New research coming out of UC San Francisco has located the”Stop Switch,” which when damaged can lead to craving and addiction issues. Also a 5-year long study from Boston University is showing use of ADHD drugs by young people can make them more susceptible to cocaine addiction, not less as is commonly thought. And a discussion of the new 10x more powerful hydrocodone – Zohydro, and the opiate addiction medication buprenorphine.
Transcript (edited):
HOWARD: Welcome to the CNS Podcast featuring Dr. Darryl Inaba, research director for CNS Productions. I am Howard LaMere. We’ve come across a lot here lately. Boston University is doing a multi-part series and were going to cover some of the items, a new ADHD study coming out of the University of California, San Francisco about where the “off switch” is and imaging it. Also a couple stories from the New York Times – one about the dark side of buprenorphine and the other on protests by treatment professional to the approval of Zohydro. So Darryl, lets start off with your alma matter, UCSF and the location and the imaging of the “off switch.”
DARRYL: Well, I just find it so validating and something we’ve looked at and inferred from a lot of human research that was being done, but now more definitely at the University of California Medical Center in San Francisco, a doctor Antonello Bonci, whos an adjunct professor there, has been funded to do research with mice again, but I didnt realize they had a significant prefrontal or frontal cortex, but I guess they do in addition to their very primitive mesocortex and they’ve located it, and indeed there is a “stop switch” located in that part of the brain When the “go switch” becomes activated, in somebody who is not prone toward addiction, or say in a mouse when their go switch is activated, its “do it again…do it again…you got to keep doing this…this is important for your survival.” But if you are a healthy individual, then your “stop switch” is located in the left orbital prefrontal cortex, actually both lateral sides, but especially the left frontal medial prefrontal cortex. And now in the prefrontal cortex of a mouse they have located a similar area. If they stimulate that area with a laser beam, the cocaine seeking behavior stops. And if they stop stimulating, the cocaine seeking behavior reactivates. So they’re calling that the “stop switch” the same name we came up with ourselves, in terms of our looking at the human corollary to this type of research. So basically, they are very excited there at the University of California. Its in their alumni newsletter this month and it caught my attention. They’re excited because they feel that they can then activate that area without any invasive therapies, like we talked about optogenetics, of actually feeding some optic wire into the brain to simulate light and different frequencies of light in parts of the brain. Well, thats pretty invasive. They’re saying that they can use transcutaneous magnetic stimulation or TMS. Transmagnetic stimulation has already been used effectively for things like depression, where they place the magnet on the surface or outside on the scalp. They can send in impulses, magnetic impulses to stimulate specific areas of the brain and thats their next step. They’re going to go toward that to see if they can get the same results on activating the “stop switch” in a mouse and then look at potential for human application. This might be a whole new approach to the treatment of craving and addiction, or the compulsivity and obsession addiction — people can go around wearing a little helmet and continue to have their “stop switch” activated so that they don’t have that nagging craving or obsession to continue doing something.
HOWARD: So this is new research and its quite interesting. Kind of related to that is one of the stories from Boston University on ADHD drugs — we’ve talked about ADHD drugs quite a bit in the last few weeks, but this is another story based on the work of a researcher there at Boston, Kathleen Kantik, who has done a 5-year research study on the relationship between adolescent ADHD use drug use — Ritalin, of course being the most popular along with Adderall — and the likelihood of becoming addicted to cocaine in adulthood. You know, it is disconcerting that the research is showing this up because this is not what’s been normally thought to be the case and especially adding to that, the fact that more and more young people, even as young as 4 years old, are being prescribed one of those ADHD drugs and so, if that leads to cocaine addiction in adulthood, that could be not a good thing. And I dont know, Darryl, how old are these drugs? Do we have any indication at this point about what happens after multiple years of use?
