The Problem with Vivitrol®

(https://www.vivitrol.com/opioid-dependence/what-is-vivitrol)

Fascinating post by guest contributor Amy Dunn, graduate student at the Rockefeller University!


What is Vivitrol®? This question is posed in countless ads depicting attractive young people across target states, such as MA, NY, NJ and PA. The ads do little to answer the question – instead just giving a drug name and a website. Vivitrol®, made by the Boston-based company Alkermes, is the brand name for the drug naltrexone and is used to treat both alcohol and opiate addiction.

Opiates like heroin or oxycodone work by stimulating the mu opioid receptor in the brain. This leads to the euphoric and rewarding effects that are characteristic of these drugs. The two most popular medications for treating opiate addictions, methadone and buprenorphine, both work by stimulating that same receptor in a slightly different way. This relieves the cravings, but doesn’t cause the same “high” as heroin or oxycodone. Methadone and buprenorphine are known as agonist, or replacement, medications. Dr. Simon Says Science wrote an excellent article for Addiction Blog that compares methadone and buprenorphine and explains how they work in greater detail. Naltrexone, on the other hand, is an antagonist of that same receptor – meaning that it completely blocks the effects of any opioid. While it seems counterintuitive, medications that stimulate the mu opioid receptor and medications that block the mu opioid receptor have both been proven to be effective treatments for opiate addiction.

Naltrexone was approved by the FDA in the 1980’s and was originally formulated as a daily pill, however it was difficult to get people to adhere to taking their medication. Because naltrexone is a mu opioid receptor antagonist, it can lead to unpleasant feelings that are the opposite of the euphoria felt with an opiate agonist. People with addictions could stop taking the medication if they wanted to get high instead. Because of these adherence issues, the drug bounced around between companies. In addition to these issues with compliance, it was difficult for companies to market an addiction medication because of the social stigma. Addiction is often seen as a moral problem instead of a medical one, which makes selling medications for addictions very difficult.

Naltrexone became far more practical when it was reformulated as an extended-release injection. The extended-release injection lasts for a month, greatly reducing the problem of adherence. Vivitrol®, the brand name for the extended-release naltrexone introduced by Alkermes, was first approved in 2006 for the treatment of alcohol addiction. Following a successful clinical trial in Russia, it was also approved for treatment of opiate addiction in 2010. Despite poor initial sales, the popularity of Vivitrol® has grown rapidly in the past couple years.

Vivitrol® Sales: (https://www.scribd.com/document/351102245/Alkermes-2016-Analyst-and-Investor-Event-Presentation#from_embed)

 

Vivitrol® is still far less utilized than methadone and buprenorphine, but this is expected probably because it is much newer on the market. Importantly, not everyone responds well to methadone or buprenorphine, and having another option for the treatment of opiate addiction should be a good thing for everyone. However, a disturbing pattern has emerged in the past couple years regarding the ethics of Alkermes’ marketing strategies and scientific data. They are missing key scientific data, and actively engaging in strategies to undermine the use of agonist medications that compete with Vivitrol®. While these marketing strategies may or may not be illegal, they still raise important questions about the ethical obligations of pharmaceutical companies to their patients.

The Science on Vivitrol®

In order for the FDA to approve a drug, a drug company must first prove that the drug is effective through a clinical trial. Clinical trials are very tightly regulated in the US which makes sense because you’re testing a drug that is technically still experimental and could be dangerous to people. Not only do you need to prove that your drug is safe, but you also need to prove that it is at least as effective as other drugs out there that treat the same condition. This is where there are holes in the data on Vivitrol®.

The clinical trial that convinced the FDA to approve Vivitrol® was done in Russia.3 Clinical trials are done in other countries for many reasons. Companies may be trying to skirt the tight regulations here in the US, or they might just need to work with a patient population that is found more commonly in other places. The FDA reviews the study design and the data to see if they want to approve the drug regardless of where the study was done. The clinical trial on Vivitrol® was designed to see if Vivitrol® was effective for treating opiate addiction, but did not compare it to either of the other approved medications for opiate addiction (methadone or buprenorphine). Neither of these agonist treatments is available in Russia. In fact, both are illegal because they are opiate agonists. Alkermes only needed to prove that Vivitrol® was more effective than placebo in this case. The results were promising – almost 90% of the addicted persons who received the naltrexone shot remained abstinent during the test period, compared to just over 60% of the control group. This was enough evidence to get FDA approval, however to date there are no clinical trials comparing Vivitrol® to either methadone or buprenorphine. In addition, there was no follow-up study examining the long-term outcomes of the participants of the clinical trial in Russia.

