Upon hearing the word “drugs,” one’s mind might travel to Boston’s “Methadone Mile” on the intersection of Melnea Cass Boulevard and Massachusetts Avenue, a stressed parent taking high doses of sleep medication in a battle against insomnia, or a loved one suffering from substance use disorder (SUD). The truth is, drugs are everywhere, and they do not discriminate. These chemical compounds have the potential to tamper with human genetics and brains and remain highly abused under certain social and physiological settings.
Despite the irony in the science industry lighting a fire under the opioid epidemic—namely, Purdue Pharma and its highly aggressive marketing of OxyContin—scientists are at work to understand how the brain and body are affected by these synthetic chemical compounds that wreak havoc in so many people’s lives. Such a long-term project will require innovative and dynamic techniques to keep up with the changes in the types of drugs both used and abused. Additionally, it will require extensive funding and collaboration from scientists across the nation and a fight against stigma from both within and beyond the field.
Since 1999, more than one million people have perished at the hands of opioids.1 What was once oxycodone and heroin are now mainly fentanyl on the streets, a two-for-one substance that is more potent and easier to traffic. The fact of the matter is that opioids aren’t going anywhere; rather than fighting against this fact, scientists are working to create medications for opioid use disorder (OUD). They are also finding methods to keep people in treatment with the long-term goal of tapering off medication without severe withdrawal symptoms.
I sat down with two professors at Harvard College, Dr. Chloe J. Jordan and Dr. Brian D. Kangas, to understand how their respective research in the field of neuroscience and substance use is seeking answers to these crucial questions.
A Clinical Research Perspective: From McLean Hospital to Pregnancy and Child Brain Development at the NIDA
Dr. Jordan has been at work in the addiction field since her undergraduate career at Boston University. In her junior year at Harvard’s neighbor across the river, she took Dr. Barak Caine’s class titled “Drugs & Behavior,” which ignited her interest in how drugs impact the brain and behavior. Jordan said she became “hooked on studying drugs,” inspiring her to start a journal club with fellow undergraduate students where they read and discussed addiction research papers. Shortly after, she commenced her wet-lab research under the guidance of Dr. Kathleen Kantak, studying cocaine self-administration in rats.
“I just loved being in the lab, and I loved the research topic,” Jordan reflected. “I also loved the day-to-day flow of running the animals, training them, and doing surgeries. It was really that whole experience in undergrad that got me into the field in general.”
Years later, Jordan is now an Instructor of Psychiatry at Harvard Medical School, alongside her teaching position in a Harvard College class titled “The Neuroscience of Addiction.” She will be taking on a new position as Scientific Program Manager at the National Institute on Drug Abuse (NIDA) for the HEALthy Brain and Child Development Study, a nationwide study tracking brain development from the prenatal age through age-ten adolescents. More specifically, she will focus on how exposure to different substances during pregnancy—such as cannabis (often used to combat morning sickness, nausea, and insomnia)—impacts the fetal brain and cognitive development, along with other factors later in life, such as performance in school.
This is a shift from her most recent work at McLean Hospital in Belmont, Massachusetts, one of Harvard’s world-renowned hospitals for its work on psychiatry and mental health. Jordan worked on a clinical trial for OUD with two main goals: (1) how to get people started on medication and (2) understanding what factors keep people in treatment.
The dropout rates for OUD treatment are extremely high, nearing a 70-90% rate within the first couple of months of treatment, according to Jordan. Her team embarked on the journey to discover what keeps people with OUD engaged in treatment. The scientists used several methods, ranging from different types of medications to a phone app where patients could receive gift cards for making progress in the different therapies.
Her team even grappled with the long-term question of what happens to those who take OUD medication for several years. Will they have to stay on medication forever? Can they safely transition out of taking medication without suffering terrible withdrawal symptoms, disrupting their quality of life, or being at high risk for relapse?
“That was a really exciting phase of the study to work on as well because no one has looked at how to get people off of this medication once they're on it—whether that's suboxone for opioid use disorder or an opioid for pain,” Jordan said. “We had a lot of success with different medication strategies to help taper people off.”
