous methodology, which had involved strapping the monkey into a restraint chair and just leaving one arm free to press the lever to deliver the drugs.

Deneau et al. found that the rhesus monkeys in these experiments would self-administer cocaine or codeine until they died. Deneau et al. reported that they had to limit access to drugs like cocaine to one dose per hour to prevent the monkeys from killing themselves with it. Interestingly, no deaths from self-administration of morphine were reported.

Two very important experiments were published in 1976. One was an experiment by Shirley Y. Hill and Barbara J. Powell on the effect of an enriched environment compared to an impoverished environment on drug self-administration in male Wistar rats. After weaning, when they were 20-days old, 15 rats were raised in an enriched environment much like rat park. They all lived together in a single chamber with a sand floor and had many toys and exercise wheels. Nine rats were raised in the standard solitary confinement of lab rats. When the rats were 100-days old, they were transferred into standard laboratory cages, given a seven hour per day drinking schedule, and given five days to acclimate to their new surroundings. After the five days were up, the rats were placed in a two-bottle choice situation for the next 16 days. Nine rats from the enriched environment group were given a choice between water and a morphine solution, six rats from the enriched environment group were given a choice between water and a cocaine solution, four rats from the solitary confinement group were given a choice between water and a morphine solution, and five rats from the solitary confinement group were given a choice between water and a cocaine solution.

The rats basically ignored the morphine solution because they couldn’t stand the bitter taste and there was no significant difference between the enriched environment rats and the solitary confinement rats when it came to consumption of the morphine solution. The cocaine solution was a whole different story. Rats from both groups drank a lot of the cocaine solution; however, the rats which had been raised in the enriched environment drank significantly more than those raised in solitary confinement.

The other 1976 experiment was conducted by Chris E. Johanson et al. This was the first study to focus exclusively on unlimited access to stimulants such as cocaine and amphetamine. The subjects were 15 rhesus monkeys, 12 male and three female. Monkeys were housed in solitary confinement in wooden boxes with plexiglass tops. Each monkey was fitted with a stainless-steel harness connected to the back of the box with a flexible spring arm, as illustrated below.

image of scientific contraption designed for an experiment with monkeys and addiction - a study similar to the rat park experiment

The experiment lasted 30 days. Two monkeys were given unlimited access to cocaine; both died after injecting themselves non-stop for five days. Two monkeys were given unlimited access to levo-amphetamine; one died after five days, the other lived through the experiment. Two monkeys were given unlimited access to methamphetamine; one died after three days, the other died after 15 days. Four monkeys were given unlimited access to dextro-amphetamine; one died on day two, one died on day four, one died on day 10, and one died on day 13. Five monkeys were given unlimited access to diethylpropion (a diet drug); one died on day 17, one became comatose on day 19 and never recovered, and three survived the experiment.

NEXT: Part 2, the rat park experiment and the studies themselves .

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Addiction: The View from Rat Park (2010)

Addiction: The View from Rat Park

Bruce K. Alexander,Professor Emeritus, Simon Fraser University If you were a cute little white rat…

…you certainly wouldn’t want to live in a psychology laboratory. When I was an experimental psychologist, between about 1960 and 1980, white laboratory rats had to live in solitary confinement cellblocks like this…

Although the rats lived in close proximity, they could neither see nor touch each other, because the sides of their cages were made of sheet metal. The only visual stimulation they got was seeing the people who brought food and water and cleaned the metal pans under their cages every few days. Unlike human prisoners, the rats did not even get an exercise period outside their cramped cages.

And that was in the best of times. In the worst of times they were starved for 24 hours or more and put into Skinner Boxes that looked like this…

Inside Skinner Boxes, the rats could get tiny pellets of food one at a time, provided they pushed a little lever on the side of the box over and over and over. The metal floor made it possible for the experiment to administer electric shocks when the experiment was about punishment rather than reward, which it often was.

Do you think that this would qualify as psychological abuse of rats? Of course it would, if there were such a crime. But we young psychologists were trained not to think about what the rats might be experiencing. We usually did not even look at the rats, but only at the data they produced in the Skinner Boxes by pressing their little levers. The data looked like this...

Do you see any sign of rat angst or depression in these data? If not, the rats must be ok, right?

In the 1960s, some experimental psychologists began to think that the Skinner Box was a good place to study drug addiction. They perfected techniques that allowed the rats to inject small doses of a drug into themselves by pressing the lever. This required tethering the rat to the ceiling of the box with tubing and surgically implanting a needle, or catheter, into their jugular veins. The drug passed through the tube and the needle into the rats’ bloodstreams almost instantaneously when they pushed the lever. It reached their brains moments later.

Under appropriate conditions, rats would press the lever often enough to consume large amounts of heroin, morphine, amphetamine, cocaine, and other drugs in this situation. The mass media of the day were quite excited about these experiments. The results seemed to prove that these drugs were irresistibly addicting, even to rodents, and by extension, to human beings. The conclusion that illegal drugs are irresistibly addicting fit well with the fearsome images that were being propagated about them. The rat research provided additional support for the War on Drugs of that day. Irresistibly addicting drugs certainly cannot be allowed to circulate in human society, especially if, as we were told, this is your brain on drugs…

 

At first, the conclusion that was reached from this rat research made sense to me. But then I began to realize that it was a stretch. Actually, it was more than a stretch; it was a bone-cracking, joint-popping contortion of normal reason, for several reasons. First, the ancestors of laboratory rats in nature are highly social, sexual, and industrious creatures. Putting such a creature in solitary confinement would be the equivalent of doing the same thing to a human being. Solitary confinement drives people crazy; if prisoners in solitary have the chance to take mind-numbing drugs, they do. Might isolated rats not need to numb their minds in solitary confinement for the same reason that people do? Second, taking drugs in a Skinner box where almost no effort is required and there is nothing else to do is nothing like human addiction which always involves making choices between many possible alternatives. Third, rats are rats. How can we possibly reach conclusions about complex, perhaps spiritual experiences like human addiction and recovery by studying rats? Aren’t we more complex and soulful than rats, even if we have similar social needs?

A small group of colleagues at Simon Fraser University, including Robert Coambs, Patricia Hadaway, Barry Beyerstein, and myself undertook to test the conclusion about irresistibly addicting drugs that had been reached from the earlier rat studies. We compared the drug intake of rats housed in a reasonably normal environment 24 hours a day with rats kept in isolation in the solitary confinement cages that were standard in those days. This required building a great big plywood box on the floor of our laboratory, filling it with things that rats like, such as platforms for climbing, tin cans for hiding in, wood chips for strewing around, and running wheels for exercise. Naturally we included lots of rats of both sexes, and naturally the place soon was teeming with babies. The rats loved it and we loved it too, so we called it “Rat Park”.

We ran several experiments comparing the drug consumption of rats in Rat Park with rats in solitary confinement in regular laboratory cages. In virtually every experiment, the rats in solitary confinement consumed more drug solution, by every measure we could devise. And not just a little more. A lot more.

Here are the results of one of our first experiments.

You will see at a glance that the rats in Rat Park, called the “Social Females” and “Social Males” in this graph, are consuming hardly any morphine solution, but the “Caged Females” and “Caged Males” are consuming a lot. In this experiment the females consumed more than the males, but that gender difference did not hold up in later experiments. It soon became absolutely clear to us that the earlier Skinner box experiments did not prove that morphine was irresistible to rats. Rather, most of the consumption of rats isolated in a Skinner box was likely to be a response to isolation itsself. So, we published the results of our experiments in psychopharmacology journals.

The Rat Park research attracted lots of attention in the local media in our city, and among our students at our university, but in the larger world of addiction theory it sank like a stone, even after other researchers replicated our findings. We had hoped that our research might initiate a serious reconsideration of the conventional wisdom on the causes of addition. When it didn’t, we were surprised and disappointed. However, we were all at an early stage in our professional careers and looking for other issues to tackle. After our satisfying, but unheralded, success with Rat Park, our individual interests took us off in separate directions.

One of the worst aspects of closing of Rat Park was that it left us with unresolved questions. A new graduate student in our lab had tried to replicate one of our original experiments but did not get statistically significant results. Non-replication is not a fatal problem in laboratory research, but it requires follow up studies to determine why it happens. Many factors can determine the outcomes of experiments and not all ofthem can be controlled. Did the non-replication occur because the researcher had to use a new substrain of rats, or because the modified, presumably improved, apparatus that measured drug and water consumption in Rat Park didnot work as well as the original machinery, or simply because the Rat Park effect was not as robust as we originally thought? We never were able to work out  the mystery, because Rat Park was closed down for good. However, we remain confident in our original experiments, partly because we had repeated them several times in different ways, partly because they were replicated with different apparatuses by researchers at other universities, and partly because more recent research with different methods has shown other fatal deficiencies in the original Skinner box research which once appeared to show that all rats and people who use addictive drugs become addicted.

But a vague question lingered in my mind. Our rats consumed much more morphine when they were isolated. This fact definitely undermined the supposed proof that certain drugs irresistibly cause addiction. But what does cause addiction? Why is there currently a flood of addiction to drugs and many other habits and pursuits? People do not have to be put into cages to become addicted – but is there a sense in which people who become addicted actually feel “caged”? It turns out that the answer to this last question is “yes”. Or rather, “YES!” The insight into human addiction that grows from the Rat Park research is not terribly complicated, but it took me about 15 years to grasp it clearly and another 10 years to assemble the evidence from human history and anthropology to show that it is true and another 5 years to write a book about it. (The Globalisation of Addiction: A study in poverty of the spirit, Oxford University Press, 2008). That’s how I got to be an old guy.

My graduate students and I first tried to replicate part of the Rat Park research with human beings, by getting people to role-play prisoners and guards in a prison. The idea was that the prisoners in a simulated prison would be in the same state of mind as the rats in Rat Park. We couldn’t offer them drugs of course, but we could at least ask them about how they felt and get an idea of the mindset that is conducive to consumption of drugs. Unfortunately, the experiment told us nothing…Back to the drawing board.

How could we do an experiment with people that was something like Rat Park, without treating our human subjects unethically or illegally? I gradually realized that history provides natural experiments of the sort I needed. The results are sitting around in dusty books just waiting to be analyzed. One of these many natural experiments is the effect of colonization on native people.

Here are the basic facts as they are recorded in the history of Western Canada, where I live, although very similar historical data can be found in many countries:

The English colonial empire overran hundreds of native tribal groups in Western Canada in the 18 th and 19 th century. The native people were moved off expansive tribal lands onto very small reserves, completely destroying the economic basis of their cultures. Their children were taken from their parents and sent off to “residential schools” to be taught the white man’s culture so they could be assimilated. They were forbidden to speak their native languages and found themselves strangers in their own communities when they finally came home.

Prior to the colonial conquest, the native people had some serious problems, of course, including frequent tribal warfare, with prisoners being killed or kept as slaves. Mental illness, personal betrayals, and epidemic diseases occasionally occurred in pre-colonial tribes. Basically, native people had all the problems of their English colonizers except one. There was so little addiction that it is very difficult to prove from written and oral histories that it existed at all.

But once the native people were colonized alcoholism became close to universal. There were entire reserves where virtually every teenager and adult was either an alcohol or drug addict or “on the wagon”. There still are a few reserves like this. Addiction was not limited to alcohol, but eventually encompassed the full range of addictions found in the wider society: drugs, television, gambling, Internet, dysfunctional love relationships, etc.

At first, the English settlers explained the universal alcoholism of the natives with the a story of genetic vulnerability. They said “Indians just can’t handle liquor” and tried to solve the problem with strict alcohol prohibition. That didn’t work and most people don’t believe the genetic vulnerability story anymore.

So why did universal addiction strike the colonized natives of Western Canada and the world as well? Certain parallels between the problems of colonized human beings and the rats in Rat Park appear to provide an explanation. In both cases there is little drug consumption in the natural environment and a lot when the people or animals are placed in an environment that produces social and cultural isolation. In the case of rats, social and cultural isolation is produced by confining the rats in individual cages. In the case of native people, the social and cultural isolation is produced by destroying the foundations of their cultural life: taking away almost all of their traditional land, breaking up families, preventing children from learning their own language, prohibiting their most basic religious ceremonies (potlatches and spirit dancing in Western Canada), discrediting traditional medical practices, and so forth. Under such conditions, both rats and people consume too much of whatever drug that is made easily accessible to them. Morphine for the rats, alcohol for the people.

In both cases, the colonizers or the experimenters who provide the drug explain the drug consumption in the isolated environment by saying that the drug is irresistible to the people or the rats. But in both cases, the drug only becomes irresistible when the opportunity for normal social existence is destroyed .

In the case of natives of Western Canada, other historical information makes it perfectly clear that a simple genetic vulnerability to alcohol was not the cause of the devastating plague of alcoholism that occurred. There are several different types of evidence:

1. In cases where alcohol was available to natives, but their cultures were not destroyed, they were able to incorporate alcohol into their native traditions without too much trouble. People drank and some people got plenty drunk on some occasions, but there was no widespread alcoholism.

