Medication Assisted Therapy Advances

I'd like to welcome everybody to today's presentation on medication assisted therapy advances. Now, last week we talked about medication assisted therapy. We kind of rehashed what we already kind of knew and looked at a few new things to Today we're going to talk about a few new advances, as it says, in medication assisted therapy. This is the third in our installment for the Recovery Month webcast series. We're going to start by reviewing the purpose and efficacy of medication assisted therapy in general. For anyone who didn't see the last presentation, then we'll review current research on medication assisted therapy for nicotine, alcohol, opioids and methamphetamine. Yes, methamphetamine is making the list now, which, you know, that's news in and of itself. Approximately 1 million people age 12 and older, or about 0.4% of the population, had a methamphetamine use disorder in 2017, which is almost 30% higher than 2016. When people have an addiction, if they can't get their drug of choice, a lot of times they will find another drug in order to get that euphoria, in order to get that high, even if they're not related. Maybe they were addicted to opioids and then they couldn't get that wherever they were and they switched over, if you want to look at it that way, to methamphetamine, because that was accessible. And a lot of people, unfortunately, can make methamphetamine. And I've seen that in multiple different states. I've seen that trend happen over the past 10 years. Unfortunately, alcohol is the third leading preventable cause of death. Let that sink in. The third leading preventable cause of death in the United States. The first is tobacco, which we're also going to talk about. And the second is poor diet and physical inactivity. According to the 2018 survey, 14.4 million adults, about 6% ages 18 and older, and 2% of adolescents had alcohol use disorder. That's a lot. Six percent of adults qualify for alcohol use disorder. And that was before COVID I'm not making light of that. I'm very concerned about the increases in alcohol use and unfortunately, probably misuse during COVID Patients who use medication assisted therapy remain in therapy longer. And we're going to talk about why that is. You're not just replacing one high for the other. Medication assisted therapy, when provided appropriately, does not give the person the same level of euphoria. It may give them a little bit of relief, and we'll talk about why that is. But medication assisted therapy Is not meant to be a forever thing. It's meant to be a stopgap, if you will, during the first, say, two years while the brain is recovering. People who are on medication assisted therapy are less likely to commit suicide and less likely to overdose with opioids. Especially with. When people detox from opioids, the body adjusts to that relatively rapidly. So if somebody has detoxed from opioids and been off them for even a couple of weeks and then they relapse and they start back at the same dose they were using before they stopped, that is going to be way too high and they are very likely going to overdose. People who are on medication assisted therapy have improved health outcomes, including reductions in transmission of infectious diseases and improved overall health. When they're not monkeying with those neurotransmitters, they tend to have more, more energy. It reduces inflammation throughout the body when they are not, you know, over overdoing it on a lot of, on drugs and a lot of drugs and alcohol that may have adult. Well, drugs may have adulterants in them. There are a lot of reasons and you can imagine why people would have better health outcomes. Their diabetes, their high blood pressure, their communicable diseases, and just their immunity would be better. When they are not abusing drugs or alcohol and when they're not using illicit drugs. People who use medication assisted therapy have reduced involvement in the criminal justice system. If they are not having to go out to try to get money to get drugs, then the chances are they're going to, you know, not have as much involvement with the criminal justice system if they are not drinking and getting into barroom brawls. We know that a lot of criminal justice involvement happens when somebody is under the influence of alcohol because it is a disinhibitor. When they're not drinking, guess what? They don't have that inhibition. So they may be less likely to get in those sorts of altercations. There are improved birth outcomes. There are significantly improved child permanency outcomes. So people who are abusing substances when they get on medication assisted therapy, partly because they're remaining in therapy, they're less likely to overdose, they're less likely to relapse. They are also more likely to be able to keep their kids if they are involved in the child welfare system. Medication assisted therapy can be a help because it does assist the person along their recovery path. They're less likely to discharge against medical advice compared with those receiving counseling and supportive care only. And that is 30% of people who are receiving counseling only tend to stay in treatment. Almost 60% of people who also have medication assisted therapy stay in treatment. So, you know, let's look at that. That's double what you would get. That is huge. And they're less likely to relapse on any drugs. Remission rates