Before this clinical transition, Jordan worked mostly in basic neuroscience labs, studying the different mechanisms of certain treatments for addiction. On the preclinical side, she worked on understanding what kinds of drugs and brain targets could be used to reduce opioid intake for reward in rats while simultaneously not interfering with opioid utility for relieving pain.
“I also worked with a lot of cannabinoid medications to look at if those could address cocaine intake in animal models… if those could kind of modify the signaling between the VTA and the nucleus accumbens to reduce dopamine reward associated with cocaine use,” Jordan added.
Returning to her upcoming work with NIDA and child development, Jordan’s preclinical and clinical research experience might just complete the circle. There are two sides to examining SUDs: treatment and prevention. The latter is a key component of increasing science’s ability to address risk for the development of SUD.
“Many people are going to try drugs, but not many of them will transition to addiction, and some will,” Jordan said. “So [for] those who are at high risk, can we use our mechanistic understanding to then prevent that transition to disorder from happening.”
It may be too early for any of the preclinical targets Jordan previously examined to be applied to human trials, in reference to the children and pregnant women she will work with at NIDA. But if these participants take substances during the study, the scientists will refer them to receive proper treatment and grant them access to more resources by virtue of being in the study—a consideration that is easily overlooked in clinical work with human subjects. These additional resources include aid with taxes or food stamps, as getting paid for being in a research study often provides an insufficient incentive to keep people engaged, according to Jordan.
“We want to really make sure that the communities that we're working in are benefiting from the study as well. It's a much bigger picture approach than what I've worked on so far in the past, but also very exciting because of that,” the Harvard professor noted.
Working with human participants is another breed of science research, which has a laundry list of challenges: Certain factors can prevent people from showing up for testing, unknown variables are difficult to control for in each patient, and the research, as well as its participants, are highly stigmatized by society. In Jordan’s work at McLean, helping people taper off from medication was not studied systematically before. Many people have tried to wean off of it themselves, but no methods are consistent or necessarily safe.
“I hope that continues to develop, even if I'm not working on that trial anymore,” Jordan added.
A more multifaceted issue that Jordan will face in her work at the HEALthy Brain and Child Development Study is the stigma associated with pregnant women using opioids, which is an ongoing issue in the United States due to high rates of criminalization.
“I hope that more women will feel encouraged and empowered to seek medication and medical treatment for opioid use disorder during pregnancy,” Jordan stated. “Especially with something like opioid use disorder where you don't really have an option, going into withdrawal is worse for the developing infant than continuing opioid use, especially if it's medication.”
The intersection between pregnancy, substance use, and fetal brain development is particularly interesting, given the potential dual effects of the drug in the brains of both the mother and infant.
“I hope that this research will kind of open up people's mindsets and improve access to treatment during pregnancy and medical care during pregnancy, in a way that's not legally, you know, risky for these women who are just trying their best a lot of times to figure things out.”
Turning back to the opioid epidemic, Dr. Jordan’s research in medication for SUD comes at a crucial time point in that the potency and pharmacology of newer substances on the streets are very polar in comparison to drugs of the past.
“There's almost no heroin or other opioids on the streets. It's 99% fentanyl. It’s really dangerous because people are overdosing and dying at rates that we have never seen before,” Jordan reflected. “I think that’s where the studies that I'm working on come in. It really is at this time point; people are using fentanyl, they're dying—can we get them on medication?”
The point of tension for scientists, however, is not getting people started on medication, but making sure that, once someone is tapered off, they don’t relapse, as this puts them at a much higher risk of overdose. Furthermore, if they do relapse, their body will not be used to a high tolerance or the potency of fentanyl, which is pervasive in the current drug market.
Conjoining this up-and-coming rise in fentanyl with Jordan’s new project at NIDA, her goals may graze a new frontier of research that science has yet to explore: fentanyl, medication, and pregnancy.
“I don't think there's a lot of information on what fentanyl use during pregnancy even looks like and what transitioning of a pregnant woman who's been using fentanyl onto medication looks like. At least from my perspective we really don't know. It's kind of a new domain of research that doesn't really have any answers yet, but it'll be great going forward to see what we can do for people to help them essentially,” Jordan said.