2. In cases where native cultures were destroyed, but alcohol was not available, native people showed many of the symptoms that are associated with mass alcoholism, without ever tasting a drop. In other words, people stopped doing productive work and taking care of their families and concentrated on aping the manners of the English invaders and idling away their time. Criminality and child neglect became problems, where they had not been before. But alcohol was not the cause because there wasn’t any!

3. We now know that native people whose cultures have been destroyed are vulnerable to all the addictions that white people are. If Indians whose cultures have been destroyed have a genetic weakness for alcohol, they also have a genetic weakness for drugs, television, gambling, bingo, Internet, and dysfunctional love relationships!

If the alcohol itself was not the cause of native alcoholism, what was? The great advantage of doing our research with human beings rather than rodents is that people are often willing to tell us the answer to our questions. Native people have described the anguish of being deprived of their traditional cultures and social networks in eloquent language and have explained how drunkeness relieved their misery temporarily, even as it ultimately led to self-destruction.

When I look at the pictures of our caged rats now, it is easy for me to think that I detect something similar to the anguish or rage that native people describe when their cultures are destroyed. However not everyone agrees. Some people seem to think that rats are pretty inscrutable. There is no way to resolve an argument what rats are feeling. So I have never gone back to rat experimentation but have instead searched out more and more parallels in the literature of human history and anthropology. This work is still in progress. There is no shortage of parallels from people of all races and many cultures.

When I talk to addicted people, whether they are addicted to alcohol, drugs, gambling, Internet use, sex, or anything else, I encounter human beings who really do not have a viable social or cultural life. They use their addictions as a way of coping with their dislocation: as an escape, a pain killer, or a kind of substitute for a full life. More and more psychologists and psychiatrists are reporting similar observations. Maybe our fragmented, mobile, ever-changing modern society has produced social and cultural isolation in very large numbers of people, even though their cages are invisible! The view of addiction from Rat Park is that today’s flood of addiction is occurring because our hyperindividualistic, hypercompetitive, frantic, crisis-ridden society makes most people feel social and culturally isolated. Chronic isolation causes people to look for relief. They find temporary relief in addiction to drugs or any of a thousand other habits and pursuits because addiction allows them to escape from their feelings, to deaden their senses, and to experience an addictive lifestyle as a substitute for a full life. At this point, it is too early to say conclusively if the Rat Park view of addiction is right or not, but it is not too early to be sure that the old theory that addiction is a problem caused by addictive drugs is far too simple. Huge amounts of research money have been spent researching the idea that addictive drugs are the cause of addiction and treatments based on that idea have been tried over the world. In the meantime, the once-small problem of addiction has globalized. Moreover, it has become absolutely clear that drug and alcohol addiction is only a corner of a much larger addiction problem!

It is definitely time for a fresh direction in the theory of addiction, and I have a hunch – as well as a hope – that Rat Park might provide the starting point. The next steps from this starting point are explained in my book  The Globalization of Addiction: A study in poverty of the spirit. (Oxford Univ. Press, 2010).

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Rat Park: How a rat paradise changed the narrative of addiction

Affiliations.

  • 1 Department of Psychological Sciences, University of Liverpool, Liverpool, UK.
  • 2 Public Health Institute, Liverpool John Moores University, Liverpool, UK.
  • PMID: 30367729
  • DOI: 10.1111/add.14481

Keywords: Biopsychosocial model; drug self-administration; morphine; popular culture; pre-clinical model; ‘Rat Park’.

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Rat Park: How a rat paradise changed the narrative of addiction

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What the 1981 Rat Park Experiment Means for Addiction and Our Need For Human Connection

Posted by Roger R. | Feb 1, 2016 | Addiction , Articles | 2

What the 1981 Rat Park Experiment Means for Addiction and Our Need For Human Connection

Though it wasn’t a popular theory at the time, the Rat Park Experiment in the 1980s showed the positive effects of socialization and connection against the temptations of addiction. | Image Source: Flickr User Jason Snyder

Where does addiction come from? From a history of viewing addicts as suffering from a lack of morals to the more contemporary view that addiction is a mental disease, our ideas around the source of addiction has become more sophisticated over recent decades. But we’re still far from understanding this complicated condition in all of its nuances. Conventional wisdom today often seems no better equipped to truly help those struggling with addiction demons. It may come as a surprise, then, that we’ve had a critical piece to the puzzle under our noses for over 30 years.

In 1981, a scientist named Bruce Alexander and his team ran a study that could have completely changed the dialogue around addiction, but at the time, it was brushed under the rug. That study is known informally as the Rat Park Experiment.

First, some background: Rat Park came in response to a number of addiction studies in the ‘60s and ‘70s where rats were placed in solitary, cramped cages. The rats were given free rein to choose between water and a solution laced with different drugs like morphine (a close relative of heroin) or cocaine. Inevitably, the rats drank enough of the drug to kill themselves, and the outcome was publicized as evidence of drugs’ all-consuming nature. These studies are still used as key support for zero-tolerance policies around drugs to this day.

The Most Important Addiction Study You’ve Never Heard Of

Bruce Alexander — a psychologist who has researched and taught on the psychology of addiction in British Columbia, Canada, since 1970 — wasn’t satisfied with this answer. Instead, he looked at the isolated condition of the rats and asked himself: who wouldn’t drug themselves to oblivion, trapped in a tiny cage alone and without stimulation?

So he designed a new study where a control group of rats was placed individually in the same solitary conditions but with another group of 20-30 rats in a place he called Rat Park: a huge, well-furnished cage with many friends, nooks and crannies to explore, running wheels, interesting objects, and places to hide. He gave the rats the same choice of water or drugs. Even with unlimited access to abusive substances, the well-socialized, community-living rats overwhelmingly chose water. Alexander’s follow-up studies found that even rats that had been stuck in drugged isolation for as many as 57 days, once transferred to Rat Park, voluntarily went through withdrawal and kicked their habit.

Here’s a great video from Kurzgesagt  that sums up the findings of the study:

If we take these results to heart, it would seem that drugs alone don’t cause addiction. Addiction comes from a deeper place: feelings of isolation, alienation, or lack of control. Alexander went on to develop his theory of addiction as coming from this lack of social integration, or what he calls “dislocation” or a “poverty of the spirit.”

Of course, we couldn’t—and shouldn’t—do an experiment like this on humans, but Alexander points to many historical examples of waves of addiction following dislocation in human society. One interesting connection that he made was that addiction epidemics have regularly occurred when indigenous cultures are colonized, subjugated, and displaced in American history. As long-standing cultural ties to the land and to community are lost, the void created gets filled with addiction to whatever substances and habits are available. Alexander argues that we are in the midst of a mass displacement today thanks to widespread economic troubles and a culture shifting more and more away from community-minded living.

What Rat Park Means for Addiction and Prohibition

What are the lessons to be learned from Rat Park? For starters, we should look at why this theory—and the evidence behind it—has been ignored. The story of Rat Park doesn’t fit neatly into the popular conception of what addiction is. It challenges the idea that drugs themselves cause all-consuming addiction once you take them , and if we “just say no,” there is nothing to fear. This is the popular reasoning behind drug prohibition , despite the War on Drugs now publicly being acknowledged as a failure . This more nuanced truth, however, doesn’t make for a very snappy headline.

On a more personal level, if we accept this idea, we can not only learn to treat those who are suffering from addiction more humanely but do a better job exploring forms of treatment that have shown to be effective . If access to drugs is not the sole cause to addiction, then merely taking those drugs away won’t cure it. Therapies that simply help an individual “kick” their drug habit are not enough. If they return to the same life, mindset, and fractured community once the treatment ends—that is, the same cage—the chance of relapse is greater.  

How Psychedelic Therapy Can Unlock the Cage

How can we make our lives look more like Rat Park instead of a solitary cage? The answer is that any effective addiction treatment will have to restore this missing piece of social integration one way or another. Psychedelic treatment holds particular promise with its ability to change your outlook , increase openness, and create deep and meaningful connections.

Dedicated psychedelic therapy institutes already seem to take this as a given—they know that those struggling with addiction often feel intense isolation and are in need of our compassion. Successful psychedelic treatment involves group counseling, open dialogue, and expert facilitators . Effective recovery coaches and psychedelic practitioners have witnessed the transformative power of listening with genuine empathy and compassion and build it into their practice with conscious conversation . Practices like these can not only bring us out of isolation — they give us the tools to create social integration in every avenue of our lives.

Unlike Alexander’s rats, our cages may not be physical but rather emotional and social. We feel alienated from our neighbors, our co-workers, even our families. Psychedelic therapy has the potential to restore our connection to humanity and unlock the cages we inadvertently build around ourselves. If you or a loved one suffers from addiction, consider your environment and your social ties. Consider the cage you may be in, and take a lesson from the Rat Park Experiment. Give those who are suffering your empathy and support, and if you are struggling yourself, realize that you deserve the same. The power of a compassionate connection can make all the difference.

About The Author

Roger R.

Roger is a writer, researcher, and advocate for psychedelic research and treatment thanks to his experience with harm reduction and stress research, in the field with a mobile syringe exchange program, and in his personal life supporting loved ones who struggle with addiction.

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rat drug experiment

‘Rat Park’ Study – A Simplistic View of Addiction

By katie macbride., in 1979, bruce alexander, a researcher at simon fraser university, separated rats into two cages, a stimulating one and an isolated one, and gave them morphine in order to measure the effect of environment on addiction rates., the so-called “ rat park ” experiment was intended to debunk some of the flawed understanding around addiction at the time, specifically the notion that the drug itself was the most important factor in whether someone became addicted. the rats in both cages became physically dependent on the morphine, but the rat park rats consumed less morphine than the group in the boring cage. “addiction isn’t you — it’s the cage you live in,” alexander concluded., the rat park study was flawed in its design and its findings, however, and it was ignored for almost three decades — until a group of experts rediscovered and started promoting it around 2008. the rat park study undermined one popular misconception about addiction, that chemistry of drugs is the single most important factor in addiction. but instead of pushing the popular understanding forward, it merely replaced that misconception with a new one: that environment is the most important factor., unfortunately, addiction isn’t that simple. the idea that there is nothing inherently dangerous about drugs — specifically opioids — is inaccurate. and with the opioid epidemic spreading throughout the country [america], it’s potentially dangerous.at the time alexander conducted his study, the united states was seven years into the war on drugs, the trillion-dollar federal government effort to eradicate illegal street drugs by focusing on arresting and imprisoning drug sellers and users., the prevailing rhetoric asserted that recreational drugs were inherently addictive and using them would “hijack” the brain, turning it from a “normal” brain into an addicted one. this was an oversimplified, damaging view that fundamentally misunderstood addiction and helped undermine more effective policy ideas like decriminalization and harm reduction. alexander called this the “myth of the demon drug.”, though many had long doubted the effectiveness of increased criminalization of drugs and drug use, it took 30 years of longitudinal studies to get hard data to support that notion. in 2008, the brookings institute compared the “punishment” model used in the u.s. to more lenient policies in europe, and found that it did not correlate with lower usage rates; in fact, the “combined hardcore user rate for hard drugs” was “approximately 4 times higher in the us than in europe,” the report concluded., as it became more apparent that the war on drugs was a costly failure, both in terms of dollars and damage to people and communities, its critics became more vocal. and in the late aughts, they found fodder in the rat park experiment., the experiment’s finding that environment is the determining factor in the development of addiction was held up as the “vital missing evidence” by the psychologist and bbc columnist tom stafford, and many other writers, journalists, and popular psychologists picked up the line., in 2008, gabor maté, a canadian doctor, addiction expert, and strong critic of the war on drugs, published  in the realm of hungry ghosts: close encounters with addiction , which was was a #1 best-seller in canada and went on to be a  new york times  bestseller as well. in the book, maté argued that the war on drugs has been a failure and argues for more comprehensive, compassionate treatment of people struggling with addiction. he devoted a chapter to establishing how environment can be a significant contributing factor in developing an addiction. he cited the rat park experiment as well as a study published in 1975 which showed that rates of heroin addiction were 20 times higher for vietnam soldiers while they were stationed in the war zone than before they shipped out. after they returned to the u.s., addiction rates fell back to pre-deployment levels., after the signal boost from  in the realm of hungry ghosts , folks interested in understanding addiction wrote excitedly about the study. the psychologist and author lauren slater devoted a chapter to rat park in her 2004 book,  opening skinner’s box: great psychological experiments of the 20th century . stuart mcmillen produced a science comic book about rat park and put it on the internet. the controversial former uk chairman of the advisory council on the misuse of drugs david nutt, who was asked to step down after saying he thought alcohol and tobacco were more harmful than cannabis, lsd, and ecstasy, referred to the study in his 2012 book  drugs without the hot air . cory doctorow, founder and editor of the popular website  boingboing , read nutt’s book and wrote an article praising the rat park study., the rat park experiment provides seemingly perfect evidence to explain why the war on drugs is such a failure, because its policies focus on drugs as the source of the problem. while the failure of the war on drugs is virtually undisputed among experts in the field of addiction — though sadly not represented by significant changes in policy, as drug offenses are the “single biggest factor” contributing to booming incarceration numbers — alexander’s emphasis on the user’s environment was novel and presented obvious implications for drug policy., the buzz dr. maté had generated around the rat park experiment became a roar in 2015, when johann hari published  chasing the scream: the first and last days of the war on drugs . focusing heavily on the work of maté and alexander, hari asserts that he has discovered the “likely cause” of addiction: a lack of human connection. just as the rats in the isolated rat park cage needed social interaction and connection with other rats, hari wrote, so do humans. alexander believed a poor environment causes addiction; hari asserted that the disconnection that arises from a poor environment creates addiction., despite a poor review in the  new york times ,  chasing the scream  went on to be on the best-seller lists for weeks. hari’s ted talk, modestly titled “ everything you know about addiction is wrong ,” has been viewed over three million times..

rat drug experiment

In 2017, the Rat Park study continues to be cited as a “classic experiment” in the field of addiction.