Since it has been approved, there have been several other clinical trials examining the efficacy of Vivitrol® in different populations (although none of these studies compared it to buprenorphine or methadone). There are still concerns about adherence to Vivitro®, as well as the possibility that a person could take a dangerous amount of opioids in order to overcome the blockade effect. Because it’s an antagonist, if an addicted person takes naltrexone while they still have opiates in their system, the naltrexone will both stop the euphoric effects of the opiate and also cause withdrawal symptoms. In fact, a person has to be over a week opiate-free and have already gone through withdrawal before they can begin naltrexone treatment.

However, no medication is ever perfect. While there are still unanswered questions about Vivitrol®, it is clearly an addition to the toolbox that healthcare providers can use to help people fight addictions. It is important that these scientific concerns are discussed and addressed, and that these issues are clearly presented to the public so that people can make informed decisions about their medications.

The Marketing on Vivitrol®

(www.vivitrol.com)

To understand more about how Alkermes is advertising Vivitrol®, we can look at a screenshot of their main website listed on their advertisements (www.Vivitrol.com). This language – “the first and only once-monthly, non-addictive medication” is problematic.  While they are correct in characterizing naltrexone as “non-addictive”, this wording implies that the other medications that are available (methadone and buprenorphine) somehow are addictive. This same language is often used in a 2016 investor presentation as well, where they describe agonist therapy as “maintain[ing] physiologic dependence on opioids”. This is scientifically correct; a person who is using agonist medication may indeed be dependent on their medication. This simply means that they would experience negative physiological consequences if they abruptly stopped use. It does not mean that they are addicted. “Addiction” is a physiologic dependence combined with compulsive drug-taking despite negative consequences. Alkermes is conflating these two terms in a way that is confusing, and is meant to manipulate the consumer into equating agonist therapies with addicting opiates of abuse. While their statement that agonist therapies lead to dependence is not incorrect, it is still reinforcing a very damaging stereotype that agonist therapy is just “replacing one drug with another.” This stigma against agonist therapies is a major hurdle for the treatment of opiate addictions. Alkermes actively reinforces and uses this stereotype in order to promote Vivitrol® as the “only non-opioid treatment.”

(https://www.scribd.com/document/351102245/Alkermes-2016-Analyst-and-Investor-Event-Presentation#from_embed)

In addition to portraying Vivitrol® as a better and safer alternative to agonist therapies in the public sphere, Alkermes is also deliberately promoting this view in the political realm. This is noted in the slide from an investor presentation that outlines their marketing strategies, above.  NPR and Side Effects Media published an excellent article detailing their investigation into Alkermes’ political involvement.  They describe Alkermes lobbyists presenting to government committees on addiction therapy and promoting the idea that agonist therapies are “replacing one drug with another”. There is overwhelming scientific evidence supporting methadone and buprenorphine as effective treatments for keeping people with addictions off of heroin and able to live their lives without experience frequent drug cravings. Despite this, there are many decision-makers in the government who do not want to support their use in treatment. Republican Rep. Tim Murphy described agonist therapy as “government –supported addiction” at a meeting in March 2015. He has received political donations from Alkermes. Tom Price, the new Health and Human Services Secretary, received a great deal of criticism for his statement that agonist therapy was “substituting one opioid for another” – despite the department’s website explicitly stating that it supports these kinds of evidence-based treatments.

Alkermes’ strategy of reinforcing of this stereotype leads to real policy consequences. The NPR and Side Effects Public Media report describes several bills that contain language steeped in these stereotypes – specifically instructing treatment providers to strive for “the goal of opioid abstinence.” This is beneficial for Alkermes, as Vivitrol® is the only non-opioid treatment available. The science however, does not indicate that opioid abstinence leads to better outcomes for patients than maintaining their agonist therapies. The report includes drafts of several bills that even mentioned Vivitrol® by name, although it was later removed because of ethical concerns. Alkermes lobbyists have also supported tightening regulations for methadone and buprenorphine, which is incredibly problematic given how restrictive the regulations already are for treatment providers.