The Unlikeliest of Trios: Animals, Drugs, and NASA
While Jordan’s passion for pharmacology and neuroscience stemmed from learning about drugs themselves, Dr. Brian D. Kangas’ interest in behavioral pharmacology arose from his interest in animals and their behavior.
“I've always been fascinated by animal behavior,” Kangas started. “In college, I had the good fortune to really just study animal behavior in its own right—no study of drugs, no study of neuroscience or the brain even, but just general behavioral patterns.”
In college, Kangas examined a variety of techniques under the research domain known as “behavioral economics”—that is, how animals forage and consume rewards and reinforcers in the environment. It was in graduate school that Kangas began to wonder how he could apply his passion for animal behavior to a particular kind of animal: humans.
“I became convinced of the importance of trying to parlay an understanding of animal behavior to help humans, and I thought that a richer understanding of not just animal behavior, but complex animal behavior, complex operant behavior if you will, could help inform the study of psychoactive drugs,” Kangas said.
Kangas found his interests align perfectly with the field of “behavioral pharmacology,” the very title of the class he teaches at Harvard College in conjunction with Harvard Medical School. Whether they be drugs of abuse or candidate medications, behavioral pharmacology is rooted in understanding how complex operant behavior of animals can give insight into how drugs work in organisms’ brains.
Kangas, who is now a trained behavioral pharmacologist at McLean Hospital and Assistant Professor of Psychiatry at Harvard Medical School alongside Jordan, studies the effects of psychoactive drugs on complex behavioral processes and cognition-related behavior in laboratory animals, from rodents to non-human primates. The first portion of his studies is dedicated to examining the effects of highly-abused drugs on humans.
“Whether they be legal or illegal, we think it's important to have some information that allows people who engage with these psychoactive substances to weigh the risks on cognition and complex behavior relative to the perceived benefits they get from recreational use,” Kangas described.
The second division of Kangas’ research efforts is dedicated to using animal models of complex behavior to study candidate medications to appraise the safety and efficacy of these candidate medications.
“We want to make sure that they are not too problematic on learning and memory processes, so we rigorously examine safety and side-effect profiles,” Kangas said.
In comparison to Jordan’s clinical work with human patients, Kangas’ study of animals calls for translational relevance in humans. Though studying animal behavior is fruitful for understanding the animals in their own right, the ultimate goal of behavioral pharmacology is to enhance the human experience and make better medications by understanding drugs of abuse.
To optimize translational relevance, Kangas uses two approaches: (1) capture features of animal behavior that are relevant to human behavior and (2) reverse translational methods. The first method is more straightforward, in that the scientists focus on fundamental aspects of behavior such as learning and memory.
The second method, however, is a bit more nuanced. In this approach, also known as “bedside-to-benchtop research,” scientists have colleagues that work with subjects to examine human behavior using computerized tasks, looking for tasks and assays that work well in the clinical setting. They then bring those methods back to the animal labs, hoping to maintain as many formal and functional similarities as possible.
Kangas gave the example of utilizing computerized tasks to study depression in a clinical setting. This method is thought to better capture anhedonia and depressive-like symptoms in humans, in comparison to general self-report questionnaires that a physician or healthcare professional may ask someone with a suspected mood disorder.
“You can see how they respond on a more objective, quantitative task to measure, for example, reward sensitivity, which obviously is impaired in many forms of depression,” Kangas said. “So, this task works. It's been touted by a lot of prominent clinical researchers, and the National Institute of Mental Health has an effective approach to accelerate medication development.”
Interestingly, Kangas’ lab has used this reverse methodological approach of using computerized tasks to better understand candidate medications.
“What we found is, if you develop meaningful stimuli for the animals, you capture a lot of the formalistic features of the human task. So, you can often recapitulate similar behavior in the animals,” he reported.
Kangas highlighted the highly translational nature of this finding, as it allows for a bi-directional interaction between the animal researcher and the clinical researcher to improve medications with shared aims.