were lower within 90 days for patients who were discharged with any form of ongoing medication assisted therapy. This is 27.3% who stayed clean, who didn't have MAT. But 42, almost 43% of people who had MAT were less likely to relapse on any sort of drugs. That's alcohol, everything in the kitchen sink there. That's a lot of information. And I will say it again. I know I've already said it like three times, but medication assisted therapy is not meant to replace one drug for another, doesn't do that. And it's not meant to be a permanent thing. It's meant to ease the transition. Interestingly, and I just threw this in here, I know it's not medication, but. In 2017, the FDA permitted the marketing of the first mobile medical application to help treat substance use disorders, except opioid dependence. They found that the utility in the reset device for opioid dependence was not good. In 2017, the reset device, or app contains a patient application and a clinician dashboard which delivers cognitive behavioral therapy to teach the user skills that are intended to increase abstinence and retention in outpatient therapy programs. In etherapy, we call this a therapist extender. It really helps the client connect with services and get tips and prompts when they're not in the counselor's office. Data showed statistically significant increases in abstinence for patients with alcohol, cocaine, marijuana and stimulant use, but not opioids in those who used the reset app? And that was again, more than double what somebody who wasn't using the app, somebody who wasn't using the app. Only 17, 0.6% were able to retain abstinence, maintain abstinence. But if they were using Reset, that jumped skyrocketed to 40%. That's more than double. What this is telling us is what most of us who've worked in substance use treatment for years have always known. Once a week counseling or even intensive outpatient counseling where they're there for three, four hours a day. Well, then they're on their own for 20, 21 hours a day. And if they are struggling, they are going to have significant difficulty staying clean and sober. Can you imagine what would happen if you paired the reset app with medication assisted therapy to Ease that transition, imagine what outcomes might be like. And interestingly enough, there were no studies on that. But I digress. Hopefully that's in the works. Recently, according to the website, and this wasn't on the FDA page, this was actually on the Reset company's website. They released Reset O for opioid dependence and allegedly have had really good outcomes with that. The initial Reset app was noted on the FDA's website as the first mobile medical app. So that was kind of interesting. In opioid treatment, when we think of medication assisted therapy, most of the time we think opioids. It's not just opioids. There are, there's the ability to help people who are addicted to a variety of things. Let's think about it. When people are abusing substances, what is it doing to their body? It's altering the neurotransmitters. What do some of our psychopharmacological medications do? Well, all of them, they alter neurotransmitters. We've got to figure out what they were increasing when they were using in order to figure out what they were feeling or what they were self medicating. So if you want to take it to the past what the intent of medication assisted therapy word means, you even can think of certain psychotropics as medication assisted therapy. If the person was self medicating their depression, for example. Well, if they leave treatment and they're on an antidepressant, guess what? They're going to be in a lot better shape for not relapsing than somebody who is still clinically depressed. But clean makes sense. FDA approves the first non opioid treatment for management of opioid withdrawal symptoms in adults. This is called Lucemyra and I wasn't able to find a lot of information on that. This was off the FDA's website. It is interesting to note though that there is a non opioid treatment. Why is this important? Well, because people who are in safety sensitive positions may not be able to take opioids. They may not be able to be on suboxone or buprenorphine or methadone. There are other people for other reasons who may not want to or may not be able to be on opioid based medications. So this is a benefit for that group of people. The FDA has also approved a once monthly buprenorphine injection and a buprenorphine implant for the treatment of opioid dependence. Now remember, buprenorphine is part of something. Suboxone. Suboxone is buprenorphine plus Naloxone. So if somebody uses too much or tries to crush, crush it up and inject it or inhale it, then the naloxone gets into their system and they go into immediate detox stage. Buprenorphine is a partial mu agonist. So what that means is you take the buprenorphine and it will give you a feeling of relaxation, so to speak, maybe a mild euphoria depending on the person. But it has a sealing effect. At a certain point, no matter how much you take, you're not going to feel any better. It's not like methadone or heroin or something else where the more you take, the more impact it has. Buprenorphine has a sealing effect, which is interesting. Now when they take the injection or the implant, you know, they're having a steady release of the buprenorphine in their system, which can be really awesome. The downside to this, and I try