Alkermes may not be making explicitly false claims in its marketing, but it is certainly playing off of existing harmful biases in order to further their sales. Whether or not this is illegal is debatable; it is illegal under the Federal Trade Commission for companies to “mislead” consumers. At the very least, it is incredibly unethical for a company to be so actively promoting stereotypes and policies that harm the very patients that they claim to be helping. This falls under the larger umbrella of the issues of advertising, pricing and political involvement of the pharmaceutical industry in our country. While there are no easy fixes, it is important that companies like Alkermes are held responsible for their unethical behavior and that consumers are able to make informed decisions about their treatment based on the available research.


About the Author: Hello! I’m currently finishing my 3rd year of graduate school at Rockefeller University. I’m studying the cell signaling changes caused by drugs of abuse and investigating the ways we can use those different pathways to treat addictions. In addition to learning more about the science of addiction through my research, I’m also interested in learning about the different political and social issues surrounding drug addiction. All of the views and opinions here are entirely my own and definitely don’t reflect those of my lab or institution! My email address is adunn@rockefeller.edu.

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Response to the June 2017 New Yorker Article on the Opioid Epidemic

At this point, I would think that knowledge about the vastness and seriousness of the prescription opioid and heroin epidemic, the biggest threat to American health and well being since the HIV/AIDS epidemic, would be common knowledge. Of course, given the abundance of shiny Internet things to tantalize easily distracted Americans, this is unfortunately not necessarily the case. Thankfully the New Yorker, with their characteristic excellence in reporting, has just released a superb and humanizing article on the opioid epidemic in their June 5 & 12, 2017 issue.

Read the article here.

The piece puts a much-needed human face to the horrors and misery of opioid addiction and the too-frequent death by overdose. Margaret Talbot, the article’s author, zeroes in on Berkeley County, West Virginia, in the heart of a region of the country hardest hit by the epidemic. I don’t want to give away much (because you should actually just read the article) except that the stories are heart wrenching yet balanced, and thorough in way that only the New Yorker can deliver. While the article is largely about the lives of people affected by and fighting against the epidemic, I was disappointed with a couple of points that were either made incorrectly, weakly, or not at all.

First, the article barely talks about how the epidemic arose in the first place. It mentions Purdue pharmaceuticals, the bastards behind Oxycontin (drug name: oxycodone), and that prescription opioid abuse led to heroin addiction but does not describe how the surge in addiction to prescription opioids occurred in the first place. The article describes the main problem with Oxycontin is that it can be crushed and snorted but a 2010 formulation of the drug reduced this risk. While this is indeed true, the article neglects to mention that when someone is first prescribed an opioid like Oxycontin for chronic pain (as was the case in the late 90s and early 2000s despite any evidence for the effectiveness of opioids in the treatment of chronic pain), the addictive potential of opioids often led to opioid substance abuse disorder in people who took it as prescribed (see this comprehensive article for more info). This is the big point, many of the people that eventually abused opioids started down that road by taking the drug as prescribed! Talbot incorrectly frames the big picture problem but she then goes on to correctly describe how those addicted to prescription opioids found their way to the cheaper and more abundant heroin.

The article goes on to mention the CDC’s release of guidelines on opioid prescription but fails to cite that this guidance came out as late as March, 2016, well after the epidemic had already taken root and thousands were already addicted and dying of overdose (I wrote an article on the CDC’s guidelines last year and highly recommend you read that article too if you want to learn more). The CDC’s guidance is mainly about the point I made above, that the over-prescription of opioids is the real cause of the epidemic, not just the crushable version of Oxycontin, and the limitation of opioid prescription is one of the huge policy interventions that is needed.

Later in the article, Talbot introduces us to Dr. John Aldis, a retired U.S. Navy Physician and resident of Berkeley County, WV who took it upon himself to educate people on how to use Narcan (generic drug name: naloxone), the treatment for opioid overdose. Dr. Aldis makes the critical point about the importance of medication-assisted treatments such as Suboxone (generic drug name: buprenorphine) and methadone. I appreciated the point made in the article that some patients may need these vital treatments long-term, or even for life, to combat the all-consuming single-mindedness of opioid addiction. However, beyond this passing mention, I felt that medication-assisted treatment was only weakly covered. There is still a great deal of ignorance about these treatments. Indeed, current HHS secretary Tom Price falsely characterized them as “replacing one opioid with another” and was majorly criticized by addiction experts. The reality is that there is overwhelming scientific evidence (I’ve written plenty on this site) describing the effectiveness of methadone and buprenorphine at 1) keeping addicts off of heroin, 2) allowing them to be able to live their lives without suffering from withdrawals and cravings, and 3) most importantly, keeping them alive. Talbot could have done a much better job of really hammering these points home but she seemed reticent, for some reason, to discuss it in detail in this article.

