Clinical trials

Background: People with substance use disorder (SUD) often have changes in brain function that can make it difficult to control drug-seeking behavior. These changes may heighten the urge to use drugs or lessen the desire to seek nondrug-related rewards. Researchers want to know how a technique called transcranial magnetic stimulation (TMS) may cause changes in brain activity that may help people with SUD. Objective: To test TMS in healthy volunteers. Eligibility: Healthy people aged 18 to 45 years who are right-handed. Design: Participants can volunteer for up to 5 different experiments. Each experiment requires 2 to 8 clinic visits. Each visit will last 3 to 7 hours. Some visits will include TMS. A coil will be placed on the participant s head. A brief electrical current will pass through the coil to create a magnetic field. Participants may feel a tapping or pulling sensation on the skin under the coil. They may feel a twitch in their face, neck, arm, or leg muscles. Participants may be asked to tense certain muscles during TMS. Some visits will include functional magnetic resonance imaging (fMRI) scans. Participants will lie on a bed that slides into a large tube. They will perform tasks on a computer inside the tube. The fMRI will show which parts of the brain are used during each task. Participants will perform tasks on a computer. Some tasks may be done at a desk as well as during TMS and fMRI. Participants may look at images, listen to sounds, smell odors, or taste flavored liquids. Their vital signs may be monitored and their eye movements may be tracked during tasks.

Background: Transcranial magnetic stimulation (TMS) uses magnetic pulses to affect brain activity. A type of TMS called theta burst stimulation (TBS) is approved to treat people with major depression. Researchers have developed a new form of TBS called high-density TBS (hdTBS). They hope hdTBS will work better than TBS. But first they need to test the new treatment in healthy adults. Objective: To test hdTBS in healthy adults. Also, to compare the aftereffects of hdTBS and TBS. Eligibility: Healthy adults aged 22 to 60 years. Design: Participants will have 4 clinic visits over about 3 to 4 weeks. They must abstain from drugs and alcohol and limit caffeine before visits. At their first visit, participants will be oriented to TBS. They will wear a cap and earplugs. A device with round coils will be placed near their head. When a brief electric current passes through the coil, it generates a magnetic pulse that stimulates the brain. Participants may feel a pulling sensation on the skin under the coil. Their fingers may move involuntarily. At their next 3 visits, participants will receive either TBS or sham TBS. A sham TBS uses a low magnetic field to minimize the effects of the treatment. Participants will have up to 9 electrodes placed on 1 arm. These electrodes will measure the electrical activity in their muscles. Each TBS session will be videotaped. At every visit, participants will answer questions about their health, including substance use. They will perform 2 tasks to test their thinking skills. They will perform a test on a computer to test their reaction time....

Background: About 1.5 million adults in the US enter alcohol or substance use treatment programs each year. Unfortunately, more than half of patients do not finish their program. For those who start treatment, about 70% return to substance use within weeks or months after starting treatment. To discover why patients drop out of treatment and return to substance use - and what can be done about it - researchers need to learn more about people who use drugs and alcohol. Objective: To create a data repository by gathering survey and smartphone data from adults who use drugs and alcohol in order to conduct future research. Eligibility: Adults who have used drugs or alcohol in the past and have a Android smartphone. The researchers will recruit targeted demographics at different times throughout the duration of the study period. Design: Data will be collected for up to 6 months. All research activities will be online. Participants will download a smartphone app called TTRU-Curtis AWARE and keep it active on their phone. The app will run in the background and collect participant data, including: screen unlocks, duration of time the screen is on; apps used; words typed (except passwords); duration and time of phone calls; estimated location (exact location is not collected); and movement, such as how many steps are taken in a day. All personally identifying information is automatically removed before the data is stored (including phone numbers, names, or locations described in messages). Each day, participants will receive a text with a link to a survey. They will answer questions about their mood, behavior, and substance use from the day before. This survey should take less than 5 minutes to complete. Every 30 days, participants will complete a longer survey. They will answer questions about their personal relationships, risky behaviors, mood, substance use, and feelings. They can skip any questions they do not feel comfortable answering. These surveys should take about 30 minutes to complete. Participants may opt to allow researchers to access their social media posts.