Another subject that piqued his lab’s interest is recent reports of the efficacy of non-traditional psychoactive drugs, like ketamine, which was recently approved by the Food and Drug Administration (FDA) for the management of treatment-resistant depression.2 Other drugs, such as psychedelics (both typical psychedelics like psilocybin, the active ingredient in “magic mushrooms,” and also atypical psychedelics like MDMA or ecstasy) are in various stages of clinical trials. The tricky part is these drugs, especially ketamine and MDMA, have long been viewed as drugs of abuse, but they clearly have some medicinal value in the patient population.
“I think some of our recent work has been able to characterize these drugs in these animal models that we think are relevant to mood disorders and to understand them in their own right, which we think is valuable because ketamine is already out there and FDA-approved, and some of these other drugs likely will be approved soon,” Kangas commented.
His lab aims to understand the short and long-term effects of these drugs — both the desirable and the undesirable. Using ketamine as an example, it is efficacious for medical treatment but causes potential abuse liability and withdrawal effects.
“One might imagine if we can improve upon that, if we can understand ketamine on its own… as a sort of benchmark to try to build a better ketamine that retains this medicinal value but has lower abuse liability, in collaboration with neuroscientists and medicinal chemists, this could be an important achievement.”
Kangas’ work in the field of behavioral pharmacology has drawn the interest of an unlikely suitor: the National Aeronautics and Space Administration (NASA). Presently, NASA’s primary goal is deep space exploration—that is, a mission to Mars. The marriage between behavioral pharmacology and NASA is how animal behavior is used to predict the human experience.
“[NASA is] interested in some of our touchscreen-based animal models of cognition to see the extent to which spaceflight stressors might produce surprising or unwanted adverse effects on mission-relevant performance,” Kangas explained.
Essentially, Kangas’ project involves conducting risk assessments for NASA, demonstrating how animal models have value in understanding psychoactive drugs.
One space stressor that flags a specific concern for NASA is galactic cosmic radiation. On a journey to Mars, humans would travel well beyond the Earth’s magnetic field, which protects us from many types of space radiation that astronauts otherwise wouldn’t experience, such as in the mission to the Moon. Scientists do not currently understand how this galactic cosmic radiation will impact learning and memory, and space suits and shuttles will likely not protect them.
“NASA is able to simulate this type of galactic cosmic radiation in the laboratory using the Large Hadron Collider at Brookhaven National Laboratory,” Kangas explained. “Then, we're able to assess the short and long-term effects of that radiation. That's one spaceflight stressor that we can actually largely simulate on Earth, again, to conduct these really important risk assessments.”
Put together, Kangas’ work with NASA underscores the importance of using behavioral pharmacological techniques to improve the human condition. Studying and characterizing opioid and prescription opioid drugs, such as heroin and oxycodone respectively, as well as addressing their analgesic effects, is one of the more crucial endpoints.
Currently, the Holy Grail of pharmacology is to develop a drug that has both moderate efficacies as a pain reliever and lower abuse liability. If this is achieved, it will allow prescription opioid pain relievers to be less necessary, curbing the number of users.
“There are a lot of folks dealing with legitimate painful conditions that need pharmacological pain management, notwithstanding the abuse liability that is clearly inherent in these same drugs,” Kangas said. “The behavior pharmacologist is just playing one role alongside the neuroscientist and the medicinal chemist, but we think that having a multimodal profile, from the analgesic effects to the abuse liability to the respiratory depressant consequences, really allows for defining a benchmark upon which we can improve available medications.”
A New Hope
Jordan and Kangas are two of many powerhouses in the field of addiction research, but their work underscores the importance of how neuroscience and pharmacology tap into wide-ranging facets of society, from pregnancy to outer space. Moreover, their research demonstrates how opioids extend beyond the streets. They are in the womb, in primates used in laboratory experiments, and in mice that we send to the Cosmos. It is in each of these research experiments and in these scientists’ dedication to addiction research, despite societal stigma to governmental standpoints, that the opioid epidemic has a chance of being curbed and increasing the chances for long-lasting treatment.
About the Author
Mairead Baker is a rising senior at Harvard College, studying Neuroscience, History of Science, and Spanish.