Finally, the article repeatedly emphasizes the importance of rehab clinics and tells the story of a huge victory for Martinsburg, WV (a town in Berkeley County) when the city council agrees to open a clinic in the town itself. I do not want to discount the importance of an addict assessing their addiction and taking an active role to end it, but this article does miss another critical point: rehab clinics only exist because addiction medicine is not part of medical school curricula and most hospitals are ill-equipped to treat those suffering from addiction. I feel this article could have really made the case for the importance of training for doctors in addiction medicine and the necessary shift that needs to happen for addiction treatment, a move away from overpriced (and often ineffective) private rehab facilities, and to public hospitals. Unfortunately, this point was not made.

Despite these missed opportunities, I commend Talbot and the New Yorker for a well-written article and thank them for this important piece that I encourage all to read.

 

The Laws You Never Heard Of that Will Help to Fight the Opioid Epidemic

When a politician is in his or her final few month in office (because either they lost their re-election or simply decided not to or can’t run), they call this the “lame duck” period. President Obama’s last few months in office were anything but “lame”.

On December 14, 2016, in a rare move of bipartisanship, Obama signed into law the massive 21st Century Cures Act. This law provides a boost in funding for NIH (which includes $1.8 billion for the cancer moonshot initiative), changes to the drug approval process through the FDA, and ambitious mental health reform. This huge bill has the stated purpose of “To accelerate the discovery, development, and delivery of 21st century cures, and for other purposes.”

I’m willing to bet many people were totally unaware of this legislation that could help millions. There are some parts that are controversial and, as with any large piece of legislation, some provision that benefit this interest or that have been worked in (the changes to drug approval at the FDA will likely benefit Big Pharma). I’m not a health policy expert so I’m not about to go through and discuss line-by-line the winners and losers in this law (if you want a more in depth discussion: NPR, Washington Post, and PBS have all written articles on the law).

There’s one piece of the law that I am particularly thrilled about: $1 billion over 2 years for treatment for opioid addiction. That’s rights billion, with a “B”. The money is to be distributed to states in the form of block grants (block grants are in essence a large allocation of federal money to be used for a specific purpose given to states but the details of how that money is used is decided by the states themselves).

This is an unprecedented amount of funding earmarked exclusively to fight the opioid epidemic that is still raging in the US. The funding is to be used for expanding and increasing accessibility to treatment, such as life saving medication-assisted treatments such as methadone and buprenorphine. The federal money will also be used to train healthcare professionals to better care for people dealing with addiction, and a comparatively smaller amount for conducting research on how best to fight the epidemic, and other provisions.

I’ve written about methadone and buprenorphine and their effectiveness ad nauseam on this site and I am personally and thrilled to see a massive federal effort to increase access to these vital tools in the fight against the opioid crisis

The Cures Act comes on the heels of another promising piece of legislation, the Comprehensive Addiction and Recovery Act (CARA), signed into law by President Obama on July 13, 2016. This law includes provisions to expand the availability of naloxone–the medication used to save people from the effects of opioid overdose–to first responders, improve prescription drug monitoring programs, make it easier for healthcare providers to administer, dispense, or prescribe medication-assisted treatments, and other provisions.

The combination of these two pieces of legislation is a promising and much needed initial federal response.

However, this huge boost in funds for treatment in the Cures Act is only for 2-years. President Trump’s budget for FY18 would add $500 million for opioid addiction but most analysts think this is just a sneaky way of making it seem as if he’s supporting addiction treatment when the money has already been written in as part of the Cures Act. Further, his cuts to the Department of Health and Human Services (which contains the NIH and other agencies that administer the Cures and CARA laws) would make it difficult to launch any type of  effective response to the crisis.

Regardless of how things shake out, Trump’s massive cuts for everything that’s not the Department of Defense will likely hurt the fight against the opioid epidemic too. The real question is by how much?