Background: Little is known about how different regions of the brain responsible for the human sense of smell guide behaviors. In this study, researchers use a technique called transcranial ultrasound stimulation (TUS) to learn how odors affect the brain and behavior. Objective: To learn more about how the human sense of smell works. Eligibility: Healthy people aged 18 to 45 years who are right-handed. Design: Participants can volunteer for up to 2 different experiments. Each experiment requires 5 visits, each about 1 week apart. Food, alcohol, and caffeine may be limited before visits. At the start of each visit, participants will answer questions about their health and how well they slept. Their sense of smell will be assessed. Some visits may include tasks on a computer: While doing these tasks, participants may be asked to smell different odors, look at pictures, and listen to sounds. They will wear devices to track breathing, blood pressure, pulse, and other body responses to the tasks. Some visits may include TUS: TUS uses ultrasound waves to briefly change brain activity. A gel will be applied to the scalp and hair, and a device will be placed against the participant s head. Participants may feel a tapping, pulling, and/or warm sensation on the skin underneath the device. They may also feel a twitch in their face, neck, arm, or leg muscles. Participants will do tasks before and after TUS. Some visits will include functional magnetic resonance imaging (fMRI) scans. fMRI uses magnet and radio waves to capture images of the activity inside the brain. Participants will lie on a table that slides into a tube. They will perform tasks inside the scanner.

Study Description: Despite the availability of pharmacotherapy for some substance use disorders, relapse vulnerability is still a significant issue. This suggests medications with alternative mechanisms of action should be explored to address this unmet need. Substantial preclinical research indicates that orexin antagonism blunts the internally and externally triggered motivation to attain abused substances. This research project will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to those with a substance use disorder. Suvorexant s ability to blunt neurobiological correlates of substance misuse will be assessed. This will be assessed following acute and repeated drug administration. Baseline individual differences will be considered to determine whether neurobiological variance influences suvorexant s impact in those with nicotine dependence. In an independent arm, the interaction between suvorexant and a dopamine agonist (methylphenidate) on cognitive function will be assessed in non-smoking individuals. Objectives: The objective is to determine the acute and chronic impact of the orexin antagonist, suvorexant, on neurobiological and behavioral factors linked with substance use disorders. Whether such effects are mediated by baseline characteristics will be tested. Given suvorexant is an FDA approved treatment for insomnia, sleep will be evaluated as well in the nicotine dependent arm. Endpoints: In nicotine-dependent individuals, suvorexant s impact on brain function will be assessed several ways by evaluating: 1) resting function, 2) reactivity to drug cues, 3) reactivity to non-drug related cognitive tasks. Sleep and nicotine use will be measured throughout the study period. In those without nicotine-dependence, the impact of suvorexant and the interaction of acute methylphenidate and suvorexant on brain function will be assessed. This arm will provide insight into how suvorexant impacts reward/cognition as well as impacts the pharmacological influence of methylphenidate on those same measures. Study Population:\<TAB\> Nicotine dependence arm:140 subjects; Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Control arm: 80 subjects; Volunteers who are between the ages of 18-60 and are non-smokers/vapers This study will be conducted at the NIDA-IRP, Biomedical Research Center, in Baltimore, MD. Description of Study Intervention: Nicotine dependence arm: Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days. Control arm: 1. Tolerability visit with one MRI scan post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max) Study Duration: 5 years Participant Duration: 1-2 months

Background: Human immunodeficiency virus (HIV) infection can affect areas of the brain that control thinking ability. These same areas of the brain also control the sense of smell. HIV infection is common in people with substance use disorder (SUD). SUD also affects thinking ability. Researchers want to learn more about the connection between the sense of smell and decision-making ability in people with HIV, SUD, or both. Objective: To test the sense of smell in people with HIV and/or SUD and how they make choices based on odors. Eligibility: People aged 18 to 65 years with any of these: (1) HIV, (2) SUD, (3) both HIV and SUD, or (4) neither SUD nor HIV. Design: Participants will have 2 visits. Each visit will last 3 to 5 hours. In visit 1, participants will have a blood draw and a saliva swab. They will answer questions about their health, sleep habits, food intake, and substance use. They will have smell tests: They will smell scented sticks and answer questions about them. They will be blindfolded for some tests. They will perform tasks on a computer. They will look at pictures and smell pleasant food odors, such as chocolate cake or pizza. Smells will be delivered using a nasal mask. Their sniffing and breathing will be measured. They may also be exposed to odor-free air. They will eat food that corresponds to one of the food odors they smelled. In visit 2, participants will do a saliva swab and a different computer task that involves odors. They will also have tests of their attention and memory. Participants may opt to have an imaging scan of the brain.