DARRYL: Oh, they’ve been around for a long time, Howard. They’ve been used in this condition for a long time, but as you mentioned and we mentioned on several shows here, that the majority the bulk of the research that comes out and the bulk of the statements being made claiming that proper diagnosis and proper use of stimulant medications that are addictive medications in even very young children actually result in lowering their risk to becoming abusers of any drugs, especially of cocaine and amphetamine, methamphetamine and other stimulants. And this is a very important study because this flies in the face of that. This is saying the opposite. This is saying that, no there’s actually some good evidence from the Centers of Disease Control and Prevention that there is an increase future addiction problem with stimulant drugs from young people who are treated for ADHD with these medications. You know, of deep concern, even when we talked about this in our other podcasts, was that most of the studies are showing a lack of concern or believing people are going on and sequelling onto stimulant drugs from the use of these things in ADHD in children. Most of those studies are funded by the drug companies who are producing those medications that are used for ADHD so they’re biased to begin with, but they have a tremendous amount of weight because that’s who has the money to do the research. Now if there’s some Center for Disease studies coming out, and this study that’s coming out that is not being funded by a pharmaceutical firm thats promoting their medication, this may be a more objective way of doing it and she feels very strongly that use of stimulating addiction-prone ADHD medication does lead to at least some future cocaine use, if not future other stimulant abuse. She goes on in her study to say that, a big factor has to be proper diagnosis and we have talked about that. Lots of kids who are being diagnosed with this condition, are not properly diagnosed. They may not have true ADHD, but may have an aggressive parent who wants their kid to excel in school and so is pushing them to get on these medications where kids tend to do better, especially if they dont have ADHD, they do better at school and then they get better grades and do better on their tests and that’s one problem about proper diagnosing. Also, there aren’t a lot of good diagnosticians for this condition, especially on the public school and grammar school levels. Oftentimes its a school consultant – a nurse or some consulting medical person who barely meets with that kid, hears the teachers report, hears the parents report and says, okay the kid has got ADHD and we’ll prescribe these things. So she is quick to point out you have to have good, rigorous proper diagnosis that meets full medical criteria and then she says, and Im glad she said this, there are medications that are effective. Stratera is one of those medications that are less stimulating and less prone toward addiction and to you use those medications or other medications that can help ADHD without activating that addiction pathway in the brain, then thats the proper way of treating it. But I like it because its the first thing coming out, the first study thats coming out strongly, pushing back and saying no, we’re prescribing too many of these stimulant medications, Adderall, that has amphetamine, methamphetamine in it. Concerta and Ritalin that has methylphenidate. Another stimulant, Cylert which is another strong stimulant. But we may be promoting, unlike whats been fed to us all these years, we might be promoting future cocaine and future methamphetamine addicts by the use of these medications and we better take another look at this situation.
HOWARD: Well and you know, it goes back to follow the money, the fact that so many studies are funded because only the private sector, in particular, the drug companies who have a vested interest, have enough money to fund a multiple year study like this. There is a relationship with this story with the last story about the “off switch” and that is that in young people in adolescence, the prefrontal cortex which we talked about as the location of this “off switch” is going through its most rapid development at this time, especially adolescence. So, if that drug use is then impacting the functioning of the “stop switch”, this is cause for some concern.
DARRYL: Absolutely. The prefrontal cortex is the last part of your brain to get myelinated. Its the last part of your brain to get hard-wired and unfortunately it takes until about age 25 — you have to be 25 years before it becomes functional and up to 40 before it becomes fully hard-wired. So any kind of medication you take that starts interfering or interacting with that development, and destroys that window or opportunity for it to fully develop is going to delay that process and make you more prone to problems. But despite us knowing all that, despite us talking about all that, the research has come out again as you say, strongly supported by pharmaceutical companies, that kids who are treated with these stimulant type of medications, even though they’re very young. Their frontal cortex has not had any opportunity to become fully wired yet. They go on to actually less levels of addiction and less levels of drug problems than do kids who aren’t treated with these medications. So they thought it was actually very healthy if you do have ADHD to take this and again, as I said, this is a pushback. This is saying hold on here. There might be something else happening and maybe we haven’t had valid research and strong enough research to show us that we’ve got to re-look at this and treat this condition in a whole new different way.