 

5 Facts on the Opioid Epidemic: National Drug and Alcohol Facts Week

Spilled prescription medication --- Image by © Mark Weiss/Corbis
Spilled prescription medication — Image by © Mark Weiss/Corbis

Well, I’m a little late to the punch on this one but National Drug and Alcohol Facts week has been going and ends tonight. This public awareness campaign is now in it’s seventh year and is all about shattering the myths about addiction.ndafw_logoI might as well throw my belated hat in the ring and share 5 facts about the opioid epidemic.

Fact #1: The opioid epidemic in the U.S. has hit all demographic groups, regardless of race, gender, age, location, or socioeconomic status.

Fact #2: Prescription opioid pain medications like oxycodone can be just as addictive as heroin, even if taken as prescribed.

Fact #3: There is no scientific evidence that prescription opioids are effective at managing chronic pain; they are extremely effect for short-term, acute pain.

Naloxone_(1)Fact #4: Naloxone is a drug that counters the effects of opioids and can immediately reverse an overdose; you cannot get addicted to naloxone.

Fact #5: Buprenorphine and methadone are opioids that can help a person to fight their heroin addiction by satisfying their craving for the drug.

To learn more, here’s a short “Best of” from Dr. Simon Says Science on the Opioid Epidemic. Check out the posts below for oodles of info on opioids.

  1. What is naloxone? Should it be available over the counter?
  2. The CDC Fights Back Against the Opioid Epidemic
  3. Is Methadone an Effective Treatment for Heroin Addiction? YES!
  4. Morphine and Oxycodone Affect the Brain Differently
  5. Important: CDC Releases Report on Heroin Epidemic
  6. Methadone Maintenance Therapy Works-End of Story
  7. Paper Review-Initiation into Injection Drug Use and Prescription Opioids
  8. New Review Paper-The Prescription Opioid and Heroin Epidemic

 

The British Medical Journal (BMJ) Calls for an End to the “War on Drugs”

war-on-drugs-no

A recent editorial in the British Medial Journal (the BMJ) has called for an end to the “War on Drugs”, which costs about $100 Billion/year and has failed to prevent both drug use and drug proliferation.

The article points out how the “War on Drugs”, the term used to collectively describe the laws penalizing drug use, has had a wide-range of negative effects. For example, the US has the highest incarceration rate in the world and about half of those arrests are due to drug-related arrests.

The health effects have been drastic as well. Stigma against opioid replacement therapies like methadone has resulted in increased deaths due to opioid overdose in countries that limit access. Stigma and discrimination against addicts, as well of fear of punishment for for usage, often leads away from health care services to unsafe drug-use practices that can spread HIV and Hepatitis C, and other unintended poor-health outcomes.

Importantly, the editors call for rational, evidence-based, drug-specific approach to regulation and strong involvement of  the scientific and medical communities. Obviously, the risks of something like marijuana are much lower than for heroin but how will drug policy reflect this? Research is required to support any efforts in order to identify the best practices and strategies.

The editors point out that a recent article in the Lancet “concluded that governments should decriminalise minor drug offences, strengthen health and social sector approaches, move cautiously towards regulated drug markets where possible, and scientifically evaluate the outcomes to build pragmatic and rational policy.”

Above all, a change in drug policy must benefit human health and there will be no “one size fits all” approach. The road ahead is difficult but one thing is certain, the road that led us here is a dead end. The “War on Drugs” has failed; the call now is to develop a national and international drug policy that won’t.

What is naloxone? Should it be available over the counter?

Naloxone_(1)

New blog post for addictionblog on naloxone, an antidote for opioid overdoses.

Read my new post here!

Methadone vs Buprenorphine: Which is Better for Treating Heroin Addiction?

Check out my new post for addictionblog!

Is Methadone an Effective Treatment for Heroin Addiction? YES!

methadose_0

NEW BLOG POST FOR ADDICTIONBLOG IS UP NOW! ALL ABOUT METHADONE.

CHECK IT OUT!

Top Scientific Leaders on Addiction Call for its Treatment as a Medical Disease

(© Alan Cleaver flickr https://www.flickr.com/photos/alancleaver/4104954991)
(© Alan Cleaver flickr https://www.flickr.com/photos/alancleaver/4104954991)

A new review article published in the prestigious New England Journal of Medicine highlights the importance of treatment of addiction as a medical disease and calls for a change in public health policy towards addiction. Written by several leaders in the addiction field including Nora Volkow, MD, the director of NIDA, and George Koob, PhD, the director of NIAAA, the article does a superb job at outlining the underlying biology of addiction and clearly explains why addiction is a disease of the brain that needs to be treated medically.