Background: Alcohol use disorder (AUD) is a chronic disease that causes more than 140,000 US deaths each year. AUD treatment often includes therapy and medication. Some people with AUD may also benefit from behavioral and lifestyle changes. Objective: To evaluate the effects of different activities and environments on drinking behaviors and mental health in people with AUD. Eligibility: People aged 21 years and older with AUD. Design: Participants will have up to 10 study visits in Baltimore. Participants will have a baseline visit. They will have a physical exam with blood and urine tests. They will have a breath test for alcohol and a test that measures body composition. They will answer questions about their alcohol and substance use; mental and physical health; mood and anxiety; and sleep quality. Participants will download an app called MetricWire. The app will send 3 sets of questions to be answered at different times throughout the day. The study visits will include 2 stages: 1. Active stage. On these visits, participants will use a virtual reality system called the Meta Quest Pro (MQP) as they choose. Then they may choose among video games, puzzles, books, crafts, and other activities.. These sessions will last for 3 hours. 2. Passive stage. On these visits, participants will watch videos selected by the research team. These sessions will last for 3 hours. On the last visit of each stage, participants will sit in a room that looks like a bar. They will answer questions about their cravings, their urge to drink, and how many drinks they would buy. Participants will be served 1 drink containing alcohol. They will be asked about their cravings and subjective effects of alcohol after drinking it.

Background: Human immunodeficiency virus (HIV) infection can affect areas of the brain that control thinking ability. These same areas of the brain also control the sense of smell. HIV infection is common in people with substance use disorder (SUD). SUD also affects thinking ability. Researchers want to learn more about the connection between the sense of smell and decision-making ability in people with HIV, SUD, or both. Objective: To test the sense of smell in people with HIV and/or SUD and how they make choices based on odors. Eligibility: People aged 18 to 65 years with any of these: (1) HIV, (2) SUD, (3) both HIV and SUD, or (4) neither SUD nor HIV. Design: Participants will have 2 visits. Each visit will last 3 to 5 hours. In visit 1, participants will have a blood draw and a saliva swab. They will answer questions about their health, sleep habits, food intake, and substance use. They will have smell tests: They will smell scented sticks and answer questions about them. They will be blindfolded for some tests. They will perform tasks on a computer. They will look at pictures and smell pleasant food odors, such as chocolate cake or pizza. Smells will be delivered using a nasal mask. Their sniffing and breathing will be measured. They may also be exposed to odor-free air. They will eat food that corresponds to one of the food odors they smelled. In visit 2, participants will do a saliva swab and a different computer task that involves odors. They will also have tests of their attention and memory. Participants may opt to have an imaging scan of the brain.

Background: Little is known about how different regions of the brain responsible for the human sense of smell guide behaviors. In this study, researchers use a technique called transcranial ultrasound stimulation (TUS) to learn how odors affect the brain and behavior. Objective: To learn more about how the human sense of smell works. Eligibility: Healthy people aged 18 to 45 years who are right-handed. Design: Participants can volunteer for up to 2 different experiments. Each experiment requires 5 visits, each about 1 week apart. Food, alcohol, and caffeine may be limited before visits. At the start of each visit, participants will answer questions about their health and how well they slept. Their sense of smell will be assessed. Some visits may include tasks on a computer: While doing these tasks, participants may be asked to smell different odors, look at pictures, and listen to sounds. They will wear devices to track breathing, blood pressure, pulse, and other body responses to the tasks. Some visits may include TUS: TUS uses ultrasound waves to briefly change brain activity. A gel will be applied to the scalp and hair, and a device will be placed against the participant s head. Participants may feel a tapping, pulling, and/or warm sensation on the skin underneath the device. They may also feel a twitch in their face, neck, arm, or leg muscles. Participants will do tasks before and after TUS. Some visits will include functional magnetic resonance imaging (fMRI) scans. fMRI uses magnet and radio waves to capture images of the activity inside the brain. Participants will lie on a table that slides into a tube. They will perform tasks inside the scanner.