HOWARD: Now, speaking of research into drugs, we’ve talked about Zohydro quite a few times here in the last few weeks and now its being reported again, I believe in the New York Times, several experts on addiction are loudly protesting the FDAs approval of this new opioid pain killer. Interestingly, the FDA panel looking at this drug when it first voted, voted against it 11 to 2 and this time they almost overwhelmingly approved it. And I guess the reason for that is that it was reformulated. Darryl, you have some background on this, I think?
DARRYL: Howard, when this was first being introduced, we raised our alarm here. They were talking about one of the most abused prescription pain killers in America, Vicodin, which the chemical is hydrocodone and they were talking about the need to increase its available amount by pill from the 5 mg hydrocodone that Vicodin is. But to better manage pain and on a full day basis, they were talking about the need for 50 mg, so they were introducing this Zohydro as 10 times stronger, 50 mg pill, to something thats already one of the most widely abused prescription drugs in America. And to add to that, they decided that the Tylenol, the pain killer that is added to boost up the effects of the opiates that was in Vicodin, was causing a lot of liver damage and causing increased death because people who got addicted to Vicodin wouldn’t take 1 pill, they would take 10 to 20 pills and that meant they were taking 10 or 20 Tylenol at the same thing which is really toxic to the liver. And so this Zohydro was being introduced as 10 times more hydrocodone, a strong opiate without absolutely no Tylenol, so that you won’t hurt the liver. And they approached the FDA and said were going to put it in a time-release form so people won’t be tempted to crush it up and shoot it or anything like that and they came out with this extended release which was shocking, as you mentioned. 11 to 2 voted against it when it first came up and now it passed and its passed the FDA panel. Its going to be available and it just looks like a nightmare waiting to happen — another heavy abuse situation. Opiate pain killer drugs are already on top of a whole era of diversion and addiction to pain killers. The interesting thing is that this is the time release mechanism, the thing that Oxycontin claimed was going to be diversion proof when they first came out with it. It was going to protect it from being abused because most people love the rush of oxycodone or opiates and if they can take each molecule and lock it up in a time release mechanism then they’re not going to get a full bolus of the you know, 80, 20, even 120 mg of oxycodone they put into the put into the new Oxycontin tablets, but that was destroyed right away when addicts just realized all they have to do is chew the tablet or crush it up before you eat it or before you shoot it and that destroys that mechanism. In 2010, Purdue Pharma who has Oxycontin said they had solved that problem. They came out with a new polymer or a new codeine that wouldn’t allow itself to be crushed up easily so they had solved that problem and of course, we reported right away my clients solved it in a week. They knew how to break through that problem so that they could indeed inject it or get the whole bolus. But in that interim, something funny happened. When it came out in 2010 and the street hadn’t figured it out yet, there was a massive increase in prescriptions for Opana and a huge increase in sales of Opana. Opana is another opiate. Its hydromorphone instead of the hydrocodone that Oxycontin is. It pretty much is the same thing and there was such an increase in prescription of this and increase of abuse of that, they tried to lock up. Then taking the same steps that Oxycontin did and tried to lock up their molecule in these polymers that made it unavailable to give immediate access in a time release form so that people wouldn’t abuse it so much and a funny thing happened. I guess not so funny from your mantra, but Oxycontin got furious and said, you can’t use our polymer, you can’t use our design, you cant steal our patent. We don’t want you to do that, that’s ours and you can’t do that. So it seems to me they weren’t interested at all in what they were saying to the public that were really concerned that our medicine is being abused and we want to make it available and safer for people so were coating it with this thing. Well, when other opiate products started trying to emulate that and coat their products with it, they came out furious saying that’s infringement on our rights or patent, so its just one of those issues thats very strange. But indeed, whats happening with Zohydro is it has 10 times more hydrocodone or 10 times more per tablet than the current Vicodin has. It has some polymers around it, but its not a very safe. Its real easy one to crush up and abuse, so street addicts are going to have access to a very abusable Vicodin thats 10 times stronger than the current Vicodin. It doesn’t have any good protective coatings around it so you know it can be crushed up and abused and on top of that, theres no Tylenol, so you dont have to worry about hurting your liver from crushing up a bunch of these.