Read the full article here.

In fact, I also covered most of the points made in the article in my own post for Addiction Blog on “Why Addiction is a Brain Disease?”

However, when it comes to public health policy towards addiction, this is where the article fell short. While treatments for opioid addiction such as methadone and buprenorphine were briefly mentioned in the article, there was no call for a national effort to be made to increase access to these vital medications. The authors had a potential to increase awareness of the opioid epidemic and the treatments already on hand to fight it but failed to make a stronger case for this critical improvement.

Nevertheless, the article is well written and a great introduction to the neuroscience of addiction and why it is a disease of the brain.

Marijuana has Long-term Effects on the Brains of Adolescents

(from wikipedia.org)
(from wikipedia.org)

After alcohol, marijuana is the most widely used illegal drug in the United States (I mean seriously, who hasn’t smoked up at least once? According to Pew Research Center, half of the country) But pot laws are rapidly changing in many parts of the country and soon it may be as ubiquitous as alcohol. Four states in the US have legalized marijuana for recreational use and 23 total states have some form of legal marijuana use (including D.C.). While the health effects of alcohol have been well studied and are significant (some 88,000 deaths/year, the third highest cause of preventable death in the US, according to the CDC and NIAAA), little is known how this shifting trend in marijuana use will affect the country. Another important trend is the amount of THC (Δ-9-tetrohydrocannabinol, the chemical that is primarily responsible for the psychoactive effects of marijuana) in marijuana strains has been steadily increasing over the past few decades [1, 2]. The big question that researchers are asking themselves is if legal marijuana use drastically increases, what are the long-term personal and public health consequences of marijuana use? Of course, this is a huge question with many complexities.

Significantly, Marijuana is the also the most widely used illegal substance amongst youths. Adolescence (ages 12-17) is an extremely critical period for brain development [3, 4] yet the effects of marijuana on the brains of kids have not been thoroughly studied. A recent paper out of Dr. Steven R. Laviolette’s laboratory at the University of Ontario sought to answer this question: what happens to brains of adolescent and adult rats that have been exposed to THC?

Renard et al. 2016 abstract

Why was the research done? What is the hypothesis?

 There have been a number of studies published that suggest there might be an association between prolonged marijuana use (especially of high-potency strains) and schizophrenic-like or psychotic-like symptoms [5, 6] although there is disagreement in the scientific community on the evidence [7, 8] (I may write a blog post discussing this issue in the future). It is has even been suggested that youths that smoke marijuana are more at risk for psychotic symptoms as adults [9, 10]. The author’s sought to test this directly by injecting adolescent and adult rats with THC for a number of days, waiting a period of time after the injections, then measuring the long-term effects on the rats. The team hypothesized THC would have induced long-term changes in the brains of adolescent but not adults rats, and subsequent changes in psychotic-like behavior.

How was it done?

Adolescent and adult rats were injected with THC twice daily for 11 days. The dose of THC administered was increased (escalating dose) to account for any tolerance that may occur. As an important control, separate groups of adolescent and adult rats were injected with vehicle (the solution that THC was dissolved in but minus the THC itself). Following a 30-day abstinence period after the last injection, THC-adolescent, control-adolescent, THC-adult, and control-adult rat groups were subjected to number of behavioral and molecular tests to see what effect the drug had on the animals. I need to point out that the 30-day abstinence period is significant in the rat life-span. This is enough time for the adolescent rats to become adults so what the scientists are primarily studying is the long-term effects of THC on adolescents vs adults in adulthood.

In the behavioral neuroscience field, we have devised another of tests to measure various aspects of animal behavior. Obviously we can’t inject humans with THC and see what happens so we have to use rodents and identify behaviors that approximate a similar behavior in humans. Of course, rodent behavior is no where near as complex as humans but rats are remarkably sophisticated animals (ask anyone living in New York) and scientists have developed a number of ways to measure things from motivation to social behavior to anxiety to depression.

In this experiment, a social test was used, two different types of anxiety tests and a motor activity test. The tests measured effects on motivation, exploratory-behavior (another indicator of how motivated rats are), social interaction, and anxiety.