Background: Transcranial magnetic stimulation (TMS) uses magnetic pulses to affect brain activity. A type of TMS called theta burst stimulation (TBS) is approved to treat people with major depression. Researchers have developed a new form of TBS called high-density TBS (hdTBS). They hope hdTBS will work better than TBS. But first they need to test the new treatment in healthy adults. Objective: To test hdTBS in healthy adults. Also, to compare the aftereffects of hdTBS and TBS. Eligibility: Healthy adults aged 22 to 60 years. Design: Participants will have 4 clinic visits over about 3 to 4 weeks. They must abstain from drugs and alcohol and limit caffeine before visits. At their first visit, participants will be oriented to TBS. They will wear a cap and earplugs. A device with round coils will be placed near their head. When a brief electric current passes through the coil, it generates a magnetic pulse that stimulates the brain. Participants may feel a pulling sensation on the skin under the coil. Their fingers may move involuntarily. At their next 3 visits, participants will receive either TBS or sham TBS. A sham TBS uses a low magnetic field to minimize the effects of the treatment. Participants will have up to 9 electrodes placed on 1 arm. These electrodes will measure the electrical activity in their muscles. Each TBS session will be videotaped. At every visit, participants will answer questions about their health, including substance use. They will perform 2 tasks to test their thinking skills. They will perform a test on a computer to test their reaction time....

Background: Alcohol use disorder (AUD) is a chronic disease that causes more than 140,000 US deaths each year. AUD treatment often includes therapy and medication. Some people with AUD may also benefit from behavioral and lifestyle changes. Objective: To evaluate the effects of different activities and environments on drinking behaviors and mental health in people with AUD. Eligibility: People aged 21 years and older with AUD. Design: Participants will have up to 10 study visits in Baltimore. Participants will have a baseline visit. They will have a physical exam with blood and urine tests. They will have a breath test for alcohol and a test that measures body composition. They will answer questions about their alcohol and substance use; mental and physical health; mood and anxiety; and sleep quality. Participants will download an app called MetricWire. The app will send 3 sets of questions to be answered at different times throughout the day. The study visits will include 2 stages: 1. Active stage. On these visits, participants will use a virtual reality system called the Meta Quest Pro (MQP) as they choose. Then they may choose among video games, puzzles, books, crafts, and other activities.. These sessions will last for 3 hours. 2. Passive stage. On these visits, participants will watch videos selected by the research team. These sessions will last for 3 hours. On the last visit of each stage, participants will sit in a room that looks like a bar. They will answer questions about their cravings, their urge to drink, and how many drinks they would buy. Participants will be served 1 drink containing alcohol. They will be asked about their cravings and subjective effects of alcohol after drinking it.

Background: About 1.5 million adults in the US enter alcohol or substance use treatment programs each year. Unfortunately, more than half of patients do not finish their program. For those who start treatment, about 70% return to substance use within weeks or months after starting treatment. To discover why patients drop out of treatment and return to substance use - and what can be done about it - researchers need to learn more about people who use drugs and alcohol. Objective: To create a data repository by gathering survey and smartphone data from adults who use drugs and alcohol in order to conduct future research. Eligibility: Adults who have used drugs or alcohol in the past and have a Android smartphone. The researchers will recruit targeted demographics at different times throughout the duration of the study period. Design: Data will be collected for up to 6 months. All research activities will be online. Participants will download a smartphone app called TTRU-Curtis AWARE and keep it active on their phone. The app will run in the background and collect participant data, including: screen unlocks, duration of time the screen is on; apps used; words typed (except passwords); duration and time of phone calls; estimated location (exact location is not collected); and movement, such as how many steps are taken in a day. All personally identifying information is automatically removed before the data is stored (including phone numbers, names, or locations described in messages). Each day, participants will receive a text with a link to a survey. They will answer questions about their mood, behavior, and substance use from the day before. This survey should take less than 5 minutes to complete. Every 30 days, participants will complete a longer survey. They will answer questions about their personal relationships, risky behaviors, mood, substance use, and feelings. They can skip any questions they do not feel comfortable answering. These surveys should take about 30 minutes to complete. Participants may opt to allow researchers to access their social media posts.