to point out both sides, is that people who are taking buprenorphine can also sometimes also take street opioids in order to enhance the feeling, or may take other medications or allergies, illicit substances, to get that high. So it's not an unbeatable system. But if you have somebody who is coming in regularly for drug tests and seems to be able to stay, stay clean, seem to be willing to stay clean, then the injection or the implant might be an option because then they're not being given something that can be easily diverted, easily sold, easily stolen, whatever. So, you know, those are some unique, interesting options for opioid treatment. Now let's talk about medication assisted therapy, specifically with opioids during pregnancy. The recommendations have actually changed since the olden days. You know, I guess five, ten years ago, when I did my first medication assisted therapy presentation. Well, I'll tell you about those in a minute. Fluctuating levels of opioids in the mother expose the fetus to repeated periods of withdrawal. So we know that periods of withdrawal activate the HPA axis in the adult, in the human, and, well, in my opinion, fetuses are humans, but whatever, in the baby, it's also doing the same thing. And that brain is undergoing so many changes, and then all of a sudden it's being just assaulted. So repeated periods of withdrawal are really bad for the fetal brain. It can also harm placental function and lead to prematurity, stunted growth, and alterations in neurodevelopment. What does that tell us? That tell us. We tells us we don't want fluctuating levels of opioids. We want to make sure that whatever the baby's exposed to, the fetus is exposed to, they are exposed to. One third of pregnant women with opioid use disorder were required to go through withdrawal contrary to medical guidelines. Now, up until not so long ago, the understanding or the belief was that forcing a pregnant woman to go through withdrawal could actually cause fetal death. And what they're finding is that may not actually be true if it is a supervised withdrawal, you know, not a cold turkey. It's a cold taper, not a cold taper, a slow taper sort of thing. Most sites stopped medication for opioid use disorder. Postpartum signaling prioritization of the fetus, not the mother. And y' all know, I've gone on this diatribe before that. The clinic that I used to work at, I had a residential mother baby unit, Loved that unit. But we also had a methadone clinic, an opioid treatment program on site, and the women who were pregnant would be maintained on methadone until they gave birth. And as soon as they gave birth, the doctor was cutting off their methadone. It wasn't a titration. It was okay, cold turkey. There's no worry about the feedback fetus anymore, so good luck. And it was, oh, my gosh, so incredibly agonizing on those mothers because not only were they experiencing more pain, they were fatigued, they were having difficulty. People who are going through opioid withdrawals when they're not postpartum have a really hard time doing it. It is a really rough withdrawal. Think about doing it postpartum. That was kind of cruel and in some ways inhumane. Evidence does not support detoxification as a recommended treatment intervention because of the result of low detoxification completion and high relapse rates. So the recommendation still is that when people, when women are pregnant, not to detox them, not to try to get them clean, so to speak, while they're pregnant, because the chances are pretty significant that they are going to relapse. It's going to be intolerable. And then that just exposes that fetus. Think about, we talked about tolerance going away really quickly. Same thing happens in the fetus. So then when the fetus is bombarded with heroin, again, think about what that does to the fetal brain. That's just chaos. Medication assisted treatment now favors buprenorphine use when compared to methadone because it results in an increased birth weight, reduced need for newborn treatment, and a shorter newborn length of stay in the neonatal intensive care unit. The infants are still Born substance exposed. Buprenorphine is a partial mu agonist, but the detox from it is allegedly less intense. And I say allegedly because some of the adults that I've worked with that have detoxed from suboxone or buprenorphine have said it was actually harder. But research, that's what the research says. As a result of conflicting findings in 2019. So this was just last year. The American Journal of Obstetrics and Gynecology indicated there was a need for a reassessment of current recommendations. Opioids adversely affect the human brain, primarily the developing oligodendrocyte and the process of myelinization, which is the white matter microstructure. Myelinization is sort of the covering of the nerves that helps the transmission. Think about electric cords, the wax or whatever rubber coating on the outside. It is akin to the myelinization. What happens when you take that coating off your electrical cord? It shorts out. Okay. So we want to make sure that the baby's brain is able to develop this myelinization so it functions as well as possible. Opioids also adversely affect connectivity between parts of the brain. The size of multiple brain regions, including the basal ganglia, the thalamus and the cerebellar white matter. You know, those are all really integral parts to, to