“all those who subscribe to [a] sociological theory of addiction trot [the rat park experiment] out as if it establishes their premise,” said dr. sam snodgrass, a member on the board of directors of the substance abuse support organization broken no more. “the problem is that most people aren’t scientists and believe whatever they read.”, unfortunately, the rat park study had some issues., despite his claims of a revolutionary breakthrough, alexander had trouble finding a journal to publish his results. both  science  and  nature  rejected the study for publication, likely due to significant problems with the methodology and results.  pharmacology biochemistry and behavior  published the results in 1981 with little response and the funding for rat park was canceled shortly thereafter., alexander lost eight days’ worth of data due to a malfunctioning piece of electronic equipment used to measure the amount of liquid the rats consumed, which may or may not have impacted his results. he also failed to control for important variables, snodgrass said. for example, male and female rats in the boring cage were isolated from each other, he said, but they were housed together in the rat park cage. soon, rat park was filled with rat pups. alexander never explained what happened to the pups, snodgrass said, such as whether they were removed or left in the cage and somehow factored into the results. “the females would wean one litter after approximately 18 days and then would begin to cycle again,” snodgrass said. “you can’t do this. you can’t have one group of subjects mating and with pups and compare it to a group that doesn’t engage in these behaviors and say that the difference between the two groups is caused by environmental differences.”, when scientists tried to replicate the rat park study, they got mixed results. in 1996, a study attempted to precisely replicate the conditions in alexander’s rat park, down to the breed of rat. the researchers conducted two experiments to see if they could replicate the rat park study’s results. in the first experiment, the happy, social rats consumed slightly more of the morphine liquid, in the second experiment, the isolated rats drank slightly more. neither experiment reflected the rat park’s results, which had the isolated rats drinking up to seven times the amount of the morphine liquid as the social rats. the authors of the study note that in 1979 the supplier both they and alexander used for wistar rats changed, noting that “the wistar rats used in the alexander, et al. study were old colony wistar rats, and the ones used in the 1996 were new colony wistar rats.” the author concluded that the difference in behavior between the rats in the initial rat park study and the 1996 study were, “likely genetic in nature” (petrie, 1996). this is especially notable considering alexander’s current position that genetics do not play any role in the development of addiction., other studies did indeed replicate the results of alexander’s rat park, as he notes on his website., finally, there is the obvious fact that rats aren’t human and thus behave differently than humans do. dr. adi jaffe notes how this specifically impacts the rat park study  here ., so if the four-decades-old rat park experiment provided important but partial, or inconclusive, evidence about the cause of addiction, why is it still being touted as the “missing link” to understanding addiction today in part, the persistence and ineffectiveness of the war on drugs is to blame., alexander’s study was an important breakthrough in understanding addiction, but the results were far from conclusive. the study’s real problems have less to do with the science and more to do with the grandiose claims made based on the results. for example, morphine (an opioid) was the only type of drug used in the experiment, but alexander extrapolated that addiction to all drugs would present similarly. this is likely because his theory states that the drug itself is almost irrelevant — addiction is determined by environment, not the drug itself. he writes that “addiction to drugs as well as other habits and pursuits” happens when people “feel ‘caged.’”, there is likely some truth to this. certain people are more vulnerable to addiction than others; many people can use any array of drug without becoming addicted. but although addiction experts disagree slightly about where certain drugs should be on a spectrum of most to least addictive, almost all agree that there is indeed a spectrum. it would be willfully ignorant to say that a person is equally likely to become addicted to cannabis as they are to oxycontin or fentanyl.  of course  the drug in question matters. so do a plethora of other factors. in reality, there are many factors that lead to addiction, including environment, stress, genetics, life-circumstances, and adverse childhood experiences (aces). it is not uncommon for people with addictions to have any combination of the above factors, nor is it an exhaustive list. these factors also have different effects on different individuals. for example, people who suffer from a mental illness are twice as likely to struggle with addiction. but both hari and alexander still claim they’ve discovered the “real,” implying singular, cause of addiction., the point that rat park is used to underscore is true. environment often plays a role in a person developing an addiction and the war on drugs does nothing to address that. in fact, the war on drugs has done tremendous harm by ignoring the sociological factors that contribute to addiction and focusing exclusively on criminalization. alexander and hari argue that we need a more humane approach to drug policy, a belief that is widely shared. but ignoring the greater body of addiction science in favor of a neat narrative is the kind of thinking that fueled the war on drugs. it’s precisely because this is such an important fight that we should make sure our arguments, and the evidence we use to support them, are sound., article orginally published by ‘ the outline ‘ online magazine 25/09/2017., share this:, 2 thoughts on “ ‘rat park’ study – a simplistic view of addiction ”.

[…] https://12stepphilosophy.org/2019/06/27/rat-park-study-a-simplistic-view-of-addiction/ […]

[…] https://12stepphilosophy.org/2019/06/27/rat-park-study-a-simplistic-view-of-addiction/ […]

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The Rat Park Experiment

The Rat Park Experiment

What can the Rat Park experiment teach us about addiction?

Last Updated:

January 4th, 2024

rat drug experiment

Today, we take a closer look at the experiment, covering everything from its setup to the conclusions we can draw from the results.

What was the reasoning behind the Rat Park experiment?

The experiment was designed to challenge and reevaluate previous studies on drug addiction , which used rats in isolated and barren environments. In these earlier experiments, rats were placed in small, individual cages with access to a water solution containing morphine. The results consistently showed that the rats developed addictive behaviours towards the morphine-laced water, often leading to the idea that the drugs themselves were inherently addictive.

Sceptical of this experiment, Bruce Alexander, a Canadian psychologist, conducted his own experiment in the 1970s. He questioned whether the isolated and stressful conditions of the previous experiments were influencing the results. He proposed that addiction might be more closely related to environmental and social factors than the pharmacological properties of the drugs themselves. To test this hypothesis, Alexander conducted the Rat Park experiment.

Why were rats used in this experiment?

Rats were chosen for the Rat Park experiment due to their significant physiological and behavioural similarities to humans. Their social nature, complex behaviours, and shared neurological pathways make them suitable subjects for studying the influence of environmental factors on addiction.

How was the Rat Park experiment conducted, and what did they find?

Here’s how the team carried out the experiment and the results they found:

Alexander and his team created a large, comfortable environment for multiple rats. This environment was spacious and enriched with toys, tunnels, and other forms of social and physical stimulation. The researchers believed that this setting was more representative of a rat’s natural habitat than the standard laboratory cages.
Two groups of rats were used in the experiment. One group lived in standard laboratory cages, isolated from other rats, while the other group lived in the enriched environment of Rat Park.
In both groups, rats were given access to two water bottles, one containing a solution of plain water and the other containing a solution of water mixed with cocaine and opiates. The rats could choose which solution to drink on their own accord.
The researchers observed and measured the rats’ drug consumption over time. They monitored how much of the morphine solution the rats in each group consumed.
The findings of the Rat Park experiment suggested that rats living in the enriched environment of Rat Park consumed significantly less morphine than those living in the standard laboratory cages. The researchers concluded that social and environmental factors in Rat Park, such as social interaction and mental stimulation, played a crucial role in reducing the rats’ inclination to self-administer the drugged water. This led them to question the prevailing view of addiction as a simple chemical dependency and emphasised the importance of social and environmental factors in understanding and addressing addiction.

What does the Rat Park experiment suggest about addiction?

The Rat Park experiment has given us hours of debating and discussion time. Below, we take a look at some of the key things that Rat Park could teach us about addiction and question how we view it:

1. Environment’s impact on addiction

When we compared the two settings, it became obvious which environment triumphed. The isolated groups of rats had tiny, dark cages with nothing to keep them entertained but drugs. On the flip side, the Rat Park was like a dream home for rodents, all fancy and full of excitement. The rats there had lots of space, interactive toys, wheels to spin on, and buddies to hang out with (and have sex with too!). Of course, the rats in this cool setup were less likely to choose the drug-laced water than those stuck in those boring, lonely cages. This tells us something important about people, too – our surroundings really matter when it comes to how likely we are to get addicted.

2. Social interaction and support

The Rat Park experiment’s key discovery was how social interaction affects addiction. Rats in a better environment were thriving when it came to community and social activities. Having a supportive community among the rats seemed to keep them away from choosing the water laced with morphine. This idea is pretty important for humans, too, hinting that having strong social ties and feeling like you belong might be key to stopping or lessening addictive behaviours. It’s a reminder of how vital social support systems are when we’re dealing with addiction in people.

3. Isolation as a risk factor

The experiment also highlighted the detrimental effects of isolation on addiction. Those stuck in solitary conditions were more likely to take more drugs compared to the rats in the socially active Rat Park. This connects with human experiences because people dealing with isolation and loneliness might turn to addictive substances for comfort. The research highlights that dealing with social isolation is crucial when coming up with ways to prevent and treat addiction.

4. Alternative rewards

The idea of alternative rewards shakes up the old idea that addictive behaviours are the only way to find pleasure and satisfaction. The idea is that if people have other things that make them happy and satisfied, they might not feel the need to turn to addictive substances. This concept is based on the fact that people have certain needs that need to be fulfilled, and if we encourage them to engage in activities that bring joy, fulfilment, and a sense of achievement, it could lead to a more balanced and satisfying life.

5. Holistic approach to addiction

A holistic approach to addiction looks at the big picture, understanding that there are many different factors that play a role, and they’re all connected. It’s not just about the substance; it considers all parts of a person’s life. This means looking at the biological, psychological, social, and environmental sides of addiction. Treating someone holistically involves a mix of medical help, talking therapies , support from friends and family, and making changes to how they live. The idea is to see addiction as something complicated involving lots of different factors. By doing this, a holistic approach aims to find complete and lasting solutions that help people stay on track for the long haul.

6. Behavioural adaptation

Behavioural adaptation means people can change the way they act and what they do based on what’s happening around them. When we’re talking about addiction, it suggests that individuals can learn and pick up new, healthier habits to replace the ones linked to addiction. This might include coming up with ways to handle stress, managing tough situations, and making healthier life choices. Understanding that people can adapt their behaviour highlights how crucial it is to give them the right tools and support. It’s about helping them make positive changes in the way they behave.

7. Recovery is by no means impossible

Recovery potential is about believing that people facing addiction can get better. It’s not about thinking that the outcome is already set in stone. Instead, it sees recovery as a continuous and changing process. To make progress, we look at a person’s strengths, resilience, and the people around them who can provide support. This method promotes giving individuals the power to play a big part in their own recovery. It encourages a feeling of control and hope. When we recognise and use a person’s natural ability to change for the better, we agree that long-lasting recovery is possible for many folks dealing with addiction.

Are you struggling with addiction and need a guiding hand?

If you or a loved one is struggling with the challenges of drug addiction, know that you’re not alone. UKAT is here to extend a helping hand, guiding you towards a brighter, healthier future.

We offer safe and comfortable environments that provide all the tools you need to lead a drug-free life.

Don’t let addiction control your life any longer. Reach out to UKAT and let our expert team guide you towards a brighter, healthier future.

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What Can the Rat Park Experiments Teach Us About Drug Addiction_ - Cirque Lodge

What Can the Rat Park Experiments Teach Us About Drug Addiction?

Alexander offered the rats a choice between water and a morphine solution. He found that the rats living together in the colony drank significantly less morphine than those living alone in isolation.

What Can We Learn From the Rat Park Experiments?

Alexander published the rat park experiments near the beginning of the war on drugs in the United States. The war on drugs was a hugely expensive and largely ineffective attempt to reduce the drug trade through harsh legal penalties and punitive policies. The consensus was that the substance itself caused addiction and that addiction could only be reduced by removing the substance from society.

Alexander argued that his experiments showed that environmental factors were the primary cause of addiction, and consequently, fighting drug addiction should involve nurturing environments where people choose not to take addictive drugs rather than simply punishing those who deal them.

Subsequent studies have supported these conclusions. A 1992 study that isolated mice for different periods of time before offering them the choice between morphine and water found that the length of time for which mice were isolated directly correlated with the amount of morphine they chose to drink.