Background: People with substance use disorder (SUD) often have changes in brain function that can make it difficult to control drug-seeking behavior. These changes may heighten the urge to use drugs or lessen the desire to seek nondrug-related rewards. Researchers want to know how a technique called transcranial magnetic stimulation (TMS) may cause changes in brain activity that may help people with SUD. Objective: To test TMS in healthy volunteers. Eligibility: Healthy people aged 18 to 45 years who are right-handed. Design: Participants can volunteer for up to 5 different experiments. Each experiment requires 2 to 8 clinic visits. Each visit will last 3 to 7 hours. Some visits will include TMS. A coil will be placed on the participant s head. A brief electrical current will pass through the coil to create a magnetic field. Participants may feel a tapping or pulling sensation on the skin under the coil. They may feel a twitch in their face, neck, arm, or leg muscles. Participants may be asked to tense certain muscles during TMS. Some visits will include functional magnetic resonance imaging (fMRI) scans. Participants will lie on a bed that slides into a large tube. They will perform tasks on a computer inside the tube. The fMRI will show which parts of the brain are used during each task. Participants will perform tasks on a computer. Some tasks may be done at a desk as well as during TMS and fMRI. Participants may look at images, listen to sounds, smell odors, or taste flavored liquids. Their vital signs may be monitored and their eye movements may be tracked during tasks.

Background: Alcohol use disorder (AUD) is a problematic pattern of alcohol use accompanied by clinically significant medical consequences. Medications can help most people reduce their drinking, but the number is limited, and additional treatment options are needed. Objective: To test if a medication named Semaglutide may reduce alcohol drinking in people with AUD. Who can participate? All Adults aged 18 or older with AUD might be eligible to participate in the study. What will happen during the study? Participants will visit the National Institute on Drug Abuse (NIDA) in Baltimore once a week for about 20 weeks (5 months). Each visit will last between 2 and 6 hours depending on the tasks scheduled for that visit. Participants will be assigned by chance (like flipping a coin) to receive either Semaglutide or placebo. A placebo looks just like a real drug but contains no medicine. The study medication is given as a shot under the skin each week. Participants will undergo different tests throughout the study: They will give blood, urine, and saliva samples. They will engage in self-paced behavioral therapy on a computer. They will answer questions about their mood, diet, alcohol drinking and craving, tobacco use, etc. They will taste several sweet liquids and tell their preferences. They will sit in a bar-like room and be exposed to cues that might make them feel the urge to eat food or drink alcohol. They will wear a virtual reality headset that creates a cafeteria setting. They will walk the virtual cafeteria and choose food and drinks from a buffet. They will have a functional magnetic resonance imaging (fMRI) scan to take pictures of their brain. During the scans, participants will be shown pictures of alcohol-containing drinks, food, and other items.They will perform tasks on a computer screen. Participants will have a follow-up visit about 7 weeks after their last shot.

Background: Alcohol use disorder (AUD) affects about 29.5 million people in the United States. Only 3 medicines have been approved by Food and Drug Administration to treat AUD. Researchers want to find better treatments for AUD. Animal studies found that a medicine called spironolactone, may decrease the amount of alcohol the animals drank. Spironolactone is approved to treat high blood pressure, or heart failure in people. It is not approved to treat AUD. Objective: To test a medicine (spironolactone) in people who sometimes drink excessive alcohol in order to understand how the body breaks down spironolactone and if there are any side effects in people who drink alcohol while taking this medicine. Eligibility: People aged 21 and older with AUD. Design: Participants will have 4 separate 7-day stays at a clinic in Baltimore over 2 months. Spironolactone is a capsule you swallow. Participants will take a capsule twice a day for 5 days during each clinic stay. During 1 of their 4 stays, they will take a placebo instead of the medicine. The placebo capsule looks just like the spironolactone capsule but contains no medicine. Participants will not know when they are taking the medicine or the placebo. Participants will not drink alcohol until day 6 of each clinic stay. Then they will be asked to drink alcohol in a bar-like area in the clinic. Their breath and blood alcohol levels and their well-being will be measured. Participants will undergo other tests in the clinic: A DEXA (dual energy X-ray absorptiometry) scan uses X-rays to measure bone density and muscle mass. Participants will lie on an open-top, padded table, then a small arm will scan the full length of their body. The radiation participants will get in this study is about the same as from one regular x-ray. Blood tests. Participants may feel some discomfort at the site of needle entry. Electrocardiogram. This test records the heart activity. Sensors are attached to the skin with stickers and removed after a few minutes. Urine tests. All urine will be collected over a 3-day period during each stay. We will measure the amount of urine, and different hormones and salts in the urine. Questionnaires and tasks. Participants will answer questions about their alcohol use. They will perform tasks to test mood, craving, mental and physical coordination, and how much they feel an effect from alcohol after drinking.