higher order thinking, impulse control, lots of stuff, and even breathing basal ganglia. That's back in the back. The long term impact of these changes in the fetal brain is unclear, but there is a possibility of lasting injury. In light of recent data on medically supervised withdrawal and the emerging evidence suggesting adverse effects of opioids on the developing fetal brain, a new paradigm of care is needed that includes the preferred option of medication assisted treatment, but also the option of medically supervised opioid withdrawal for a select group of women. Now, my concern and the concern of many in this recommendation is that, for example, women who are in jail may be forced into the option of medically supervised opioid withdrawal because there is the belief that they won't be able to get hold of any opioids while they are in jail or in prison. And that may not be the best course for that particular woman. They didn't say in the article in the statement what would put one woman in the preferred option of medication assisted treatment versus the alternative. I think that's going to be something that needs to be made on the. Seems to need to be made on a person by person basis. But I did think that it was interesting, you know, they have backed off from the scary notion that withdrawal would always cause fetal death, they've moved on to showing demonstratively that opioid exposure can adversely affect the brain. Now, trexone and buprenorphine were not associated with high rates of neonatal mortality or the congenital anomalies that are seen in methadone exposed neonates. So there is a lower risk of harm to the fetus when the mother is on buprenorphine, which is that partial agonist or naltrexone. Now, remember, naltrexone is the antagonist, so naltrexone is the one that's going to keep them clean. So if they do detox and they're on naltrexone, then they're not going to be using it all. Naltrexone does cross the placenta. Opioid signaling is believed to play a role in neurodevelopment. So our natural endogenous opioids, not the stuff that we take, but the brain's natural opioids play a role in neurodevelopment. It's important to understand, which we don't, exactly what role those endogenous opioids play on neurodevelopment, to know what the effects of blocking that signaling may be. So if the mother takes naltrexone, then the fetus is taking naltrexone, which means even the endogenous opioids aren't able to do their job. So what's the impact on the fetus? Neurodevelopmental effects of naltrexone in animal studies includes alteration in brain size, alterations in opioid receptor expression. So there aren't as many opioid receptors and altered neuronal development. However, in 2020, a study of 230 pregnant women found no differences in outcome between women on buprenorphine versus naltrexone for newborn outcomes. Now, that was just for the moms. For newborn outcomes, the rate of neonatal abstinence syndrome in neonates that were more than 34 weeks gestation was significantly lower in the naltrexone medication assisted treatment group. Well, yeah, because naltrexone is not an opioid. That kind of didn't make sense. But I think what they were getting at was even the moms that were on naltrexone were less likely to relapse, so they didn't have opioids in their system. The treatments for opioids we talked about in the last presentation, I'm not going to spend a lot of Time, obviously talking about that, it's just you've got your, your basic suboxone which is buprenorphine plus naltrexone. You've got buprenorphine itself and you've got methadone. Those are the primary first line treatments for medication assisted therapy for opioids. Let's talk about alcohol. Now. A lot hasn't changed with alcohol either, but there are some interesting points we didn't talk about last week. I keep saying that substances, when we take them, alter our brain chemicals. When we alter our brain chemicals, we alter our mood, our motivation, our energy, our ability to sleep. You know, everything is affected by alterations in neurotransmitters and neurotransmitters like to stay in a particular balance. Alcohol increases gaba, which is our natural anti anxiety neurotransmitter, glycine, adenosine and adenosine when additionally consumed. Now remember, interestingly, we've talked about adenosine before. As we think throughout the day, adenosine goes up. As adenosine goes up, it causes what they call sleep pressure. When we go to sleep and we get into that deep sleep, our brain clears out the adenosine and helps us feel awake and alert for the next day. So adenosine is also somewhat of a sedative, if you want to think about it that way. Alcohol also reduces glutamate, which is our main excitatory neurotransmitter, which is one of the reasons or many of the reasons that people when they're stressed out a lot of times think, oh, I want to drink, because it prompts the, this sedation, if you will. Alcohol reduces 5HT2 and prompts increased development of 5HT2 receptors. So what does that mean? 5HT is the umbrella arm or umbrella term for serotonin. And Remember, there are 17, I believe, different types of, of serotonin receptors. 5 HT1 is the serotonin that is usually addressed with our antidepressants. 