Similarly, a 2010 study on rats found that as little as sixty minutes of daily social interaction with another rat was enough to bring their morphine consumption down to the same level as the colony rats. It implies that social factors in the environment may be especially important in preventing or treating addiction.

What Are the Limitations of the Rat Park Experiments?

It is, however, important not to draw firm or specific conclusions from these experiments alone - the rat park experiments have several limitations.

Firstly, they are studies on rats, not humans, and there are, of course, many differences between them and us. Secondly, the number of rats in each experiment was small, and the results were only generated under very specific conditions. Also, some subsequent studies with different kinds of rats failed to replicate the same results.

Given this, it would be wrong to conclude from the experiments that we could solve drug addiction crises just by providing certain social settings for people to live in or that environmental conditions are the only factors at play. But the experiments do suggest we should consider environmental factors in our research on addiction treatment methods, prevention programs, and policies impacting drugs and crime.

How Do the Rat Park Experiments Fit in With Other Research on Drug Addiction?

Other scientific research and observations support the idea that environmental conditions are important risk factors for developing addiction and may be key to treating it.

For example, by the end of the Vietnam War, many US soldiers were addicted to opioids. However, when they returned to their hometowns, they found that quitting was a relatively easy process. Whether this was because of the absence of triggers, lack of availability of drugs, or other reasons, it seemed the change in environment made a big difference.

Research into addiction treatment methods has also found that environmental factors - in particular supportive social networks - can be crucial in the addiction recovery process. Support groups like 12-steps meetings, where people in recovery help one another overcome addiction, are proven to help people maintain abstinence from drugs and alcohol in the long term.

Equally, environmental factors also affect the risk of developing an addiction in the first place. Studies have found, for example, that exposure to traumatic events during childhood increases the likelihood of developing an opioid dependency .

Like the rat park experiments, these findings point to the role of environmental factors in drug addiction. This does not mean, however, that they are the only relevant factors. Brain chemistry, genetics, and the substance itself may also play a role, and it is important to consider all these elements together when studying addiction.

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rat drug experiment

What Does “Rat Park” Say About Addiction?

What Does “Rat Park” Say About Addiction?

Author: Ilana Jael

One famous series of studies of addiction known as the “Rat Park” experiment has a lasting impact on how people and professionals think about it to this day. In the late 1970s, researcher Bruce Alexander noticed the fact that most rat studies of addiction involved rats who were kept in, effectively, solitary confinement, alone in cages by themselves. These studies showed heroin, morphine, amphetamine, cocaine to be highly addictive, so much so that rats would sometimes starve to death rather than stopping their drug use to eat. 

Alexander thus became curious about whether rats who did not live under the same isolated conditions would show as strong of a preference for addictive drugs and designed an experiment to study the question. So he built a “rat park”— a large housing complex for his rats where they would be able to socialize freely, and that was full of “things that rats like, such as platforms for climbing, tin cans for hiding in, wood chips for strewing around, and running wheels for exercise.”

Then, he gave these fortunate rats access to morphine and measured how much of it they consumed relative to a solitary control group. Incredibly, the solitary rats were found to consume 19 times more morphine than the rat park rats. In a follow up experiment, when rats were deliberately made addicted to morphine and then given a choice as to how much to consume, the solitary rats continued to choose the drug but the rat park rats actively attempted to resist it despite the presence of withdrawal symptoms, presumably so they could soberly continue with their satisfying rat social lives.

The rat park model of addiction could partially explain the fact that most people who try even the most addictive drugs do not ultimately become addicted to them, while social conditions like poverty that limit opportunities are found to greatly increase addiction risk. 

Alexander later found further evidence for this theory by studying alcoholism in Native American populations, whose cultures were destroyed by colonial conquest, coming to the conclusion that  “the drug only becomes irresistible when the opportunity for normal social existence is destroyed.”

However, later researchers questioned the methodology and replicability of these experiments and the wisdom of extrapolating rat conclusions to human addiction problems. For instance, this oversimplification doesn’t account for other factors that might drive addiction, like genetic vulnerability, the lingering effects of trauma, and social rituals surrounding drug use.

It also doesn’t explain why drug use would be so rampant in populations who do not appear to be so obviously “in cages.” But Alexander also suggested that the “hyperindividualistic, hypercompetitive, frantic, crisis-ridden society” of modern day America “makes most people feel socially and culturally isolated.” And the chronically high rates of loneliness among Americans, a problem which the pandemic has only deepened, seems to suggest that he may have a point.

Whether or not they represent a literal truth about rats and drug use, the Rat Park experiments and their intuitive appeal do seem to tell a powerful story about addiction that has value in how we, as a society, should approach it. Maybe people who are struggling with a substance use disorder don’t need moralizing or punishment, but rather empathy, opportunity, and connection.

The rat park experiments also may offer some important advice when it comes to building a stable, lasting, recovery. If you isolate yourself from others and fail to engage in life, there will be little to keep you from relapsing into your addiction when the craving hits. 

But if you instead cultivate meaningful relationships with others, fulfilling, stimulating hobbies, and career or charity pursuits that are in line with your values, there will be plenty of friends to reach out to for support, fun activities you can use to distract yourself, and purpose-driven reasons for you not to return to drug use. In time, you may even learn how you can help build these opportunities for growth for others.

In the meantime, just remember: if you do ever find yourself overwhelmed by the rat race, taking the time to decompress with something like a trip to a human park with a group of trusted pals might be just the thing to put you back in touch with the expansive, wide-open world that sobriety allows you to be fully present in.

A sober living community like the one offered by the Reco Institute is a perfect first step toward getting back in touch with your capacity for connection and engagement. To learn more about how we can help, feel free to reach out to us today at 561-665-5925.

www.brucekalexander.com/articles-speeches/rat-park/148-addiction-the-view-from-rat-park

brucekalexander.com/articles-speeches/281-rat-park-versus-the-new-york-times

mcc.gse.harvard.edu/reports/loneliness-in-america

psycnet.apa.org/record/2019-19427-011

Adi Jaffe Ph.D.

Addiction, Connection and the Rat Park Study

If only connection was enough..

Posted August 14, 2015 | Reviewed by Ekua Hagan

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Recently, I was bombarded with Facebook messages and posts about an addiction story everyone got really excited about.

This story followed Johann Hari’s book, Chasing the Scream , and his follow-up TED talk . In the talk, Johann mentioned the Rat Park experiment conducted by Bruce Alexander.

In this experiment, rats, who are participating in drug studies, are given a large cage with free food, access to sex , toys, and many playmates (the childhood kind, not Hugh Hefner’s). As Hari said in his talk, it was more a Rat Heaven then Rat Park... but still.

Under such conditions, Dr. Alexander found that rats actually refused drug cocktails, unlike their solo-caged study-mates.

The conclusion — it’s not the drugs that are an addiction but rather the environmental stressors that are placed on the rats we are studying. Eliminate the stress and you get rid of the addiction!

How amazing is that? If only things were really that simple…

Dealing with the real world

Let's ignore for a moment the methodological issues with Dr. Alexander's study (more on that here ). Assuming that what we are aiming for is not a world free of addicted rats, but rather a world free of addicted people, I have been wondering for quite a few years how we could translate these findings into real life.

The decriminalization efforts in Portugal , which Hari mentioned as well, are also something I’ve written about years ago and I agree that arresting drug users for their crimes leads to more , not less, addiction in the world.

The issue I am struggling with it this — marriages are imperfect, children are abused (physically and psychologically), wars affect citizens and soldiers and bad luck brings about traumatic loss. Our environment, unlike the environment created for the rats in Rat Heaven, is far from stress-free.

Worse still, as far as I can tell, we will, for the foreseeable future, be unable to create such a utopia for most people on Earth. If this is so, there is little doubt that some of the people affected by negative circumstances, traumatic experiences, or biological disturbances will be led down the path towards struggles with drugs and such.

To make matters more complicated, we know that biological influences related to genetic differences, neonatal (birth-related) circumstances, and early nutrition can alter brain mechanisms and make people more, or less, susceptible to the effects of trauma.

For instance, we now know that early life trauma alters the function of the hypothalamic-pituitary-adrenal axis, making individuals who have been exposed to trauma at an early age far more susceptible to stress, anxiety and substance use; or that hypoxia during delivery (certainly a form of trauma) can increase the chances of mental health defects later in life.

Like the Rat Heaven experiment, it should be somewhat obvious that without these early traumas, the individuals in question would experience less “need” for heavy-duty coping strategies like, let’s say, opiates. So biology is important here at least in this regard.

So trauma and stress are is not at all objective truths but rather individually determined patterns of influence. I am fully on board with making sure that the treatment system we use does not exacerbate the problems that stress and trauma bring about (so no shaming , breaking-down, or expulsion of clients for their struggles), but I think that the picture this TED talk and the related book presents is far too simplified to be as helpful as we want it to be.

I believe that more focus should be given to improved prevention efforts in order to reduce the likelihood of these early traumas and therefore of later drug-seeking experience in the first place. I also know that significant efforts are already being put into this sort of work through a multitude of social-services organizations and government agencies.

Needless to say, the demand for drug use has not abated despite these efforts. The work must be more difficult than setting children up with a big box, water, and some chew toys.

How oversimplification hurts us

And this brings up a question for me — what if humans are not like rats? I know it’s a shocking suggestion but just stay with me for a second.

rat drug experiment

What if human life is somewhat more complicated than rat life, science lab or not? What if Rat Heaven is not a recipe for success in eradicating human addiction because our own internal struggles , social networks and consciousness-seeking drive us farther in seeking mind-alteration than they do rats? Isn’t it possible that even if we were somehow able to make Earth a Utopia (and I would argue we are moving farther from such a reality and not closer) we would still be dealing with substance use? It’s been happening for at least 8000 years already and I’m thinking it’s here to stay.

So while I agree that social connection is very important for dealing with substance use problems (that is why we don’t shame our clients at I GNTD and don’t expel them for using when the program doesn’t call for it), it also matters who we’re connecting to and that, unfortunately, is something we control only to a limited extent.

We have to deal with the circumstances we are born into — dysfunctional marriages, depression , dietary limitations, and gang violence — and sometimes substances are the solution, not the problem.

So let’s keep moving towards a shame-free way of looking at addiction but let’s not pretend that wishing the struggles away will make it so.

An earnest hug is great, but it is not a panacea.

We have a lot of hard work to do.

© 2015 Adi Jaffe, All Rights Reserved

Read Dr. Jaffe's book, The Abstinence Myth , and be sure to check out his TEDx talk, Rebranding Our Shame , as well as his podcast .

Adi Jaffe Ph.D.

Adi Jaffe , Ph.D. , is a lecturer at UCLA and the CEO of IGNTD, an online company that produces podcasts and educational programs on mental health and addiction.

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April 10, 2003

Rat Studies Elucidate the Neurochemistry of Addiction

By Laura Wright

Scientists have long wondered what happens in the brain during the moments before a drug addict succumbs to the urge for a fix, or an animal behaves in some other way that it knows will lead to pleasure. But an inability to obtain sufficiently fine-grained measurements of the amount of dopamine--a neurotransmitter associated with feelings of reward--present in the brain has hindered investigations into the neurochemical nature of such cravings. To that end, researchers writing today in the journal Nature describe a novel technique for assessing dopamine levels. The work allowed them to observe instantaneous spikes in the chemical when cocaine-addicted rats were given visual cues that the drug was available.

Paul Phillips and his colleagues at the University of North Carolina surgically outfitted rats with newly developed brain electrodes that recorded dopamine levels 10 times a second--200 times faster than earlier technology permitted. They then trained the animals to associate the pressing of a tiny lever, and the accompanying flash of light and noise, with the pleasure of a hit of cocaine. The team found that brain dopamine surged as the drug-addicted rats turned to walk over to the lever. Levels of the neurotransmitter fell as the creatures approached the lever but then spiked again as they pressed down for a hit. Because the spike was instantaneous, occuring before the cocaine could have reached the brain, Phillips suspected the spike was an anticipatory signal.

To test that theory, the researchers shut off the cocaine pump but continued to place the addicted rats in the same cage. Even though no reward followed when the animals pressed the lever, their dopamine levels shot up when the light flashed and noise sounded.

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These findings are the first to measure changes in neurochemistry that lead to pleasure seeking or addictive behavior. "It's a signal in the brain that's highly influential in drug taking," Phillips says. "All that was known before was that dopamine would increase in rats' brains a few minutes after they got cocaine, but there were no specifics to be able to relate this to any particular behavior." Phillips plans to investigate what happens when drug-addicted rats are deprived of cocaine for a period of time and then subjected to the visual cues that they associate with a fix. The hope is to unravel the dopamine cycles that lead to addiction and figure out what causes relapses among those trying to ditch the habit.

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The Rat Park Study: on Addiction & the Power of Community to Heal

rat drug experiment

“My definition of addiction is this: any behavior that gives you temporary relief and pleasure but in the long term causes harm and has negative consequences but you can’t give it up despite those negative consequences… and from this perspective, you can understand that there are many different kinds of addictions- to drugs, work, consumerism, sex, relationships, the internet, food. The Buddhists have this idea of hungry ghosts. Hungry ghosts can never get enough. They can’t fill the emptiness from the inside. So many of us in this society are hungry ghosts, and the addiction is all about trying to fill the emptiness from the outside, and if you want to ask the question of why people are in pain, you can’t look at their genetics, you have to look at their lives.”