References
Despite the irony in the science industry lighting a fire under the opioid epidemic—namely, Purdue Pharma and its highly aggressive marketing of OxyContin—scientists are at work to understand how the brain and body are affected by these synthetic chemical compounds that wreak havoc in so many people’s lives. Such a long-term project will require innovative and dynamic techniques to keep up with the changes in the types of drugs both used and abused. Additionally, it will require extensive funding and collaboration from scientists across the nation and a fight against stigma from both within and beyond the field.
Since 1999, more than one million people have perished at the hands of opioids.1 What was once oxycodone and heroin are now mainly fentanyl on the streets, a two-for-one substance that is more potent and easier to traffic. The fact of the matter is that opioids aren’t going anywhere; rather than fighting against this fact, scientists are working to create medications for opioid use disorder (OUD). They are also finding methods to keep people in treatment with the long-term goal of tapering off medication without severe withdrawal symptoms.
I sat down with two professors at Harvard College, Dr. Chloe J. Jordan and Dr. Brian D. Kangas, to understand how their respective research in the field of neuroscience and substance use is seeking answers to these crucial questions.
A Clinical Research Perspective: From McLean Hospital to Pregnancy and Child Brain Development at the NIDA
Dr. Jordan has been at work in the addiction field since her undergraduate career at Boston University. In her junior year at Harvard’s neighbor across the river, she took Dr. Barak Caine’s class titled “Drugs & Behavior,” which ignited her interest in how drugs impact the brain and behavior. Jordan said she became “hooked on studying drugs,” inspiring her to start a journal club with fellow undergraduate students where they read and discussed addiction research papers. Shortly after, she commenced her wet-lab research under the guidance of Dr. Kathleen Kantak, studying cocaine self-administration in rats.
“I just loved being in the lab, and I loved the research topic,” Jordan reflected. “I also loved the day-to-day flow of running the animals, training them, and doing surgeries. It was really that whole experience in undergrad that got me into the field in general.”
Years later, Jordan is now an Instructor of Psychiatry at Harvard Medical School, alongside her teaching position in a Harvard College class titled “The Neuroscience of Addiction.” She will be taking on a new position as Scientific Program Manager at the National Institute on Drug Abuse (NIDA) for the HEALthy Brain and Child Development Study, a nationwide study tracking brain development from the prenatal age through age-ten adolescents. More specifically, she will focus on how exposure to different substances during pregnancy—such as cannabis (often used to combat morning sickness, nausea, and insomnia)—impacts the fetal brain and cognitive development, along with other factors later in life, such as performance in school.
This is a shift from her most recent work at McLean Hospital in Belmont, Massachusetts, one of Harvard’s world-renowned hospitals for its work on psychiatry and mental health. Jordan worked on a clinical trial for OUD with two main goals: (1) how to get people started on medication and (2) understanding what factors keep people in treatment.
The dropout rates for OUD treatment are extremely high, nearing a 70-90% rate within the first couple of months of treatment, according to Jordan. Her team embarked on the journey to discover what keeps people with OUD engaged in treatment. The scientists used several methods, ranging from different types of medications to a phone app where patients could receive gift cards for making progress in the different therapies.
Her team even grappled with the long-term question of what happens to those who take OUD medication for several years. Will they have to stay on medication forever? Can they safely transition out of taking medication without suffering terrible withdrawal symptoms, disrupting their quality of life, or being at high risk for relapse?
“That was a really exciting phase of the study to work on as well because no one has looked at how to get people off of this medication once they're on it—whether that's suboxone for opioid use disorder or an opioid for pain,” Jordan said. “We had a lot of success with different medication strategies to help taper people off.”
Before this clinical transition, Jordan worked mostly in basic neuroscience labs, studying the different mechanisms of certain treatments for addiction. On the preclinical side, she worked on understanding what kinds of drugs and brain targets could be used to reduce opioid intake for reward in rats while simultaneously not interfering with opioid utility for relieving pain.