5 HT2 is more of a stimulatory part of our serotonin. So when people's serotonin levels increase, they found that sometimes when serotonin levels are high, people have anxiety. Well, a lot of times they find that when 5HT2 serotonin is high, people have anxiety. Alcohol reduces 5HT2, so it reduces anxiety initially, but it also prompts increased development of 5 HT2 receptors. The body is going, we need that, I need that. So I've got to put out more feelers to kind of try to grab the 5HT2 when it's there. Well, that means that there are more doorways open, if you will, more gateways open for that 5ht2 to go through. When the alcohol leaves the system, then 5ht2 starts coming back at its normal rate and it floods the system, which increases anxiety. We know when people start to sober up, they often have feelings of anxiety. Alcohol also increases serotonin levels, especially 5HT3, which is another form of your stimulating aspects of serotonin. The body responds to the reductions of glutamate and 5ht by trying to rebalance the system. It either produces more of the neurochemical or it produces more receptors on the other side. Now, as you can think, when it produces more receptors, those are actual physical structures. So think about how long it takes to shut down a physical structure in the recovery process, which is why sometimes it takes a year or two years for people to really feel grounded when they are not using medication assisted therapy. The brain has to, you know, shut down some of those receptors. What do we do for alcohol? And we've talked about some of these before, FDA approved interventions for alcohol are the ones that we've always talked about. Acamprosate, which is camprol, it stabilizes chemical signaling in the brain in the NMDA receptors, which is response, those receptors are responsible for that glutamate, GABA balance. Remember, GABA is made from glutamate. So when glutamate is reduced, the body can't produce as much GABA anyway. When we don't have gaba, we feel anxious. So Kamprol stabilizes the glutamate GABA balance that would otherwise become overactive during alcohol withdrawal, causing symptoms such as agitation, high hypertension and seizures. So it keeps that flood of glutamate and the overactivity caused by the increased activity of 5 HT2 and 5 HT3. Disulfiram, or antabuse is something that people take and it makes them physically ill because it prohibits the body from breaking down alcohol in the normal way. So it builds up to toxic levels a whole lot faster, which makes you sick. And then naltrexone, like we talked about with opioids, is also an option. And it can be taken as a pill or as a monthly injection. Naltrexone prevents the person from experiencing the beneficial effects, if you will, of the alcohol. It prevents the activation of opioid receptors. It prevents the activation of or the body from secreting those endogenous opioids. Now There are other treatments that have been experimented with or looked at out there, and there are articles in these additional resources in your class and you can also click on these different links to learn more about them. But Zofran is a 5ht3 agonist. Interestingly, it's mainly used in people who are undergoing chemotherapy because it's typically an antiemetic. It keeps you from throwing up. But they've also found that when 5ht3 is antagonized, when it's shut down, if you will, it reduces anxiety. So people who are struggling with anxiety when they are not drinking, some have benefited from Zofran. Anticonvulsants including gabapentin and topiramate have also been used. And gabapentin is a GABA analog. So it goes into the body and it acts like GABA and it attaches to some of the same GABA receptors. And it has been used for neuropathic pain and seizures. They've also found that it can be helpful for reducing anxiety by activating those GABA receptors in people. To Pyramid is used in a lot of for a lot of different things and is associated with reductions in relapse as well as reductions in anxiety and depression. It works by increasing 5ht2, which is one of those modulating serotonin receptors and dopamine via 5HT2. When 5HT2 is activated, dopamine goes up. When 5HT2 is squelched, dopamine goes down. So this helps the person have a little more energy, a little more focus, and generally they find that it actually does help reduce anxiety a little bit because they're not having the super increase in 5ht2 just enough so the person has energy and focus and motivation. Now varenicline, also known as Chantix, works on nicotinic and dopamine receptors, not serotonin. So you can see from these different medications, depending on the person, depending on their biological constitution, they may need different neurotransmitters assisted, if you want to put it that way, in order to get the adequate or the beneficial effects of medication assisted therapy. For some, they need assistance with 5ht3. For others it's dopamine and 5ht2. For others, it's the nicotinic and dopamine receptors. It's going to be unfortunately, there is no way to measure the receptor activity in the brain. There are certain really experimental things that they're looking at right now that are kind of like MRIs that can help help us identify receptor activation sites in the brain. But right now, for the average person, it's not possible to assess which neurotransmitters are too high and which are too low in the brain. And a lot of them do very similar things. I mean, dopamine and serotonin overlap in their functions a lot. So it may be an experimental period where the psychiatrist or the attending works with