-Dr. Gabor Maté

In my private practice and within the Let Go & Grow program , I take a holistic approach that encompasses and takes all aspects of each unique individual’s life experience into consideration. This includes mindset, diet, lifestyle, your unique systems, relationships, environment, etc- all factors that can be changed through your own power of choice . When we focus on changing the landscape in this way and building out a solid foundation from within, with a focus on fundamentals, symptoms can resolve spontaneously, disease labels can be removed and true healing can happen.

The Rat Park Study

Certain studies stand out like gems, like a notable story, able to paint a picture, bring principles to light and make them far more tangible. So when I found this one in particular, I knew I had to share it.

Cue the Rat Park Study- which illuminates the power of community and its ability to influence behavior.

In the late 1970’s, psychologist Bruce Alexander tested the hypothesis that drugs do not cause addiction. The study design included a “rat park” where rats had a community based environment which allowed them to freely socialize, play and have fun- basically like rat heaven. The rats were given the choice of reg ular water and drugged water. The rats hardly ever chose the drugged water over the regular water in this environment.

Other studies have been conducted which involved rats in confined cages and the option between drugged water or regular water. In this setting, the rats almost always chose the drugged water due to the fact that they had no one to bond or socialize with- aka rat hell.

This opens up new possibilities and questions around addiction and suggests that having the ability to bond with others and being involved in a community could be healing in it of itself and perhaps more powerful and fulfilling than drugs.

From an evolutionary standpoint , this makes complete sense.

Why is this study important?

Understanding this study can shine a light onto the importance of connection, support and a loving community- as it goes to show how a healthy or unhealthy lifestyle can be the driver of or a potential antidote to addictive behavior, amongst many other disease states. This challenges the idea that biochemistry alone influences our behavior- once again, illuminating our power of choice and the exposome .

With a proper foundation and a focus on the fundamentals, you can unlock your own power to heal. We are not meant to travel this path alone, and there are places where you can breathe, show up as yourself and feel the presence of a community that has your back.

For more information, community support and a tried and true springboard that can help you address the fundamentals and put these principles into practice, feel free to check out the  Let Go & Grow program . We would love to have you in there! This is the exact process I teach my patients and apply in my own life, and have seen time and time again become a catalyst for radiant health, freedom and a life lived true to you.

Alexander, B. (2010). Addiction: The View from Rat Park. Retrieved November 25, 2018, from Addiction: The View from Rat Park.

Alexander, Bruce K., (2001) “The Myth of Drug-Induced Addiction”, a paper delivered to the Canadian Senate, January 2001.

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  • Addiction: Genetics and the Brain

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Note: The simplified mechanisms of drug action presented here are just a small part of the story. When drugs enter the body they elicit very complex effects in many different regions of the brain. Often they interact with many different types of neurotransmitters and may bind with a variety of receptor types in a variety of different locations. For example, THC in marijuana can bind with cannabinoid receptors located on the presynaptic and/or postsynaptic cell in a synapse. Where applicable, this presentation primarily depicts how drugs interact with dopamine neurotransmitters because this website focuses on the brain's reward pathway. Mouse Party is designed to provide a small glimpse into the chemical interactions at the synaptic level that cause the drug user to feel 'high'.

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The Rat Park Addiction Experiment

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The Rat Park Addiction Experiment proved there’s both an existential and environmental component to addiction. Or didn’t it? Four decades later scientists are still disagreeing about the study’s findings. So we’re here to ask, once and for all: Could Rat Park really be a thing?

Back in the late ’70s, Canadian psychologist Bruce Alexander and some colleagues at British Columbia’s Simon Fraser University conducted a series of drug addiction studies that would come to be known as the Rat Park Addiction Experiment (Rat Park, for short). The studies were based upon a set of experiments where various groups of rats were given a choice between water and morphine. One group was placed in a cage by themselves; another group was set loose in a structure called Rat Park. The first group’s cage was small, very small, and, like we said, they were placed there alone. Rat Park, on the other hand, was 200 times the size of a standard laboratory cage. It also included 16–20 rats of both sexes, food, playthings and enough space for mating.

As you might suspect, Group 1 obsessively went back to the morphine until they eventually overdosed and died. Group 2, however, rarely if ever touched the morphine, instead opting to frolic with their new rat friends and start new rat families. Alexander concluded that it wasn’t so much the drugs that were causing addiction, but the environment. That a happy rat had no need to get high. And, consequently, neither would a happy human.

Reactions to the Rat Park Addiction Experiment

Both Science and Nature rejected Alexander’s Rat Park findings. The former is the peer-reviewed academic journal of the American Association for the Advancement of Science (AAAS) and has been publishing since 1880. The latter is a multidisciplinary scientific journal out of Britain that dates back to 1869. Having these two esteemed journals reject one’s findings must have been a major blow. Then again, the scientific community has a history of being slow to catch up with new science. So maybe, just maybe, the peers at these journals were simply being reactionary fuddy-duddies.

That was Alexander’s take anyway. That’s why he submitted his paper to Pharmacology Biochemistry and Behavior ( PBB ). Like Science and Nature , PBB is a peer-reviewed scientific journal. Unlike its 19th century predecessors, however, it came of age in the 1970s.

And oh what a difference a century makes. PPB promptly published Alexander’s findings and gave Rat Park some much-needed credibility. It also gave Alexander the respect he sought, as well as a long and storied career. (The clinical psychologist retired in 2005 and continues to serve as Professor Emeritus at Simon Fraser.)

Further studies though showed some mixed results. One found that both caged and “park” rats showed a decreased preference for morphine. That suggested there might be a genetic difference. Another found social isolation can indeed influence drug self-administration levels, but that isolation is not a necessary condition for reinforcing drug use.

Other studies reinforced Alexander’s Rat Park findings. Environmental enrichment did reduce drug-seeking behavior. It also did much to eliminate already established addiction-related behavior. Or, to paraphrase the below video , ‘it wasn’t the chemical; it was the cage.’

Healing Properties’ Take on Rat Park

Healing Properties both applauds and concurs with Alexander’s Rat Park Addiction Experiment findings. Don’t get us wrong. We respect both Science and Nature . But in this case, both esteemed journals were wrong. Way wrong. We’re not saying environment is entirely responsible for addiction. But we are saying it plays a major role. Environment is especially important to addiction recovery.

How do we know? First-hand experience. To begin with, there’s the magic that springs up in Healing Properties’ courtyard. It’s an organic magic. That is, it’s what organically arises when men with similar issues immediately form common bonds. The magic comes when those bonds forge to fight — and then vanquish — a common foe. Here, of course, the foe is addiction. And its defeating is due largely to the camaraderie that develops here at HP.

That camaraderie is by no means limited to our courtyard. Healing Properties institutes a variety of camaraderie-creating endeavors, from our trust-building ropes course and our graduation skydiving adventure, to the weekly recreational outings and thrice-weekly Health & Wellness program.

But perhaps the most evident testament to the deep-rooted camaraderie we create is to be found in our monthly Recovered Alumni Program. This is where scores of Healing Properties success stories come together to provide strong sober support, for themselves as well as the newcomers. They also show the newcomers the benefits to be had from strong sober camaraderie, not to mention sobriety.

But though HP grads may gather around for the monthly Recovered Alumni Program; they don’t stay at the center forever. In fact, the big idea behind our addiction treatment is to equip each man to leave here and go on to lead full — and fulfilling — lives. In other words, to go out and build their own Rat Parks. Because once they’ve got a place where they’ll forever be surrounded by caring friends and loving family and have all the room in the world to live, work and play, they’re much better poised to become sober and productive members of society.

To Sum it Up

Yes, we’ve learned a thing or two since we started treating addiction back in 2002. And one of those things is that the men who went on to live in their own Rat Park had a much better chance at long-term recovery. Was it always easy? Nope. But it was always beneficial. Then again, you don’t need a Rat Park Addiction Experiment to know that putting a person in a nice, safe place and surrounding them with family and friends will be beneficial. That’s just common sense.

Michael Wright

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This 38-year-old study is still spreading bad ideas about addiction

The Rat Park study was flawed and its findings have been oversimplified, but it keeps getting cited.

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Pop science

In 1979, Bruce Alexander, a researcher at Simon Fraser University, separated rats into two cages, a stimulating one and an isolated one, and gave them morphine in order to measure the effect of environment on addiction rates.

The so-called “Rat Park” experiment was intended to debunk some of the flawed understanding around addiction at the time, specifically the notion that the drug itself was the most important factor in whether someone became addicted. The rats in both cages became physically dependent on the morphine, but the Rat Park rats consumed less morphine than the group in the boring cage. “Addiction isn’t you — it’s the cage you live in,” Alexander concluded .

The Rat Park study was flawed in its design and its findings, however, and it was ignored for almost three decades — until a group of experts rediscovered and started promoting it around 2008. The Rat Park study undermined one popular misconception about addiction, that chemistry of drugs is the single most important factor in addiction. But instead of pushing the popular understanding forward, it merely replaced that misconception with a new one: that environment is the most important factor.

Unfortunately, addiction isn’t that simple. The idea that there is nothing inherently dangerous about drugs — specifically opioids — is inaccurate. And with the opioid epidemic spreading throughout the country, it’s potentially dangerous.

At the time Alexander conducted his study, the United States was seven years into the War on Drugs, the trillion-dollar federal government effort to eradicate illegal street drugs by focusing on arresting and imprisoning drug sellers and users.

The prevailing rhetoric asserted that recreational drugs were inherently addictive and using them would “ hijack ” the brain, turning it from a “normal” brain into an addicted one. This was an oversimplified, damaging view that fundamentally misunderstood addiction and helped undermine more effective policy ideas like decriminalization and harm reduction. Alexander called this the “Myth of the Demon Drug.”

Though many had long doubted the effectiveness of increased criminalization of drugs and drug use, it took 30 years of longitudinal studies to get hard data to support that notion. In 2008, The Brookings Institute compared the “punishment” model used in the U.S. to more lenient policies in Europe, and found that it did not correlate with lower usage rates; in fact, the “combined hardcore user rate for hard drugs” was “approximately 4 times higher in the US than in Europe,” the report concluded.

As it became more apparent that the War on Drugs was a costly failure , both in terms of dollars and damage to people and communities, its critics became more vocal. And in the late aughts, they found fodder in the Rat Park experiment.

The experiment’s finding that environment is the determining factor in the development of addiction was held up as the “ vital missing evidence ” by the psychologist and BBC columnist Tom Stafford, and many other writers, journalists, and popular psychologists picked up the line.

In 2008, Gabor Maté, a Canadian doctor, addiction expert, and strong critic of the War on Drugs, published In the Realm of Hungry Ghosts: Close Encounters with Addiction , which was was a #1 best-seller in Canada and went on to be a New York Times bestseller as well. In the book, Maté argued that the War on Drugs has been a failure and argues for more comprehensive, compassionate treatment of people struggling with addiction. He devoted a chapter to establishing how environment can be a significant contributing factor in developing an addiction. He cited the Rat Park experiment as well as a study published in 1975 which showed that rates of heroin addiction were 20 times higher for Vietnam soldiers while they were stationed in the war zone than before they shipped out. After they returned to the U.S., addiction rates fell back to pre-deployment levels.

After the signal boost from In the Realm of Hungry Ghosts , folks interested in understanding addiction wrote excitedly about the study. The psychologist and author Lauren Slater devoted a chapter to Rat Park in her 2004 book, Opening Skinner’s Box: Great Psychological Experiments of the 20th Century . Stuart McMillen produced a science comic book about Rat Park and put it on the internet . The controversial former UK chairman of the Advisory Council on the Misuse of Drugs David Nutt, who was asked to step down after saying he thought alcohol and tobacco were more harmful than cannabis, LSD, and ecstasy, referred to the study in his 2012 book Drugs Without the Hot Air . Cory Doctorow, founder and editor of the popular website BoingBoing , read Nutt’s book and wrote an article praising the Rat Park study.

The Rat Park experiment provides seemingly perfect evidence to explain why the War on Drugs is such a failure, because its policies focus on drugs as the source of the problem. While the failure of the War on Drugs is virtually undisputed among experts in the field of addiction — though sadly not represented by significant changes in policy, as drug offenses are the “single biggest factor” contributing to booming incarceration numbers — Alexander’s emphasis on the user’s environment was novel and presented obvious implications for drug policy.

The buzz Dr. Maté had generated around the Rat Park experiment became a roar in 2015, when Johann Hari published Chasing the Scream: The First and Last Days of the War on Drugs . Focusing heavily on the work of Maté and Alexander, Hari asserts that he has discovered the “ likely cause ” of addiction: a lack of human connection. Just as the rats in the isolated rat park cage needed social interaction and connection with other rats, Hari wrote, so do humans. Alexander believed a poor environment causes addiction; Hari asserted that the disconnection that arises from a poor environment creates addiction.