“I also worked with a lot of cannabinoid medications to look at if those could address cocaine intake in animal models… if those could kind of modify the signaling between the VTA and the nucleus accumbens to reduce dopamine reward associated with cocaine use,” Jordan added.
Returning to her upcoming work with NIDA and child development, Jordan’s preclinical and clinical research experience might just complete the circle. There are two sides to examining SUDs: treatment and prevention. The latter is a key component of increasing science’s ability to address risk for the development of SUD.
“Many people are going to try drugs, but not many of them will transition to addiction, and some will,” Jordan said. “So [for] those who are at high risk, can we use our mechanistic understanding to then prevent that transition to disorder from happening.”
It may be too early for any of the preclinical targets Jordan previously examined to be applied to human trials, in reference to the children and pregnant women she will work with at NIDA. But if these participants take substances during the study, the scientists will refer them to receive proper treatment and grant them access to more resources by virtue of being in the study—a consideration that is easily overlooked in clinical work with human subjects. These additional resources include aid with taxes or food stamps, as getting paid for being in a research study often provides an insufficient incentive to keep people engaged, according to Jordan.
“We want to really make sure that the communities that we're working in are benefiting from the study as well. It's a much bigger picture approach than what I've worked on so far in the past, but also very exciting because of that,” the Harvard professor noted.
Working with human participants is another breed of science research, which has a laundry list of challenges: Certain factors can prevent people from showing up for testing, unknown variables are difficult to control for in each patient, and the research, as well as its participants, are highly stigmatized by society. In Jordan’s work at McLean, helping people taper off from medication was not studied systematically before. Many people have tried to wean off of it themselves, but no methods are consistent or necessarily safe.
“I hope that continues to develop, even if I'm not working on that trial anymore,” Jordan added.
A more multifaceted issue that Jordan will face in her work at the HEALthy Brain and Child Development Study is the stigma associated with pregnant women using opioids, which is an ongoing issue in the United States due to high rates of criminalization.
“I hope that more women will feel encouraged and empowered to seek medication and medical treatment for opioid use disorder during pregnancy,” Jordan stated. “Especially with something like opioid use disorder where you don't really have an option, going into withdrawal is worse for the developing infant than continuing opioid use, especially if it's medication.”
The intersection between pregnancy, substance use, and fetal brain development is particularly interesting, given the potential dual effects of the drug in the brains of both the mother and infant.
“I hope that this research will kind of open up people's mindsets and improve access to treatment during pregnancy and medical care during pregnancy, in a way that's not legally, you know, risky for these women who are just trying their best a lot of times to figure things out.”
Turning back to the opioid epidemic, Dr. Jordan’s research in medication for SUD comes at a crucial time point in that the potency and pharmacology of newer substances on the streets are very polar in comparison to drugs of the past.
“There's almost no heroin or other opioids on the streets. It's 99% fentanyl. It’s really dangerous because people are overdosing and dying at rates that we have never seen before,” Jordan reflected. “I think that’s where the studies that I'm working on come in. It really is at this time point; people are using fentanyl, they're dying—can we get them on medication?”
The point of tension for scientists, however, is not getting people started on medication, but making sure that, once someone is tapered off, they don’t relapse, as this puts them at a much higher risk of overdose. Furthermore, if they do relapse, their body will not be used to a high tolerance or the potency of fentanyl, which is pervasive in the current drug market.
Conjoining this up-and-coming rise in fentanyl with Jordan’s new project at NIDA, her goals may graze a new frontier of research that science has yet to explore: fentanyl, medication, and pregnancy.
“I don't think there's a lot of information on what fentanyl use during pregnancy even looks like and what transitioning of a pregnant woman who's been using fentanyl onto medication looks like. At least from my perspective we really don't know. It's kind of a new domain of research that doesn't really have any answers yet, but it'll be great going forward to see what we can do for people to help them essentially,” Jordan said.
The Unlikeliest of Trios: Animals, Drugs, and NASA
While Jordan’s passion for pharmacology and neuroscience stemmed from learning about drugs themselves, Dr. Brian D. Kangas’ interest in behavioral pharmacology arose from his interest in animals and their behavior.