HOWARD: Well, maybe the use of heroin will then go down and there won’t be so many needle problems.
DARRYL: You know, that did happen when Oxycontin changed their formulation in 2010, the Opana increased and when Opana tried to crack down and make their medicine less abusable, the thing that happened right then was that we saw a great increase in heroin addiction, so you’re right – maybe if we get these things out and Zohydro is very accessible and gives all the kicks people want, maybe there’s going to be less heroin abuse.
HOWARD: Yeah, but its still so powerful that you’ve got to wonder whats going to happen next. There’s a follow the money component here also, in that Zohydro is manufactured or is going to be manufactured by the pharmaceutical company, Alkermes which also makes the popular medication, Vivitrol that is used to treat addicts, both pain killers and alcohol. So that would appear to be a little bit of conflict of interest there and some of the critics including the head of the American Society of Addiction Medicine are saying they just found out about that and they’re going to figure out what to do next.
DARRYL: Actually, I thought that was your perception more than anybody elses. I didn’t know it was part of any article, but certainly it would be a brilliant, brilliant tactic, don’t you think? Well, we’ve got them coming or going here! Come on get this stuff if you got a problem? Now you’ve got to buy our other stuff at twice the price to get off of it. You know, its one of the greatest salesmen things I’ve ever seen in the world, but that is an interesting phenomenon – they’re going to be offering 2 ends of the stick there and maybe capturing, sort of like mouse trapping in the computer – they’re going to trap people into the system and have a huge continual list of customers for their products.
HOWARD: I tell you — its always something. We have about enough time for just one more story, I think, and in another drug related, medication related story, this also coming out of the New York Times recently, the addiction treatments dark side. And this is a story about the abuse of buprenorphine, which is a popular drug used to treat addiction also and it is also an opioid and so there has always been some concern about this like methadone. Apparently it plateaus and is not as powerful as methadone, so it is billed as being safer, but there are definite concerns as pointed out in this article, Darryl.
DARRYL: There are concerns about any psychoactive substance, especially if it is an agonist, an opiate agonist and when this first came out, we definitely raised our concerns. We didnt want it to become another methadone. We didnt want it to become just pure replacement and then pure abusable, for everyone that knows that right now methadone causes more overdose deaths every year in American then does heroin and that prescription opiates are the number one cause of preventable death in America with more deaths occurring every year than kids being killed by auto accidents or human beings being killed by auto accidents so its a real concern, but we also recognize that this medication offered a tremendous benefit to what was existing in terms of other medications, not only for the treatment of addiction to opiates, but also for the treatment of pain. Very quickly, we recognize that in parts of Asia and India and Nepal, those areas, buprenorphine became the number one abused opiate drug. It was easy to get and people found it cheaper than heroin or other opiates and it became a strongly abusable drug. But the saving grace on it, as you point out was that it is both an agonist and an antagonist, meaning that at low doses its actually stronger than heroin, a lot stronger than heroin, it makes you feel great. It actually gives you a rush and all the other things but as you keep pushing up the dose at about 32 or 40 mg, it becomes an antagonist. It becomes actually an opiate blocker and some people start to get sick if they develop dependence on buprenorphine itself if they push it up to that dose. Or if you were a heroin addict and you took a high dose of this stuff, you would go into withdrawal sickness. So it had a plateauting effect, or dose response was that: as you increase the dose you certainly get more and more opiate like responses but when you hit that 32, 40 mg dose, it levels off and you dont get that response. What made it one of the safest drugs we could ever use to treat opiate addiction, and indeed thats what we saw. I think theres a document even in this article in the New York Times, 420 deaths to this substance, primarily it doesn’t mention it, but those deaths occurred because people were abusing multiple drugs at the