Despite a poor review in the New York Times , Chasing the Scream went on to be on the best-seller lists for weeks. Hari’s TED talk, modestly titled “Everything You Know About Addiction Is Wrong,” has been viewed over three million times.

In 2017, the Rat Park study continues to be cited as a “ classic experiment ” in the field of addiction.

“All those who subscribe to [a] sociological theory of addiction trot [the Rat Park experiment] out as if it establishes their premise,” said Dr. Sam Snodgrass, a member on the Board of Directors of the substance abuse support organization Broken No More. “The problem is that most people aren't scientists and believe whatever they read.”

Unfortunately, the Rat Park study had some issues.

Despite his claims of a revolutionary breakthrough, Alexander had trouble finding a journal to publish his results. Both Science and Nature rejected the study for publication, likely due to significant problems with the methodology and results. Pharmacology Biochemistry and Behavior published the results in 1981 with little response and the funding for Rat Park was canceled shortly thereafter.

The Rat Park experiment provides seemingly perfect evidence to explain why the War on Drugs is such a failure

Alexander lost eight days’ worth of data due to a malfunctioning piece of electronic equipment used to measure the amount of liquid the rats consumed, which may or may not have impacted his results. He also failed to control for important variables, Snodgrass said. For example, male and female rats in the boring cage were isolated from each other, he said, but they were housed together in the Rat Park cage. Soon, Rat Park was filled with rat pups. Alexander never explained what happened to the pups, Snodgrass said, such as whether they were removed or left in the cage and somehow factored into the results. “The females would wean one litter after approximately 18 days and then would begin to cycle again,” Snodgrass said. “You can’t do this. You can’t have one group of subjects mating and with pups and compare it to a group that doesn’t engage in these behaviors and say that the difference between the two groups is caused by environmental differences.”

When scientists tried to replicate the Rat Park study, they got mixed results. In 1996, a study attempted to precisely replicate the conditions in Alexander’s Rat Park, down to the breed of rat . The researchers conducted two experiments to see if they could replicate the Rat Park study’s results. In the first experiment, the happy, social rats consumed slightly more of the morphine liquid, in the second experiment, the isolated rats drank slightly more. Neither experiment reflected the Rat Park’s results, which had the isolated rats drinking up to seven times the amount of the morphine liquid as the social rats. The authors of the study note that in 1979 the supplier both they and Alexander used for Wistar rats changed, noting that “the Wistar rats used in the Alexander, et al. study were Old Colony Wistar rats, and the ones used in the 1996 were New Colony Wistar rats.” The author concluded that the difference in behavior between the rats in the initial Rat Park study and the 1996 study were, “likely genetic in nature” (Petrie, 1996). This is especially notable considering Alexander’s current position that genetics do not play any role in the development of addiction.

Other studies did indeed replicate the results of Alexander’s Rat Park, as he notes on his website .

Finally, there is the obvious fact that rats aren’t human and thus behave differently than humans do. Dr. Adi Jaffe notes how this specifically impacts the Rat Park study here .

So if the four-decades-old Rat Park experiment provided important but partial, or inconclusive, evidence about the cause of addiction, why is it still being touted as the “missing link” to understanding addiction today? In part, the persistence and ineffectiveness of the War on Drugs is to blame.

Alexander’s study was an important breakthrough in understanding addiction, but the results were far from conclusive. The study’s real problems have less to do with the science and more to do with the grandiose claims made based on the results. For example, morphine (an opioid) was the only type of drug used in the experiment, but Alexander extrapolated that addiction to all drugs would present similarly. This is likely because his theory states that the drug itself is almost irrelevant — addiction is determined by environment, not the drug itself. He writes that “addiction to drugs as well as other habits and pursuits” happens when people “feel ‘ caged .’”

There is likely some truth to this. Certain people are more vulnerable to addiction than others; many people can use any array of drug without becoming addicted. But although addiction experts disagree slightly about where certain drugs should be on a spectrum of most to least addictive, almost all agree that there is indeed a spectrum. It would be willfully ignorant to say that a person is equally likely to become addicted to cannabis as they are to oxycontin or fentanyl. Of course the drug in question matters. So do a plethora of other factors. In reality, there are many factors that lead to addiction, including environment, stress, genetics, life-circumstances, and adverse childhood experiences (ACEs). It is not uncommon for people with addictions to have any combination of the above factors, nor is it an exhaustive list. These factors also have different effects on different individuals. For example, people who suffer from a mental illness are twice as likely to struggle with addiction. But both Hari and Alexander still claim they’ve discovered the “real,” implying singular, cause of addiction.

The point that Rat Park is used to underscore is true. Environment often plays a role in a person developing an addiction and the War on Drugs does nothing to address that. In fact, the War on Drugs has done tremendous harm by ignoring the sociological factors that contribute to addiction and focusing exclusively on criminalization. Alexander and Hari argue that we need a more humane approach to drug policy, a belief that is widely shared. But ignoring the greater body of addiction science in favor of a neat narrative is the kind of thinking that fueled the War on Drugs. It’s precisely because this is such an important fight that we should make sure our arguments, and the evidence we use to support them, are sound.

Opioid crisis

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The number of babies born in 2012 suffering from opioid withdrawal

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The opioid crisis is prompting calls for safe injection sites

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The amount opioid makers and associated nonprofits spent on lobbying and political donations over the past decade. That's eight times what the gun lobby spent.

The Outline

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  • Published: 31 July 2024

Effect of magnetic microbeads on sustained and targeted delivery of transforming growth factor-beta-1 for rotator cuff healing in a rat rotator cuff repair model

  • Jeongkun Lee 1 ,
  • Jinwoo Park 2 ,
  • Yeongjun Chang 2 ,
  • Jong Pil Yoon 3 &
  • Seok Won Chung 1  

Scientific Reports volume  14 , Article number:  17632 ( 2024 ) Cite this article

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Structural failure is a well-established complication of rotator cuff repair procedures. To evaluate the effect of magnetic microbeads, designed for precise drug delivery via magnetic force, on sustained transforming growth factor-beta-1 (TGF-β1) release and rotator cuff healing in a rat rotator cuff repair model. TGF-β1 laden microbeads were prepared, and baseline in vitro experiments included the magnetization of the microbeads and TGF-β1 release tests. In an in vivo experiment using a rat rotator cuff repair model on both shoulders, 72 rats were randomly assigned to three groups (24 per group): group A, conventional repair; group B, repair with and simple TGF-β1 injection; and group C, repair with magnet insertion into the humeral head and TGF-β1 laden microbead injection. Delivery of TGF-β1 was evaluated at 1 and 7 days after the intervention using PCR, Western blot, and immunohistochemistry. At 6 weeks post-intervention, rotator cuff healing was assessed using biomechanical and histological analysis. The in vitro experiments confirmed the magnetization property of the microbeads and sustained delivery of TGF-β1 for up to 10 days. No difference in the TGF-β1 expression was found at day 1 in vivo. However, at day 7, group C exhibited a significantly elevated expression of TGF-β1 in both PCR and Western blot analyses compared to groups A and B (all P  < 0.05). Immunohistochemical analysis revealed a higher expression of TGF-β1 at the repair site in group C on day 7. At 6 weeks, biomechanical analysis demonstrated a significantly higher ultimate failure load in group C than in groups A and B ( P  < 0.05) and greater stiffness than in group A ( P  = 0.045). In addition, histological analysis showed denser and more regular collagen fibers with complete continuity to the bone in group C than in groups A and B, a statistically significant difference according to the semi-quantitative scoring system (all P  < 0.05). The use of the TGF-β1 laden magnetic microbeads demonstrated sustained delivery of TGF-β1 to the repair site, improving rotator cuff healing.

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Introduction.

Rotator cuff tear is a common condition that causes severe pain and disability. 1 , 2 , 3 . The prevalence of rotator cuff tear in the general population is reported to range from 20.7 to 22.2%, with the rate increasing with age 4 , 5 , 6 . Surgical repair is commonly performed to treat rotator cuff tears, aiming to achieve safe biologic tendon-bone healing 7 , 8 , 9 . Although surgical techniques and instruments have improved considerably, the failure rate of rotator cuff repair remains high and an unresolved problem 10 , 11 , 12 . Thus, the use of biological materials, such us stem cells, atelocollagen, platelet-rich plasma, and growth factors has been explored as novel ways to improve healing 5 , 13 , 14 . Transforming growth factor-beta-1 (TGF-β1) is a protein that performs various cell functions, including the control of cell growth and differentiation 15 .

The sustained and targeted delivery of different biological materials remains a challenge. Previous studies have evidenced that TGF-β1 is a key mediator in healing, promoting collagen production, angiogenesis, and tissue formation 16 ; moreover, it has a positive effect on rotator cuff healing by increasing the synthesis of collagen and proteoglycan and stimulating cell proliferation 17 . Generally, local injections of various growth factors, platelet concentrates, and stem cells directly into the target site have been used to improve tendon healing 18 , 19 . However, it is challenging to accurately deliver the biological materials to the desired site through this conventional method, and the injected materials may be degraded over time 20 . Although biomaterials such as alginate, collagen gels, sponges, and various absorbable constructs have been used for sustained delivery 21 , these delivery methods have the disadvantages of being cumbersome, time-consuming, and have an increased risk of infection 22 , 23 .

Microbeads made from naturally occurring polymers have the potential to be drug delivery vehicles that can be administered by simple injection. In medical applications, microbeads are defined as spherical capsules or solid particles with a drug coated on the surface or encapsulated inside a core. 24 Beads have a high surface to volume ratio, which enables encapsulation of large amounts of drug, allows for uniform distribution and sustained release of the drug 25 , and is one of the most widely studied carriers for various types of drug delivery 26 . A method to keep the microbeads in the desired area by adding an iron oxide component to the microbead configuration and driving the beads using a magnet has been studied 27 . If the driving microbead structure contains biostable iron oxide, magnetic force can be used to keep the beads in the target site 28 . This kind of magnetic microbeads as a scaffold may be good option for the sustained and targeted delivery of drugs, expecting a biological effect of a delivered drug on the target site, by a simple injection method. The biological effect of a TGF-β1 delivered to the rotator cuff repair site would be an increased rotator cuff healing by promoting collagen production, angiogenesis and tissue formation.

However, to the best of our knowledge, no study has evaluated the effects of magnetic microbeads on rotator cuff healing. Therefore, the objective of this study was to evaluate the effect of magnetic microbeads on the sustained and targeted delivery of TGF-β1 and rotator cuff healing using a rat rotator cuff repair model.

All animal experiments were approved by the Institutional Animal Care and Use Committee of the Senior Authors’ Institute (Konkuk University IACUC) (No. KU21235-1) and conducted according to the Guide for the Care and Use of Laboratory Animals published by the US National Institutes of Health(This study is reported in accordance with ARRIVE guidelines).

Preparation of the TGF-β1 laden microbead

The magnetic microbead(Biot Korea Inc., Republic of Korea) is an carboxydextran-coating iron oxide (Ferucarbotran), sodium alginate (ALG) and sodium hyaluronate (HA) based microbead made by electrospinning method, and it has characteristics of being magnetic and ability to contain a drug in the alginate/hyaluronate structure. Mix HA solution-ALG solution-Ferucarbotran (weight ratio of 11.0:7.3:4.0) at room temperature for 1 h at 200 rpm using a Programmable Ball Mill. Disperse with a sonicator for 5 min at 40 °C. Drop into 1.5 kg of 0.99% CaCl 2 solution at 110 rpm with Frequency (2200 Hz), Electrode (1000 V), Heating (70 °C), Nozzle hole size (150 μm), and drop distance (12.5 cm) (Fig.  1 ). The dropped beads are cured using a 200 rpm Programmable Ball Mill at room temperature for more than 16 h. Washing is repeated 3 or more times for 5 min using a 150 μm sieve and 5 L of ultrapure water. Freeze in an ultra-low temperature freezer at − 65 °C or lower for more than 2 h. Frozen beads are freeze-dried in a freeze dryer at temperatures below − 45 °C and below 100 mTorr for more than 72 h. After freeze-drying is complete, the beads are recovered and stored in a desiccator. Microscope images were taken to confirm the morphology and size of the microbead. The prepared microbeads were observed using a Microscope (KI3000, OPTINITY) at ×20 magnifications. To contain the TGF-β1 in this prepared magnetic microbead, we soaked the microbead in saline containing TGF-β1 dose of 400 ng/mL before use.

figure 1

Schematic image of microbeads fabrication. Preparation of magnetic microbeads by using electrospinning technology. Disperse with a sonicator and drop into CaCl 2 solution at 110 rpm with Frequency (2200 Hz), Electrode (1000 V), Heating (70 °C), Nozzle hole size (150 μm), and drop distance (12.5 cm).