Background: People with addictions often find it hard to choose the long-term benefits of abstinence over the short-term effects of using drugs. Researchers think this is partly due to parts of the brain involved in certain types of learning and decision-making. Researchers want to test these basic functions using a simple task with pictures and odors. Objective: To see if performance in a learning task differs between people who have opioid-use disorder and people who don t. Eligibility: Adults 21-60 years old who are willing to fast for at least 6 hours and smell food odors. Those with an opioid-use disorder must either not use for at least 3 weeks or be in treatment. Design: Participants will have 1 visit that will take up to 5 hours. Before the visit, participants will be asked to not eat or drink anything except water for at least 6 hours. At the visit, participants will be checked for signs of intoxication. Participants will give urine and breath samples. Participants will have tests of learning and behavior. They will look at shapes on a computer screen. The shapes will be paired with different food odors. The odors will come from a sterile tube placed under the nose. Participants will have their breathing monitored with a belt around the upper abdomen. About 30 days and 60 days later, participants will be called and asked about their drug use over the past 30 days.

Background: \- Functional and structural magnetic resonance imaging (MRI) techniques have allowed researchers to map and study how the brain works when at rest and when engaged in specific tasks. MRI scans have provided more information about how drugs affect the brain, and about how drug addiction changes the brain and influences behavior, mood, and thinking processes. To better understand the underlying mechanism of drug addiction and to develop strategies for more effective treatment, researchers are interested in developing new MRI techniques to study the effects of addiction on the brain. Objectives: \- To develop new functional and structural MRI techniques, and to evaluate their potential use in brain imaging studies related to addiction. Eligibility: * Individuals between 18 and 80 years of age. * Participants may be smokers or nonsmokers, and may use drugs or not use drugs. Design: * During the initial screening, participants will complete questionnaires about family and personal history, drug use, and other information as required by the researchers. Participants who will be asked to complete tasks during the MRI scan will be shown how to perform these tasks before the scanning session. * Before each study session, participants may be asked to complete some or all of the following: questions about their drug use during the last week, a breathalyzer test, a urine drug-use assessment, a urine pregnancy test, or a measure of carbon monoxide. Participants will also provide blood samples before the start of the scan. * For each scanning session, participants will have an MRI scan that will last approximately 2 hours. * MRI scans may include specific tasks to be performed during the scan, or an experiment that studies the brain's response to carbon dioxide.

Background: Nicotine dependence leads to about 480,000 deaths every year in the United States. People with major depressive disorder (MDD) are twice as likely to use nicotine compared to the general population. They have greater withdrawal symptoms and are more likely to relapse after quitting compared with smokers without MDD. More research is needed on how nicotine affects brain function in those with MDD. Objective: To understand how nicotine affects symptoms of depression and related brain function. Eligibility: People aged 18 to 60 years, at the time of consent, with and without MDD who do not smoke cigarettes or use other nicotine products. Design: Participants will have 2 or 3 study visits over 1 year. Participants will have 2 MRI scans no less than 4 days apart. Each scan visit will last 5 to 7 hours. At each scan, they will have urine and breath tests to screen for recent use of alcohol, nicotine, and illegal drugs. Before each scan, they will take 1 of 2 medications: nicotine or placebo. Participants will receive each medication once. They will not know which medication they are receiving at each scan. For each MRI scan, they will lie on a table that slides into a cylinder. Sometimes they will be asked to lie still. Sometimes they will complete tasks on a computer. Tasks may include identifying colors or playing games to win money. Each scan will take about 2 hours. Participants will answer questions about their thoughts, feelings, and behaviors before and after each scan. They will have a blood test after each scan.