“I've always been fascinated by animal behavior,” Kangas started. “In college, I had the good fortune to really just study animal behavior in its own right—no study of drugs, no study of neuroscience or the brain even, but just general behavioral patterns.”
In college, Kangas examined a variety of techniques under the research domain known as “behavioral economics”—that is, how animals forage and consume rewards and reinforcers in the environment. It was in graduate school that Kangas began to wonder how he could apply his passion for animal behavior to a particular kind of animal: humans.
“I became convinced of the importance of trying to parlay an understanding of animal behavior to help humans, and I thought that a richer understanding of not just animal behavior, but complex animal behavior, complex operant behavior if you will, could help inform the study of psychoactive drugs,” Kangas said.
Kangas found his interests align perfectly with the field of “behavioral pharmacology,” the very title of the class he teaches at Harvard College in conjunction with Harvard Medical School. Whether they be drugs of abuse or candidate medications, behavioral pharmacology is rooted in understanding how complex operant behavior of animals can give insight into how drugs work in organisms’ brains.
Kangas, who is now a trained behavioral pharmacologist at McLean Hospital and Assistant Professor of Psychiatry at Harvard Medical School alongside Jordan, studies the effects of psychoactive drugs on complex behavioral processes and cognition-related behavior in laboratory animals, from rodents to non-human primates. The first portion of his studies is dedicated to examining the effects of highly-abused drugs on humans.
“Whether they be legal or illegal, we think it's important to have some information that allows people who engage with these psychoactive substances to weigh the risks on cognition and complex behavior relative to the perceived benefits they get from recreational use,” Kangas described.
The second division of Kangas’ research efforts is dedicated to using animal models of complex behavior to study candidate medications to appraise the safety and efficacy of these candidate medications.
“We want to make sure that they are not too problematic on learning and memory processes, so we rigorously examine safety and side-effect profiles,” Kangas said.
In comparison to Jordan’s clinical work with human patients, Kangas’ study of animals calls for translational relevance in humans. Though studying animal behavior is fruitful for understanding the animals in their own right, the ultimate goal of behavioral pharmacology is to enhance the human experience and make better medications by understanding drugs of abuse.
To optimize translational relevance, Kangas uses two approaches: (1) capture features of animal behavior that are relevant to human behavior and (2) reverse translational methods. The first method is more straightforward, in that the scientists focus on fundamental aspects of behavior such as learning and memory.
The second method, however, is a bit more nuanced. In this approach, also known as “bedside-to-benchtop research,” scientists have colleagues that work with subjects to examine human behavior using computerized tasks, looking for tasks and assays that work well in the clinical setting. They then bring those methods back to the animal labs, hoping to maintain as many formal and functional similarities as possible.
Kangas gave the example of utilizing computerized tasks to study depression in a clinical setting. This method is thought to better capture anhedonia and depressive-like symptoms in humans, in comparison to general self-report questionnaires that a physician or healthcare professional may ask someone with a suspected mood disorder.
“You can see how they respond on a more objective, quantitative task to measure, for example, reward sensitivity, which obviously is impaired in many forms of depression,” Kangas said. “So, this task works. It's been touted by a lot of prominent clinical researchers, and the National Institute of Mental Health has an effective approach to accelerate medication development.”
Interestingly, Kangas’ lab has used this reverse methodological approach of using computerized tasks to better understand candidate medications.
“What we found is, if you develop meaningful stimuli for the animals, you capture a lot of the formalistic features of the human task. So, you can often recapitulate similar behavior in the animals,” he reported.
Kangas highlighted the highly translational nature of this finding, as it allows for a bi-directional interaction between the animal researcher and the clinical researcher to improve medications with shared aims.
Another subject that piqued his lab’s interest is recent reports of the efficacy of non-traditional psychoactive drugs, like ketamine, which was recently approved by the Food and Drug Administration (FDA) for the management of treatment-resistant depression.2 Other drugs, such as psychedelics (both typical psychedelics like psilocybin, the active ingredient in “magic mushrooms,” and also atypical psychedelics like MDMA or ecstasy) are in various stages of clinical trials. The tricky part is these drugs, especially ketamine and MDMA, have long been viewed as drugs of abuse, but they clearly have some medicinal value in the patient population.