the person to identify, you know, which one of these medications is better for you at helping reduce cravings. Now, remember these last ones, the Zofran, the anticonvulsants and the varenicline are off label uses. That's not. The FDA is not saying these are the recommended treatments. These are treatments that have come out that have been identified as somewhat effective. And doctors are using these medications in some cases to treat alcohol abuse issues. Now, methamphetamine, this is a new one in the market because up until very recently, there wasn't very much out there for the treatment of methamphetamine in terms of medication assisted therapy. It was alcohol, nicotine and opioids, and that was it. So methamphetamine is awesome that they are finding some assistance with that because it is becoming such a huge problem, especially in rural areas, but I imagine in urban areas as well. Five medications have been subjected to multiple randomized controlled trials and demonstrated limited evidence of benefit for reducing amphetamine use. Now, the first one, or first two are amphetamines themselves. Methylphenidate and dexmethamphetamine. You know, these are the ones that you think about sort of as your ADHD medications. Dexmethylphenidate is a ADHD medication. What do they do? They are a controlled stimulation, sort of like buprenorphine for opioids. Controlled stimulation via norepinephrine and dopamine reuptake and inhibition. So these prevent the body from putting away, if you will, the norepinephrine and the dopamine. It leaves it in the synapse of little bit longer. Buprenorphine is another treatment that they've looked at for methamphetamine because it blunts the opioid receptors that are associated with euphoria. It gives them again, it goes up and may give them that mild euphoria, relaxation, feeling, that's the ceiling. But then all of those receptors are kind of blocked in, if you will. So when the methamphetamine is taken, there's no way for them to produce the euphoria. They can't push those buttons anymore because the buttons already done been pushed. Modenafil is an sdri, which is a selective dopamine reuptake inhibitor. And so you can see again, methylphenidate inhibits the reuptake of norepinephrine and dopamine. So norepinephrine provides focus, energy, concentration, dopamine provides concentration, and stick to it. Iveness as well as energy. You see these overlap a lot. It's hard to ferret out which one is doing what. The Modenafil is only a dopamine reuptake inhibitor, so it increases the level of dopamine in somebody's system. Now, remember, dopamine is the main neurochemical that we think about when we think about restless leg syndrome, when we think about some of the symptoms of Parkinson's, and when we think about issues with psychotic disorders. So monkeying with dopamine can be very challenging to get the right dose for people. So they may start having other side effects that need to be addressed, or they may find that dopamine is not actually the target that needs to be addressed in that person. And when they give them the sdri, they start having symptoms of too much dopamine. It's important that our patients are encouraged, strongly encouraged, to keep logs of how they're feeling, their physical symptoms, their emotional symptoms, and advocate for themselves with their physician. Naltrexone is another one that's been promoted for methamphetamine because it blocks the opioid receptor associated euphoria. Remember, buprenorphine only provides a little bit of euphoria. So then the person wouldn't, theoretically wouldn't need the methamphetamine. Naltrexone just goes up there and blocks off of those receptors, if you want to think about it that way. And so there's no chance for the methamphetamine to get in. SSRIs and antipsychotics are also being studied. Remember, your SSRIs are your selective serotonin reuptake inhibitors, but they also include selective serotonin, norepinephrine and dopamine reuptake inhibitors. There's, there's lots of different types of antidepressants that are out there and antipsychotics, your antipsychotic medications typically reduce the amount of dopamine in the system. So it'll be interesting to see which ones seem to be most helpful for methamphetamine. There are none that are FDA recommended at this point. These are all medications that are currently in study. Let's talk about nicotine. Nicotine of any Sort. Whether it's from dip, whether it's from smoking, whether it's from vaping or even patches. Nicotine stimulates norepinephrine, which helps people have focus. It also stimulates your HPA axis or your stress response system. Well, that's okay. Sometimes when people are wanting smoking nicotine, they are needing to wake up, or they're needing to control anxiety, or they're needing help focusing. I've heard my mother was a hardcore smoker for many, many years. So I know there were a lot of reasons why she would say I need to have a cigarette. GABA is also stimulated. And GABA also block. And it also blocks gaba's ability to block dopamine. Generally when GABA goes up, dopamine goes down. You know, dopamine is our perseveration chemical and it helps give us energy. Well, GABA is our chillax neurochemical, so it makes sense. When GABA goes up, dopamine goes down. Well, nicotine says, nah, why don't you just have both of them? So it blocks gaba's ability to, to block dopamine, which is kind of interesting. The