Sustained release of TGF-β1 in magnetic microbeads

To confirm the capacity of the sustained release of TGF-β1 contained in the magnetic microbeads, we performed an in vitro experiment for sustained release in advance of the in vivo experiments. The magnetic microbeads (Biot Korea Inc., Republic of Korea) carrying 400 ng of TGF-β1 were incubated in 100 mL of deionized water at 4 °C for 10 days. The 400 ng/mL TGF-β1 dose has previously demonstrated to significantly enhance rotator cuff healing in animal models 29 , 30 . At various time points (0, 1, 3, and 6 h; and 1, 3, 6, 8, and 10 days) a 0.2-mL aliquot of incubation liquid was collected and stored at -20 °C for 10 days 30 . After 6 h and 10 days, all aliquots were analyzed using an enzyme-linked immunosorbent assay (ELISA) kit (Human LAP TGF-β1 Quantikine ELISA Kit; R&D Systems) to measure the resealed amount of TGF-β1.

Animal model and procedure

We used 72 Sprague Dawley rats (Orient Bio Inc., Seongnam Gyeonggi, Republic of Korea) aged 10 weeks with a mean body weight of 250 g: 48 for evaluating the TGF-β1 delivery and 24 for evaluating the effect of the TGF-β1 magnetic microbead on the rotator cuff repair model. Power analysis indicated that eight specimens per group were required to detect a significant difference in the ultimate load to failure at 6 weeks after repair (comparison between the two groups): mean difference, 7 N; standard deviation, 5 N; error = 0.05, b error = 0.2, 2-tailed comparison 31 . Accordingly, 8 rats per group for 6 weeks were required to evaluate the effect of TGF-β1 magnetic microbeads on rotator cuff repair, and the same number was used to evaluate TGF-β1 delivery on days 1 and 7.

The rats were acclimatized to a 12-h light–dark cycle at 22 °C with free access to food and drinking water. Surgical procedures were performed under anesthesia using an intraperitoneal injection of Zoletile 30 mg/kg (Virbac, Carros, France) and Rompun 10 mg/kg (Bayer Korea Ltd., Seoul, Korea). Subsequently, the shoulders of each rat were shaved and prepared in the usual sterile surgical technique. A 3-cm lateral skin incision was made on both shoulders, and the deltoid muscle was retracted to expose the supraspinatus tendon at its insertion into the greater tuberosity. The supraspinatus tendon was severed from the greater tuberosity by using a sharp scalpel. Using a motor drill, two bone tunnels were created at the articular margin of the footprint to the lateral humeral cortex. A suture (3–0 Ethilon; Ethicon Inc., Johnson & Johnson, Belgium) was passed through the bone tunnels and tied, reattaching the supraspinatus tendon to the footprint.

Seventy-two rats were randomly allocated to three groups (24 rats per group). Group A served as the control group and no additional procedures were performed after supraspinatus repair (repair only). In group B, we injected 400 ng of TGF-β1 in the repair site after supraspinatus repair. In group C, we injected TGF-β1 laden magnetic microbeads in the repair site after supraspinatus repair surgery. In Group C, a micro-magnet was implanted into the humeral head near the greater tuberosity to attract the magnetic microbeads to the repair site (Fig.  2 ). The experimental flowchart is illustrado in Fig.  3 .

figure 2

Surgical procedure for group C. After the supraspinatus tendon was cut at the insertion site ( A ), a magnet is inserted into the humeral head ( B ). After rotator cuff tear repair ( C ), TGF-β1 laden magnetic microbeads are applied locally at the repair site ( D ).

figure 3

Experiment flowchart. At 1 and 7 days after the procedure, qRT PCR and western blot analyses were performed using the supraspinatus tendon of the left shoulder and immunohistochemical analysis was performed on the en-bloc bone-to-tendon repair site of the right shoulder (n = 8 for each group). At 6 weeks after the procedure, biomechanical analysis was performed on the en-bloc bone-to-tendon repair site of left shoulder and histological analysis was performed on the en-bloc bone-to-tendon repair site of the right shoulder (n = 8 for each group).

At 1 and 7 days after surgery (8 rats per group), the supraspinatus tendon of the left shoulder and the en bloc bone-to-tendon repair site of the right shoulder were harvested, PCR and Western blot analyses were performed using the supraspinatus tendon of the left shoulder, and immunohistochemical analysis was performed in the en bloc bone-to-tendon repair site of the right shoulder. Six weeks after surgery (8 rats per group), the en bloc bone-to-tendon repair sites of both shoulders were harvested, biomechanical analysis was performed on the left shoulder, and histological analysis was performed on the right shoulder.

Quantitative reverse transcription PCR: qRT PCR

To evaluate gene expression, Quantitative Reverse Transcription PCR (qRT-PCR) was performed on the TGF-β1 gene. Total RNA was extracted from the isolated deltoid muscles using the TRIzol reagent (Invitrogen) according to the manufacturer’s instructions, and cDNA was generated using the Maxime RT Premix Kit (iNtRON Biotechnology). qRT-PCR was performed on a Light Cycler 480 System (Roche Diagnostics) using 2X qPCR BIO SyGreen Mix Lo-ROX (PCR Biosystems). All data were normalized to glyceraldehyde3-phosphate dehydrogenase (GAPDH) expression levels. The primer sequence of TGF-β1 is (F) 5′-ATGCACACTGGTGCAGAGAG-3′ (R) 5′-′TGTAAGCACACAGGCAGGTC-3.

Western blot analysis

To assess protein expression, the rats were euthanized in a CO 2 vacuum cage, and the entire supraspinatus tendon of each rat was harvested and lysed in 20 mm Tris–HCl buffer (pH 7.4) containing a protease inhibitor mixture (0.1 mm phenylmethylsulfonyl fluoride, 5 μg/ml aprotinin, 5 μg/ml pepstatin A, and 1 μg/ml chymostatin) and phosphatase inhibitors (5 mm Na3VO4 and 5 mm NaF) for 1 h. Subsequently, cell lysates were centrifuged at 13,200 × g for 5 min at 4 °C for extraction. The concentration of the extracted protein was measured using a BCA protein assay kit (Thermo Scientific, Rockford, IL, USA). Equal amounts of protein (30 μg) were loaded in each well of 9% SDS-PAGE and transferred onto a polyvinylidene fluoride membrane. The transferred membranes were blocked with 5% non-fat dry milk in Tris-buffered saline for 1 h at room temperature and incubated with primary antibody overnight at 4 °C. Each primary antibody was diluted 1:1000 with 1% bovine serum albumin. Antibodies used in this study were GAPDH, TGF-β1 (catalog no. 25778, 514302, respectively; Santa Cruz Biotechnology, Santa Cruz, CA, USA). Subsequently, membranes were incubated with anti-rabbit or anti-mouse secondary antibodies for 1 h. Each secondary antibody was diluted 1:5000 with 5% nonfat dry milk in Tris-buffered saline. Finally, membranes with proteins were treated with enhanced chemiluminescence solution and exposed to X-ray film. The band intensities developed on the film were quantified using ImageJ software (NIH, Bethesda, MD, USA).

Immunohistochemistry

Immunohistochemistry was performed on the en bloc bone-tendon repair sites of the right shoulder to determine local expression of the target protein TGF-β1. For immunohistochemical analysis, 5-mm paraffin-embedded tissue sections were prepared, deparaffinized in xylene, and rehydrated in an ethanol series. Antigen retrieval was performed using citrate buffer (pH 6.0). The slides were incubated with primary antibodies for 1 h at room temperature, washed three times with phosphate-buffered saline, incubated with the corresponding secondary antibody conjugated to horseradish peroxidase for 30 min at room temperature, and washed with phosphate-buffered saline three times. Immunohistochemical staining was conducted using anti-TGF-β1 (Abcam, Cambridge, UK) on each slide. All slides were evaluated under an Eclipse Ni-U microscope (Nikon), and images were acquired using a DS-Ri1 camera (Nikon) and analyzed using NIS Elements (v 4.0; Nikon). Supraspinatus tendon repair site analysis was performed at ×20 and ×100 magnifications under a microscope.

Biomechanical analysis

Six weeks after the repair, the entire supraspinatus tendon of both shoulders with the humeral head of each rat was harvested, and the left shoulder was used for biomechanical analysis. The mechanical evaluation parameters were stiffness and load to failure (maximum load that could withstand external forces until failure, measured at a rate of 10 mm/s with a preload of 20 kg using a custom fixture clamping system and a universal test machine (Shimadzu AGS-X 500N, Japan). The supraspinatus tendon was wrapped with a cotton gauze sponge to minimize slippage and fixed to this system along its anatomical direction to allow tensile loading and the tendon-to-bone interface to form a right angle. The data were automatically collected using a personal computer-based data acquisition system.

Histological analysis

Six weeks after surgery, all right shoulder specimens from each group were fixed in 10% deionized buffered formalin (pH 7.4), decalcified, and paraffin blocks containing the repair site were prepared. Sections (4-µm thick) were cut in the coronal plane and stained with hematoxylin and eosin. Specimen slides were evaluated for fiber continuity, tissue cellularity, and collagen organization at the tendon-to-bone interface. The assessment included orientation and density of the collagen fibers, maturation of the tendon-to-bone interface structure, and cellularity. Each item was graded semi-quantitatively (0, 1, 2, or 3). For collagen fiber continuity and orientation (i.e., collagen fibers oriented in parallel), we divided their grades by percentages as follows: < 25%, 25–50%, > 50–75%, and > 75%, which corresponded to grades 0, 1, 2, and 3, respectively. Collagen fiber density was graded as very loose, loose, dense, and very dense, corresponding to grades 0, 1, 2, and 3, respectively 30 . The maturation of the tendon-to-bone interface structure was graded as poorly organized, mildly organized, moderately organized, and markedly organized, corresponding to grades 0, 1, 2, and 3, respectively. Cellularity was graded as none or minimally present, mildly present, moderately present, or markedly present, corresponding to grades 0, 1, 2, and 3, respectively (Table 1 ). To eliminate observer bias, all examinations were performed in a randomized fashion by a pathologist with 7 years of training (J.Y.K.) who was blinded to the group assignment. An Eclipse Ni-U microscope (Nikon) was used for histological analysis at ×100 magnification. The histological analysis was performed with referring to a previous study 29 .

Statistical analysis

Data were evaluated using SPSS software (version 20.0; IBM Corp., Armonk, NY, USA). A Kruskal–Wallis test was performed to determine whether there were differences between groups, followed by a post-hoc Mann–Whitney U test with Bonferroni correction for multiple comparisons. Data were expressed as the mean ± standard error, and P  < 0.05 was considered statistically significant.

Magnetization test of magnetic microbeads and analyze uniform shape and spherical morphology

Electromagnetic tests were performed to confirm the magnetization of the magnetic microbeads. Magnetization was confirmed through the detection of magnetic microbeads that moved according to the direction of the external magnetic force (Fig.  4 ). Microscopic observations were conducted to analyze the morphology and size of the magnetic microbeads. Uniform shape and spherical morphology were observed (Fig.  4 D).

figure 4

Photographs showing the responses of magnetic microbeads to the external magnetic attraction. Initial state ( A ), magnetic force direction left ( B ), and magnetic force direction right ( C ). Optical microscope image of the magnetic microbeads ( D ). Magnification: ×20 original. Scale bar, 500 µm.

Confirmation of TGF-β1 sustained release in vitro

The level of the TGF-β1 release from the microbeads was measured using ELISA and a 450-nm ultraviolet spectrophotometer at numerous time points. Sustained release of TGF-β1 up to 6 h and 10 days was observed (Fig.  5 ). These results may suggest that TGF-β1 would have the possibility of being continuously released to the repair site when the magnetic microbead-based delivery system is applied in-vivo as well.

figure 5

Sustained release of TGF-β1 in the magnetic microbead.

Biomolecular analysis: qRT-PCR analysis showed higher expression of TGF-β1 in group C

TGF-β1 gene mRNA levels were evaluated using qRT-PCR analysis at days 1 and 7. Although there were no differences between groups at day 1, at day 7, we found a significantly higher expression of TGF-β1 in group C compared with that in groups B ( P  = 0.011) and A ( P  = 0.003) (Fig.  6 ).

figure 6

Ratios of the relative mRNA expression level for days 1 ( A ) and 7 ( B ). Results are the means of three independent experiments (bars represent SEM). * P  < 0.05, ** P  < 0.01.

Biomolecular analysis: Western blot analysis showed higher expression of TGF-β1 in group C

TGF-β1 protein levels were evaluated using Western blot analysis at days 1 and 7. Similar results were obtained by qRT-PCR. Even though there was no significant difference between groups at day 1, we observed a significantly higher expression of TGF-β1 in group C compared to that in groups B ( P  = 0.027) and A ( P  = 0.005) at day 7 (Fig.  7 ).

figure 7

The TGF-β1 protein levels by Western blot analysis for days 1 ( A ) and 7 ( B ). Each value is illustrated as a ratio of the relative protein level. Results are the means of three independent experiments (bars represent SEM). * P  < 0.05, ** P  < 0.01.