Background: Transcranial magnetic stimulation (TMS) is form of non-invasive brain stimulation. It is approved to treat depression. TMS may help decrease drug craving. It is important to understand how TMS affects the brain. Such a better understanding would help to design ways to treat drug addiction. Objectives: To learn how TMS affects the brain when it stimulates an area in the front of the brain. Also, to see how the stimulation affects the area stimulated and other connected areas. Eligibility: Healthy, right-handed adults ages 18-60 who are non-drug users. Design: Participants will be screened under protocol 06-DA-N415. Participants will have at least 3 visits. The first visit will last about 3 hours. All other visits will last up to 6 hours. Participants cannot use drugs or alcohol at least 24 hours before a visit. They cannot have more than half a cup of a caffeinated drink at least 12 hours before a visit. Each visit will include a brief medical history update, urine test for drugs and pregnancy (if female), a breath test for alcohol and smoking, and questionnaires. Participants will have a TMS orientation visit. A wire coil will be placed on the head. An electrical current will pass through the coil to create a magnetic pulse that stimulates the brain. The other visits will include 2 sessions of TMS-MRI. Participants will lie on a table that slides into a cylinder. The TMS coil and the MRI coil will be placed over the head. Pictures will be taken of the brain with and without stimulation. Participants will complete a questionnaire about how they feel before and after each TMS session and in a follow-up call 1-3 days after their last session.

This research study is the first time the new medication MG001 is being tested in people. MG001 is a formulation of mitragynine, a compound that comes from a plant called Mitragyna speciosa (sometimes known as kratom), which some people use on their own to help manage symptoms of opioid withdrawal. The purpose of this study is to understand how safe MG001 is, how well it is tolerated, and how the body processes it. About 32 healthy adult volunteers, both men and women, will take part. Before joining, participants will undergo screening tests up to four weeks in advance to make sure they are eligible and healthy enough. On the day before dosing, participants will be admitted to the clinic for final health checks, and those who qualify will be randomly assigned-by chance, like flipping a coin-to receive either a single dose of MG001 or a placebo (an inactive substance). Neither the participants nor the staff giving the medicine will know which one is given. The study drug will be administered after at least 10 hours of fasting, and participants will then remain in the research clinic under close medical observation for three nights, until Day 4. During this time, doctors and nurses will monitor participants' health, look for any side effects, and collect blood samples to see how MG001 moves through the body. A follow-up clinic visit on Day 7 will provide one last check-in and blood test. This design helps researchers gather important first information on the safety and tolerability of MG001, while protecting the health and well-being of participants.

Background: People who will participate in research studies need to undergo proper screening, evaluation, and assessment (SEA). SEA helps keep those who participate in studies safe. It also helps ensure accurate study results. The National Institute on Drug Abuse (NIDA) Intramural Research Program (IRP) wants to screen people with alcohol and/or substance use disorders (ASUD) as well as people without ASUD for ongoing studies at NIDA in Baltimore, MD Objective: To screen people with or without ASUD for ongoing studies at NIDA. The ultimate goals are to learn why some people (1) use drugs; (2) stop using drugs; (3) use drugs but do not get addicted; and (4) never use drugs snd to develop ASUD treatments. Eligibility: People aged 18 years and older. They may (1) currently use nicotine, alcohol, opioids, cocaine, or other drugs; (2) no longer use them; or (3) have never used them. Design: Participants will have 1 screening visit that could last up to 8 hours. The visit may be split over more than 1 day. The duration of the screening may vary for each individual based on which studies they are interested in and screened for. The tests they undergo may vary and may include the following: * Physical exam. * Blood, saliva, and urine tests. * Breath samples that test for alcohol and carbon monoxide. * Test of heart function. * Smell test that measures sense of smell. * Tests of memory, attention, and thinking. * Mental health evaluation. * Mock magnetic resonance imaging (MRI) scan. * Questionnaires about alcohol and other drug use, mental health, medical history, and life in general.

The primary objective of this study is to evaluate the efficacy of extended release naltrexone plus bupropion XL (XR-NTX/BUP-XL) compared to matched injectable and oral placebo (iPLB/oPLB) in reducing methamphetamine (MA) use in individuals with moderate or severe methamphetamine use disorder (MUD) seeking to stop or reduce MA use.