release of dopamine and endogenous opioids is also occurring when people are smoking. So they're getting perseveration, they're getting dopamine, they're getting the endogenous opioids, which help with pleasure and even pain management. They're interestingly enough, and I'm not sure how I feel about this, looking at nicotine as an alternative to treatment for chronic pain, which seems like a bad idea, but you know, given the options, maybe it's, maybe it's better than some. However, I digress. So let's just kind of recap. When people smoke, it increases their norepinephrine, it increases their gaba, it increases their dopamine, and it increases their endogenous opioids. That sounds like a pretty good cocktail right there. And it also increases mao, which reduces the rate of dopamine breakdown, which is another way that dopamine gets a boost. You can see why nicotine is one of the most addictive chemicals on the planet because it just. All those pleasure chemicals plus a little bit of relaxation in there, all at the same time. Varenicline increases dopamine, but there's a ceiling effect, just like with buprenorphine. Varenicline helps increase what buprenorphine does to the mu opioid receptors. Varenicline does the same thing to dopamine receptors. It turns them on but you can't turn them on. If you want to think of it like an oven, you can't turn it on more than medium. There's just no way to get it any hotter than that. It also increases gaba. A lot of people smoke when they feel anxious. They want to feel relaxed, they want to feel that euphoria, they want to feel better, less anxious. So varenicline increases dopamine, which gives them a little bit of the perseveration, a little bit of energy, but it also increases gaba, which helps them not feel anxious. Bupropion is a norepinephrine dopamine reuptake inhibitor. So you've heard that one before when we were talking about methamphetamines. Norepinephrine is your focus chemical, and that's increased with nicotine. Normally, dopamine is your perseveration. My I want to keep doing that again chemical that's increased with nicotine. So it's increasing both of those, but only a certain amount. So if somebody is smoking in order to self medicate or on their own increase their norepinephrine and dopamine by taking bupropion, the thought is that they won't need to smoke, they won't have the cravings and the withdrawal symptoms. And the bupropion needs to be tapered when people stop using it because the body is. Even if it's a psychotropic medication, the body does adjust to having these medications ingested. So it's not. You don't want to quit any of these cold turkeys, so to speak. And then nicotine replacement patches, sprays and lozenges, obviously that's nicotine. You're just putting nicotine in the system, ideally less nicotine than if you were chain smoking, but you're still putting nicotine in the system. When people use nicotine replacement patches, sprays or lozenges, they're also not getting the myriad of other chemicals that come along with smoking and some other things. It's just theoretically pure nicotine. But nicotine is the one that does all that stuff to the neurotransmitters. So a nicotine replacement patch is going to be a way that people can start stepping down, but it is one of those that is akin to harm reduction. And you are doing more replacing one form of nicotine with another. However, most people titrate on their patches. Once they break that smoking habit, then because they have more of a steady stream of it, they break the smoking habit and they start to develop More effective coping skills. They found that nicotine replacement medications are much, much, much more effective in conjunction with counseling because the person needs to learn how to deal with those things that are stressing them out so they don't feel like they need a cigarette because their anxiety is so high. We need to help them develop skills for moderating their HPA axis. And that's what it comes down to sometimes they say dealing with life on life's terms. Well, let's think about it. When people get stressed out, their HPA axis gets turned way on their threat response system. They go into fight or flee. So they feel anxious, they feel angry. However they're feeling that increases norepinephrine, dopamine and glutamate, reduces certain types of serotonin, reduces certain sex hormones. There are a lot of neurochemical changes that take place when people get stressed out. When that HPA axis gets over activated. So in order to keep that from happening and when it gets over activated, then the body adapts to it. And so then you've got basically withdrawal from your own natural excessive dopamine and norepinephrine and all that kind of stuff. If that happens over a long period of time. And that's what we call hypocortisolism. And I've talked about that in other videos. But what's important to recognize is these coping skills that we're giving people. It's not just doing lip service to talking. What we're doing is trying to help them learn how to regulate that HPA axis and regulate the dump of those excitatory neurochemicals without the use of other external chemicals. That's what we're trying to help them learn how to do it naturally, if you will. Some progress has been made for the treatment of substance use disorders with medications. Medications help replace self medication behaviors. If somebody is using a substance