same time — drinking with it, taking depressants with it, and other drugs and you’re going to get an easier death that way, but 420 deaths since 2003. And if we look at the number of say, Vicodin deaths, or Oxycontin deaths, or especially methadone deaths, that is miniscule in terms of just on a year. If we had 420 methadone deaths a year, that would be much less of a problem than the huge problem it is now. We looked at the studies in France and herein Jackson County, our Dr. Jim Shames looked at the number of people dying from opiate drugs and when buprenorphine came around as it did in France, the people started taking that instead of the other opiates around like methadone or heroin or other things you had a great decrease, so it does offer us a relative benefit over whats been around to treat addiction and to help and to interact with the opiate addicts out there. Its one of the safer drugs and I think its being underused for pain. I think its effective for pain and much safer than using methadone for pain. The other aspects I think that this article is missing — it does talk about people who get addicted to it and having somebody having very much trouble getting off of it. Now, we do have an overdose on it, so it does document correct things, but its not doing it on a relative sense to Vicodin, Oxycontin, to morphine, to methadone. When it does that, I think you have a much safer drug. But the other big benefit that came out of this it provided accessibility. Even now, to get treatment for opiate addicts, you have to go pretty much to a registered clinic. You have to go to certain license, certain people providing those services, certain things that you have to provide in terms of identification. We really control the medications like methadone or even buprenorphine that were given. But what this allowed doctors to do was it pushed opiate treatment, heroin treatment, or Vicodin or Oxycontin addiction treatment, it pushed it into the primary care level. Now any doctor, as long as you took a little test, you got approval for it, so out of your doctors office anywhere in the United States, you can provide this medication to help detoxify and help treat opiate addicts and thats a big boom. I mean people continue to believe that addiction occurs in the ghettos in the barrios, in the inner cities of our big metropolitan centers like Chicago, New York, Los Angeles, San Francisco, you know, places like that, Atlanta but in reality still, the largest pool and the largest incidence of addicts and even opiate addicts occur in rural America and in suburbia, places that some places that don’t have easy access to getting to a clinic to get to somebody who is valid to treat addiction and what the buprenorphine allowed was access. It allowed doctors in various communities to get onto this and provide treatment and it was an effective treatment. So I agree with this article. I think we always have to be concerned, but I think its overdoing it a little bit in terms of its not comparing this to the other treatment forms and what else is being done in the opiate addiction field.
HOWARD: Well, what I got out of it is theres a cash only kind of underground clinic movement developing and that sounds kind of dangerous.
DARRYL: Hey, they also mentioned the dark side they mentioned is that there is a conspiracy that somehow our government with other foreign governments are really vested into buprenorphine which is making them turn a blind eye toward potential problems. I think all of us were concerned about the potential problems and were all monitoring it. We know its a street drug. We know it has a great potential for a street drug. We know that if its Suboxone, meaning mixed with Naloxone, its a much safer street drug to be diverted out there than Buputex or Subutex itself which is just buprenorphine thats in India and Nepal, the biggest drug of addiction, and so we have to monitor it but I think it does offer tremendous amounts of benefits to the addiction treatment field anyway.
HOWARD: Well, its good to have treatments that are effective and that are working. So thats all the time we have for this time. As ever, thanks for listening. Questions, comments, suggestions always welcome. Stop by the website, cnsproductions.com, drop us a note there. And well be back in a little while – Thanksgiving is coming up, so we won’t be recording next week probably, but we’ll be back before too long. So, as ever, thanks Darryl and well talk again soon.
DARRYL: Always great ruminating with you, Howard.
HOWARD: That wraps our pod for today. Thanks for visiting the CNS Podcast. Please check back soon for the next in the series and visit our website, www.cnsproductions.com