Background: Substance use disorders (SUD) can be considered disorders in the way people process incentives, learn, and make decisions. To understand why some people develop SUD, researchers need to develop reliable tests that show how people think and learn. This natural history study seeks to develop a set of tasks that could then be used to test how people learn and make decisions. Objective: To develop and validate behavioral tasks that could be used in future studies. Eligibility: Healthy people aged 18-45 years from the Baltimore area. They must also be enrolled in the NIDA screening protocol. Design: Participants will perform different tasks. Most tasks require 1-4 study visits; some may require up to 12. Visits are 1-14 days apart. All visits will last about 1-7 hours. Participants will perform tasks on a computer. As they work they may be given different stimuli: Smells. Participants will sniff odors through a plastic tube or mask on their nose. Flavors. Participants will wear a mouthpiece and small amounts of different flavored liquids will be placed in their mouth. Pictures. Participants will look at different images. Sounds. Participants will wear headphones and various sounds will be played for them. Food. Participants may be asked to eat a meal before, during, or after a task. The researchers will provide the meal. During each task, participants will wear sensors to monitor their heart rate, blood pressure, breathing, and other physical changes in their bodies. Some participants will have a functional magnetic resonance imaging (fMRI) scan. They will lie on a table that slides into a cylinder. They will perform tasks on a computer screen during the fMRI.

Study Description: Despite the availability of pharmacotherapy for some substance use disorders, relapse vulnerability is still a significant issue. This suggests medications with alternative mechanisms of action should be explored to address this unmet need. Substantial preclinical research indicates that orexin antagonism blunts the internally and externally triggered motivation to attain abused substances. This research project will translate these preclinical findings into the clinical domain by administering the FDA approved orexin antagonist, suvorexant, to those with a substance use disorder. Suvorexant s ability to blunt neurobiological correlates of substance misuse will be assessed. This will be assessed following acute and repeated drug administration. Baseline individual differences will be considered to determine whether neurobiological variance influences suvorexant s impact in those with nicotine dependence. In an independent arm, the interaction between suvorexant and a dopamine agonist (methylphenidate) on cognitive function will be assessed in non-smoking individuals. Objectives: The objective is to determine the acute and chronic impact of the orexin antagonist, suvorexant, on neurobiological and behavioral factors linked with substance use disorders. Whether such effects are mediated by baseline characteristics will be tested. Given suvorexant is an FDA approved treatment for insomnia, sleep will be evaluated as well in the nicotine dependent arm. Endpoints: In nicotine-dependent individuals, suvorexant s impact on brain function will be assessed several ways by evaluating: 1) resting function, 2) reactivity to drug cues, 3) reactivity to non-drug related cognitive tasks. Sleep and nicotine use will be measured throughout the study period. In those without nicotine-dependence, the impact of suvorexant and the interaction of acute methylphenidate and suvorexant on brain function will be assessed. This arm will provide insight into how suvorexant impacts reward/cognition as well as impacts the pharmacological influence of methylphenidate on those same measures. Study Population:\<TAB\> Nicotine dependence arm:140 subjects; Volunteers who are between the ages of 18-60 and are daily smokers/vapers. Control arm: 80 subjects; Volunteers who are between the ages of 18-60 and are non-smokers/vapers This study will be conducted at the NIDA-IRP, Biomedical Research Center, in Baltimore, MD. Description of Study Intervention: Nicotine dependence arm: Suvorexant at 10 mg single dose, and Suvorexant at 10 mg daily for approximately 7 days. Control arm: 1. Tolerability visit with one MRI scan post-20mg methylphenidate, 4 acute drug administration (6-14 days in randomized order: 1. Placebo + placebo; 2. 20mg suvorexant + Placebo; 3. Placebo + 40mg methylphenidate; 4. 20 mg suvorexant + 40mg methylphenidate max) Study Duration: 5 years Participant Duration: 1-2 months

This first-in-human, randomized, double-blind, placebo-controlled, single ascending dose (SAD), phase I study is designed to assess the safety, tolerability and pharmacokinetics of VK4-116 in healthy volunteers in fasted and fed state.