because they are depressed and they found something that helps increase the dopamine and the serotonin levels and they're just, they're feeling a lot better. Well, let's figure out what was not in balance before they started using or what's normally not in balance for them and help them figure out a different way to rebalance those neurotransmitters in a safe way. And this is a lot of what we do when we're talking about just your typical psychotropic medications, when we're talking about your anti anxiety meds, your antidepressants, we're trying to figure out, okay, which neurochemical was not quite imbalanced and, and what can we do to help with that? Medications also help transition off the drug gradually to maintain neurotransmitter balance while allowing the brain to recover. We don't really want to have somebody coming to us and knowing that they're on heroin, for example, and saying, okay, we're going to slowly back off of the heroin. That's not something we're going to do. We, we don't want them to be on an illegal substance. We want to be able to help them access something that is legal and safe, that can be controlled. So we can help them titrate. But the titration is put there so people don't have this hit all of a sudden where their neurotransmitters go from. They were kind of balancing them. We take away the substance of abuse, then their neurotransmitters are super out of balance. And that doesn't just make them feel sick. It affects their mood, it affects their pain levels, it affects their sleep, it affects their blood pressure. It affects every aspect of their life and their physical functioning and emotional and cognitive functioning. And it's not realistic to think that if somebody's been using for three years, you know, I'll use a small, a short duration. If they've been using for three years, it's not realistic to think that after three days of detox that they're going to feel better. You know, the substances are out of their system, but they still have too many of certain types of receptors, not enough of other types of receptors, and their brain is in this limbo going, okay, what the heck? When I'm, when am I going to get the next hit? Hit. It takes the body a while to recover. Medications either provide controlled activation, that sealing effect, block activation like naltrexone, or in the case of ant abuse, make use unpleasant. Pat points out it would be interesting to know the impacts of these meds with other meds someone might be on for asthma, diabetes, etcetera, etcetera. And there is a lot of interaction. When the HPA axis is activated, it increases. When our fight or flight system is turned on, it causes our body to dump blood glucose to prepare us to have the energy to fight or flee. So when people are withdrawing, that triggers that HPA axis. And it's much harder to control things like diabetes and hypertension and in people who are abusing substances. But also, like Pat points out, some of these medications are probably going to, in people increase their blood pressure a little bit. It may alter the amount of insulin that they have to take. Now the nice thing, if you want to think about it that way with some of these medications, let's go back to. Your NDRIs. For example, I don't like methylphenidate as much, but any of your NDRI's and your medications that help people have a little bit more energy, that increases norepinephrine, for example, most of those, when you take them, they're going to be pretty stable in your system. A lot of your medications that are most helpful are actually long acting medications. They're not the four hour medications, but they're long acting. So it keeps those levels stable, which would theoretically keep the insulin demand, thinking about diabetes, insulin demand more stable as opposed to, you know, having a dump of insulin and then, you know, withdrawing and then an hour, three hours later having to get another hit. So I think in the long term, the impact on the body of these medications, you know, like I said, some of them are going to mildly mimic the substance of abuse. So it is still activating and aggravating those receptors. However, as people taper off of them, yes, they will probably also need to adjust their other, the other medications that they're on. And you know, if they're taking inhalers for asthma that has a steroid in it, obviously that's going, that steroid impacts their neurotransmitters as well. And it's important for the prescribing physician to be well aware of all the medications they're on, but also aware of, you know, what is it, what are the side effects, if you will, of this medication that this person is on. Steroids, for example, can cause depression in some people, it can cause agitation in others. And in looking at the impact of the medications the person's already on to, to make sure that that medication isn't causing a primary problem. And also looking at the interaction with medications the person needs to be on with medication assisted therapy, which may be one reason why the option for the non opioid treatment for opioid dependence is available. You know, there may be some people who cannot tolerate the side effects of the opioids or they're on other medications that negatively interact with opioids, for example benzodiazepines or muscle relaxants. So it's interesting, definitely interesting to consider. 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