“I think some of our recent work has been able to characterize these drugs in these animal models that we think are relevant to mood disorders and to understand them in their own right, which we think is valuable because ketamine is already out there and FDA-approved, and some of these other drugs likely will be approved soon,” Kangas commented.
His lab aims to understand the short and long-term effects of these drugs — both the desirable and the undesirable. Using ketamine as an example, it is efficacious for medical treatment but causes potential abuse liability and withdrawal effects.
“One might imagine if we can improve upon that, if we can understand ketamine on its own… as a sort of benchmark to try to build a better ketamine that retains this medicinal value but has lower abuse liability, in collaboration with neuroscientists and medicinal chemists, this could be an important achievement.”
Kangas’ work in the field of behavioral pharmacology has drawn the interest of an unlikely suitor: the National Aeronautics and Space Administration (NASA). Presently, NASA’s primary goal is deep space exploration—that is, a mission to Mars. The marriage between behavioral pharmacology and NASA is how animal behavior is used to predict the human experience.
“[NASA is] interested in some of our touchscreen-based animal models of cognition to see the extent to which spaceflight stressors might produce surprising or unwanted adverse effects on mission-relevant performance,” Kangas explained.
Essentially, Kangas’ project involves conducting risk assessments for NASA, demonstrating how animal models have value in understanding psychoactive drugs.
One space stressor that flags a specific concern for NASA is galactic cosmic radiation. On a journey to Mars, humans would travel well beyond the Earth’s magnetic field, which protects us from many types of space radiation that astronauts otherwise wouldn’t experience, such as in the mission to the Moon. Scientists do not currently understand how this galactic cosmic radiation will impact learning and memory, and space suits and shuttles will likely not protect them.
“NASA is able to simulate this type of galactic cosmic radiation in the laboratory using the Large Hadron Collider at Brookhaven National Laboratory,” Kangas explained. “Then, we're able to assess the short and long-term effects of that radiation. That's one spaceflight stressor that we can actually largely simulate on Earth, again, to conduct these really important risk assessments.”
Put together, Kangas’ work with NASA underscores the importance of using behavioral pharmacological techniques to improve the human condition. Studying and characterizing opioid and prescription opioid drugs, such as heroin and oxycodone respectively, as well as addressing their analgesic effects, is one of the more crucial endpoints.
Currently, the Holy Grail of pharmacology is to develop a drug that has both moderate efficacies as a pain reliever and lower abuse liability. If this is achieved, it will allow prescription opioid pain relievers to be less necessary, curbing the number of users.
“There are a lot of folks dealing with legitimate painful conditions that need pharmacological pain management, notwithstanding the abuse liability that is clearly inherent in these same drugs,” Kangas said. “The behavior pharmacologist is just playing one role alongside the neuroscientist and the medicinal chemist, but we think that having a multimodal profile, from the analgesic effects to the abuse liability to the respiratory depressant consequences, really allows for defining a benchmark upon which we can improve available medications.”
A New Hope
Jordan and Kangas are two of many powerhouses in the field of addiction research, but their work underscores the importance of how neuroscience and pharmacology tap into wide-ranging facets of society, from pregnancy to outer space. Moreover, their research demonstrates how opioids extend beyond the streets. They are in the womb, in primates used in laboratory experiments, and in mice that we send to the Cosmos. It is in each of these research experiments and in these scientists’ dedication to addiction research, despite societal stigma to governmental standpoints, that the opioid epidemic has a chance of being curbed and increasing the chances for long-lasting treatment.
About the Author
Mairead Baker is a rising senior at Harvard College, studying Neuroscience, History of Science, and Spanish.
References
- Hedegaard, H., Miniño A. M., Spencer M. R., Warner M. (2021). Drug Overdose Deaths in the United States, 1999–2020. National Center for Health Statistics.
- Walsh, S. (2019). FDA approves new nasal spray medication for treatment-resistant depression; available only at a certified doctor’s office or clinic. FDA; FDA.