Biomolecular analysis: immunohistochemical analysis showed higher staining intensity of TGF-β1 at day 7

We performed immunohistochemistry for TGF-β1. The expression of TGF-β1 at the repair site was not evident in all groups at day 1. However, a higher staining intensity at the repair site was observed in group C than in groups B and A on day 7 (Figs.  8 and 9 ).

figure 8

An example of group C immunohistochemical analysis, ( A ) day 1, ( B ) day 7. The red squares indicate the supraspinatus tendon repair site. The blue arrows indicate the location where the magnet was inserted. Detection using anti-TGF-β1. Magnification: ×20 original. Scale bar, 50 µm.

figure 9

Immunohistochemical analysis of the supraspinatus tendon repair site at day 1 ( A , B , and C ) and day 7 ( D , E , and F ) between groups (Left, group A; Middle, group B; and Right, group C). Detected using anti-TGF-β1. Magnification: ×100 original. Scale bar, 100 µm.

Evaluation of the rotator cuff healing: biomechanical analysis showed higher score in group C

In the biomechanical evaluation at 6 weeks after surgery, the stiffness in group C was significantly higher than in group A ( P  = 0.045). In addition, the ultimate failure load of group C was significantly higher than that of group B ( P  = 0.016) as well as the group A ( P  = 0.005) (Fig.  10 ).

figure 10

Results of the biomechanical analysis. Results are the means of three independent experiments (bars represent standard error of the mean). * P  < 0.05, ** P  < 0.01.

Evaluation of the rotator cuff healing: histological analysis showed higher score in group C

Histological analysis showed denser and regularly oriented collagen fibers with complete continuity to the bone in group C compared to groups A and B. In the semi-quantitative scoring system comparing cellularity, collagen fiber continuity, orientation, density, and repair site maturation, the differences were statistically significant (Fig.  11 and Table 2 ).

figure 11

Histology at the repair site in hematoxylin and eosin stain ( A , group A; B , group B; C , group C). Magnification: ×100 original. Histology at the repair site in Masson trichrome stain ( D , group A; E , group B; F , group C). Magnification: ×100 original. ( G ) The graph shows the difference of the histology scores between groups. * P  < 0.05, ** P  < 0.01, *** P  < 0.001.

In this study, we demonstrated the therapeutic effectiveness of magnetic microbeads in the sustained and targeted release of TGF-β1 at a desired repair site with enhanced healing. Among various growth factors, TGF-β1 has been of interest due to its previously proven effectiveness in enhancing rotator cuff healing 29 , 30 . However, the effectiveness of TGF-β1 may be limited when administered through a single injection due to its short half-life, in vivo instability, and challenges in accurately reaching the target site 32 . Consequently, various scaffolds, such as collagen gels and sponges, have been used for the sustained delivery of growth factors to the target site 33 , 34 . However, the reliability of growth factors delivery to the tendon through the scaffold may still be uncertain, necessitating additional efforts to affix the scaffold to the repaired tendon 30 . The delivery of growth factors through scaffolds has the inherent disadvantage of being feasible only during the surgery, which can be cumbersome, time-consuming, and pose an increased risk of infection 22 , 23 . In this study, we used magnetic microbeads loaded with TGF-β1, delivering the growth factor to the repair site through a simple injection. This method offers the advantage of sustained and targeted delivery of the growth factor.

The microbeads used in this study contained alginate and hyaluronic acid, which are known to effectively carry and release various growth factors 35 , and additionally contained iron oxide so that the microbeads can be delivered and fixed to the desired site using magnetic force (magnetic microbeads). Iron oxide use in microbeads is an FDA-approved biosafe material that is used as a component of contrast agents 36 , 37 . The magnetic property of the microbeads was proven in a previous study, evidencing targeted movement of the magnetic microbeads to knee cartilage lesions 38 . In the in vitro magnetization test for our study, we confirmed that the microbeads were well magnetized through the microbeads movement toward the outside magnet. The magnetic microbeads should not easily move from the target repair site and have sustained release of TGF-β1, improving rotator cuff healing. Our in vivo results evidenced enhanced expression of TGF-β1 at the repair site in the group C on day 7, suggesting sustained and targeted delivery of TGF-β1 by the magnetic microbeads. On day 1, we could not find differences in the expression of TGF-β1 between groups, which suggests that 1 day was not enough time for the growth factor to be sufficiently absorbed to the repair site. In immunohistochemical analysis, we confirmed that TGF-β1 was present at both the repair interface and tendon substance, where growth factors may directly stimulate cell differentiation and matrix synthesis 39 , 40 . The vascularization or cell infiltration within the tendon may be accelerated by TGF-β1 released from the magnetic microbeads, improving the healing process 41 . We think the prolonged time of the magnetic microbeads at the repair site due to the magnetic force minimizes the loss of TGF-β1, allowing maximum TGF-β1 transfer to the repair site and enabling efficient and improved tissue healing 42 .

Magnetic microbead-laden growth factors offer several advantages. They can carry various types of growth factors and therapeutic drugs in the alginate and hyaluronic acid components and can be applied to various areas, including the shoulder joint we studied. We believe that it will be possible to use magnetic microbeads for the treatment of rotator cuff disease, cartilage diseases, cancers, and other diseases that require effective targeted drug delivery 43 . Magnetic microbeads can be easily delivered to the desired area through injection. Scaffolds for delivering growth factors or drugs can only be used during surgery; however, magnetic microbeads can be used in outpatient clinics without surgery 44 , 45 . However, a magnet is needed for localization; in our experiment, it was inserted into the humeral head near the greater tuberosity of the animals. Because it is still not possible to insert a magnet into human bones, there has been ongoing research into the development of orthoses employing external magnets to concentrate the magnetic field at the target site 46 , 47 . Thus, to implement magnetic microbeads in humans, the development of magnet-mounted braces or guidance devices is required 38 .

Our study is the first to evaluate the effect of the TGF-β1-laden magnetic microbeads on sustained and targeted delivery to the repair site and rotator cuff healing in a rat rotator cuff repair model. This study has some limitations. First, as this was an animal study, differences in the anatomical features, reactions to injury, and immobilization between humans and rats limit the generalization of the results. Second, shoulder trauma and surgical procedures are commonly encountered in older patients. This study was conducted in young rats; therefore, comparing the results with those of older rats may be necessary. Third, other additional biomechanical tests such as gait analysis or staircase test were not performed, which may strengthen the conclusion of this study. Fourth, 6 weeks of evaluation for rotator cuff healing may not have been sufficient, and further long-term studies are needed to confirm our results. Fifth, those conducting the biomechanical testing were not blinded, unlike those conducting the histological analyses; this may have decreased the reliability of the biomechanical results. Sixth, the in vivo release kinetic properties are unknown and are likely to differ from those in the in vitro environment. Finally, other growth factors and extracellular matrix proteins not analyzed in this study may be involved in the rotator cuff healing process, and the molecular pathways by which TGF-β1 affects rotator cuff tendon-to-bone healing were not identified. TGF beta target genes such as Snail or Twist would be beneficial to strengthen the results; therefore, this should be further researched.

We demonstrated the therapeutic effectiveness of TGF-β1 laden magnetic microbeads in the sustained and targeted release of TGF-β1 at a desired repair site with enhanced rotator cuff healing in a rat rotator cuff repair model. Considering the effectiveness and convenience of its use, the findings of this study may provide another possible solution for the treatment of rotator cuff tears.

Data availability

The datasets used and/or analysed during the current study available from the corresponding author on reasonable request.

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Acknowledgements

The authors would like to thank all those who helped conduct this study.

This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (No. RS-2023-00249219 and NRF-2022R1A6A3A01087378).

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All authors contributed to the study’s conception and design. J.L., J.P., Y.C., J.P.Y., and S.W.C. performed material preparation, data collection, and analysis. J.L. wrote the first draft of the manuscript. All authors commented on previous versions and read and approved the final manuscript.

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Lee, J., Park, J., Chang, Y. et al. Effect of magnetic microbeads on sustained and targeted delivery of transforming growth factor-beta-1 for rotator cuff healing in a rat rotator cuff repair model. Sci Rep 14 , 17632 (2024). https://doi.org/10.1038/s41598-024-67572-y

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rat drug experiment

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  1. Rat Park

    Rat Park was a series of studies into drug addiction conducted in the late 1970s and published between 1978 and 1981 by Canadian psychologist Bruce K. Alexander and his colleagues at Simon Fraser University ... In another experiment, he forced rats in ordinary lab cages to consume the morphine-laced solution for 57 days without other liquid ...

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    Alexander's experiments, in the 1970s, have come to be called the "Rat Park. 1 Researchers had already proved that when rats were placed in a cage, all alone, with no other community of rats, and offered two water bottles-one filled with water and the other with heroin or cocaine-the rats would repetitively drink from the drug-laced bottles ...

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    A small group of colleagues at Simon Fraser University, including Robert Coambs, Patricia Hadaway, Barry Beyerstein, and myself undertook to test the conclusion about irresistibly addicting drugs that had been reached from the earlier rat studies. We compared the drug intake of rats housed in a reasonably normal environment 24 hours a day with ...

  7. Rat Park: How a rat paradise changed the narrative of addiction

    Rat Park: How a rat paradise changed the narrative of addiction. Rat Park: How a rat paradise changed the narrative of addiction. Addiction. 2019 May;114 (5):917-922. doi: 10.1111/add.14481. Epub 2018 Nov 16.

  8. PDF "Drugs cause addiction." This was the conclusion drawn from repeated

    This was the conclusion drawn from repeated rat experiments in numerous university research centres in the 1950s and 60s. These studies had involved the use of tiny cages with contraptions that allowed isolated animals to drink drug-laced sugar water or inject drugs by pressing a lever. The rats consumed large amounts of heroin, morphine ...

  9. Rat Park: How a rat paradise changed the narrative of addiction

    A fifth female rat died during the abstinence phase of the experiment, where a choice between morphine and water was available on test days but only water was available for 5 weeks.

  10. What the 1981 Rat Park Experiment Means for ...

    That study is known informally as the Rat Park Experiment. First, some background: Rat Park came in response to a number of addiction studies in the '60s and '70s where rats were placed in solitary, cramped cages. The rats were given free rein to choose between water and a solution laced with different drugs like morphine (a close relative ...

  11. 'Rat Park' Study

    The so-called " Rat Park " experiment was intended to debunk some of the flawed understanding around addiction at the time, specifically the notion that the drug itself was the most important factor in whether someone became addicted. The rats in both cages became physically dependent on the morphine, but the Rat Park rats consumed less ...

  12. The Rat Park Experiment

    The famous Rat Park experiment offered some fascinating insights into the nature of addiction. Rats are often used for "psychological experiments" due to their genetic similarity to humans. Ninety-five percent of the human genome is identical to that of rats. Studies involving rats are always conducted in controlled environments (in other ...

  13. What can the Rat Park experiment teach us about addiction?

    The experiment was designed to challenge and reevaluate previous studies on drug addiction, which used rats in isolated and barren environments. In these earlier experiments, rats were placed in small, individual cages with access to a water solution containing morphine. The results consistently showed that the rats developed addictive ...

  14. Rat Park: How a rat paradise changed the narrative of addiction

    Addiction is an SSA journal publishing peer-reviewed research reports on pharmalogical and behavioural addictions spanning many different disciplines.

  15. Rat Park Experiment

    At the end of the 1970s, Bruce Alexander published a series of clinical studies known as the rat park experiments. The studies compared two groups of rats, all pre-addicted to morphine. The first group lived separately in isolated cages, and the second group lived together in a rat colony where they could play, have sex, and socialize.

  16. What Does "Rat Park" Say About Addiction?

    Incredibly, the solitary rats were found to consume 19 times more morphine than the rat park rats. In a follow up experiment, when rats were deliberately made addicted to morphine and then given a choice as to how much to consume, the solitary rats continued to choose the drug but the rat park rats actively attempted to resist it despite the ...

  17. Addiction, Connection and the Rat Park Study

    In this experiment, rats, who are participating in drug studies, are given a large cage with free food, access to sex, toys, and many playmates (the childhood kind, not Hugh Hefner's). As Hari ...

  18. Rat Studies Elucidate the Neurochemistry of Addiction

    Rat Studies Elucidate the Neurochemistry of Addiction. Scientists have long wondered what happens in the brain during the moments before a drug addict succumbs to the urge for a fix, or an animal ...

  19. The Rat Park Study: on Addiction & the Power of Community to Heal

    In the late 1970's, psychologist Bruce Alexander tested the hypothesis that drugs do not cause addiction. The study design included a "rat park" where rats had a community based environment which allowed them to freely socialize, play and have fun- basically like rat heaven. The rats were given the choice of reg ular water and drugged water.

  20. Mouse Party

    Where applicable, this presentation primarily depicts how drugs interact with dopamine neurotransmitters because this website focuses on the brain's reward pathway. Mouse Party is designed to provide a small glimpse into the chemical interactions at the synaptic level that cause the drug user to feel 'high'. Genetic Science Learning Center.

  21. The Rat Park Addiction Experiment

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    In an in vivo experiment using a rat rotator cuff repair model on both shoulders, 72 rats were randomly assigned to three groups (24 per group): group A, conventional repair; group B, repair with ...