The scientists also measured the activity of dopamine-releasing neurons in the living animal using a technique called in vivo electrophysiology. Recall from my post I am Neuron! that when activated, brain cells (called neurons) conduct an electrical current that results in the release of neurotransmitters onto another neuron. This electrical current is called an action potential and we can measure this by inserting a special probe into the those neurons in the animals brain (the probe measures electrical currents). Therefore, with in vivo electrophysiology we can measure every time a neuron fires (i.e. an action potential is generated) in a specific part of the brain. Using this technique, the scientists measured dopamine neurons in an important region of the brain called the VTA and how often these neurons fire in THC vs control rats. Check out this video for more details on in vivo electrophysiology.

Finally, brains from animals were dissected and a number of protein molecules were studied using a common technique in molecular biology called a Western blot (or known as an immunoblot). A Western blot takes advantage of antibodies that are able to recognize and stick to one specific type of protein. Therefore, this assay can tell you two main things 1) if your protein of interest is present in your sample and 2) approximately how much of your protein there is compared to other samples. In this paper, tissue from a specific brain region is used and the protein is analyzed by Western blots in order to comparing quantities of proteins between the different experimental groups. Of course, the limitation of a Western blot is if you have a good antibody for your protein of interest. Luckily there are many biotech companies such as Cell Signaling that specialize in making and testing reliable antibodies. The scientists used the Western blots to study many proteins in a region of the brain called the prefrontal cortex (PFC), which is believed to be important in self-control and other high-function brain processes. Check out this video for more details on Western Blots.

What did they find?

THC-adolescent rats exhibited deficits in numerous behavioral experiments compared to controls while THC-adult rats did not appear to have any behavioral changes.

*Recall that these experiments were conducted 30 days after the last THC dose so the author’s show that these are long-term effects of THC on the brain of adolescent rats.

In the social activity test, rats showed little interest in interacting with a stranger rat (normal rats are usually curious about the novel stranger). THC-adolescents also did not walk around or explore a new cage as much. In the two different anxiety tests, THC-rats appeared to have be more anxious (demonstrated more anxiety-like behavior).

In the electrophysiology experiment, VTA DA neurons fired more frequently for some reason in THC-adolescents compared to the other groups.

Finally, numerous protein changes in the PFC were observed in a number of important signaling pathways such as Wnt and mTOR pathways. Interestingly, THC-adolescents vs THC-adults seemed to have opposite effects on this proteins.

Limitations to the study?

  1.  The behavioral changes observed were statistically significant (meaning, most likely a real effect and not some kind of fluke of random chance) but were modest changes in some of the tests performed. Would the changes last beyond the 30 days post injection in this study?
  2. There are impressive arrays of behavioral tests that rats can perform to measure numerous aspects of cognition (for example, memory and learning) but none of these experiments were performed. A far greater range of behavioral experiments would have made this study more compelling.
  3. While the electrophysiology and Western blot data are intriguing, the author’s performed no experiments to determine if these changes are responsible for the difference in behavior (association vs causation). These changes could merely be an incidental change and have nothing to do with the behaviors studies.
  4. The doses that the mice were injected with, while based on a previous study, are somewhat arbitrary. Would the changes be more pronounced or less pronounced with higher/lower doses or a shorter/longer dosing regimen?
  5. Only male rats were studied. Would the same behavioral and molecular changes occur in female rats?

What does it mean?

Based on the behavioral and molecular data presented, this data paper suggests that adolescent rats (but not adults) exposed to THC have long-lasting changes in the brain. The author’s argue that these effects recapitulate schizophrenia-like symptoms but I am not entirely convinced. Also, THC given to rats is not the same thing as marijuana smoked by human teenagers. So it’s important to keep in mind that this is one study. In science, we never draw grand conclusions about anything based on one study. Nevertheless, several other reports have corroborated these findings (see this review paper for a summary of many of them [11]). Indeed, it does seem that marijuana use can cause long-term deficiencies in human and rodent brains. The results of this paper are certainly intriguing and, if true, a whole host of stricter regulations on marijuana use in states that have legalized it may need to put in place to help curb increasing marijuana abuse amongst youths.

References

  1. Cascini F, et al. Increasing delta-9-tetrahydrocannabinol (Delta-9-THC) content in herbal cannabis over time: systematic review and meta-analysis. Current drug abuse reviews. 2012;5(1):32-40.
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