drug addiction research title

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429 Drugs Essay Topics & Research Questions + Examples

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• Drug Addiction: Advantages and Disadvantages
• Impacts of Drugs on the Society
• Drug Abuse among Teenagers Causes and Effects
• Drug and Alcohol Abuse among Young People
• Ethical and Legal Implications of Prescribing Drugs
• The Consequences of Drug Abuse
• Adolescent Drug Abuse, Their Awareness and Prevention
• Causes and Effects of Drug Addiction Drug abuse entails constant and excessive usage of drugs to create feelings of happiness and blot out reality despite its well-known harmful effects.
• Drug Abuse and Its Effects on Families Because of the lack of control that a substance abuse patient has over their actions, families of the people that develop chemical dependency are under constant threat.
• Alcohol, Tobacco, and Illegal Drugs: Use Consequences Although tobacco, alcohol, and drugs cause severe physical and mental health problems and spoil a person’s social life, the image created for them contributes to harm devaluation.
• Teenage Drug Addiction Problem The modern world is full of diverse activities and hobbies that can have both positive and negative effects. This essay aims at discussing the phenomenon of teenage drug addiction.
• Drug Abuse and Theories Explaining It This paper aims to examine several theories explaining drug addiction. The theories for analysis are biological, psychological, and sociological.
• Case Study of Drug Addiction The case study provides a platform for evaluating treatment priorities and agencies crucial for the full recovery of substance abuse patients.
• Drug Use and Heroin Addiction: Informative Speech The illegality of drugs makes it impossible to research the actual numbers of people using drugs and situations making these persons initiate drug abuse and harm their health.
• Drug Misuse and Its Effects on Children Health and body functioning are negatively affected, and the condition may manifest itself in drug dependence or an array of other harmful and problematic behaviors.
• The Use of Performance-Enhancing Drugs The information herein identifies particular risk factors that expose the global community to the objectionable concerns linked with the goods.
• Drug Abuse Relation to the Violent Behavior Various groups of drugs greatly vary and relate to violence in different ways. Any person with heavy drug habits may act negatively and involve in violent acts punishable by law.
• Criminal Justice System: Drugs and Crime The main objective of the criminal justice system is ensuring delivery of justice for all. It mainly concentrates in detection of crime.
• Social Problems Related to Alcohol and Drugs The present paper will explain the content of three articles relating to the issue of Alcohol and drug use while also providing a personal reflection on the readings.
• Overcoming the Drug Abuse Addiction The use of narcotic drugs brings irreparable harm to health and diminishes the quality of life. Opioid abuse is a predominant problem that continues to be a concern.
• Effects of Drug Use on Society Every society encounters a variety of problems that it needs to address, and one of the most common is drug use among the population.
• Canadians’ Reaction to Alcohol as a Newly-Invented Illicit Drug The possible reaction of Canadians to alcohol, if it was a newly-invented illicit drug, will differ depending on their personal characteristics and external circumstances.
• How Drugs Influence the Crimes This essay discusses five major questions about ‘Drug and Crimes’, namely, what is the extent to which the drug subculture influences criminal behavior?, etc.
• Drug Addiction and Best Treatment Practices This paper will determine the role of treatment in the recovery process and analyze the best evidence-based practices.
• Drug Addiction in America: Effects and Solutions The problem of illegal drug use is a major health issue in the United States, it affects thousands of people, the specified concern must be handled on the level of state policies.
• Social Factors of Substance Drug Abuse Substance abuse refers to the pattern of continued use, despite adverse consequences. Socio determinants of substance abuse imply social factors that affect the outcome of drugs.
• Pharmaceutical Industry: Drug Development Drug development is a lengthy process but rightly so since the result should be playing a curative role and not disease inducer.
• Drug Legalization from the Utilitarian Perspective The focus of the paper will be mainly on marijuana use, and such utilitarian principles as the principle of utility and the felicific calculus will be primarily applied.
• The History of Drug Addiction and Control The paper states that drug initiation can be considered a system of relations between the adolescent, family, drug culture, and society.
• The Influence of Drugs and Alcohol on Date Rape While drugs can affect mental health and make the victim forget everything, the perpetrators indulge in alcohol abuse to escape the blame and deny non-consensual sex.
• Victimless Crimes: Drug Abuse and Sex Work This work’s primary objective is to research and analyze victimless crimes, namely drug abuse and sex work, from the viewpoint of criminology.
• Forensic Drug Analysis Course: Reflection The most interesting part of the course is the study of various techniques for the analysis of substances and their impact on forensic research.
• Classification of Legal and Illegal Drugs The classification of drugs as either legal or illegal provides a baseline foundation for the effect on victims and the attribute of addiction.
• Analysis of Drug Classification The article argues drug reactions depend considerably on patients and administration methods, that’s why employees must know the basics of drug classification.
• Drugs and Alcohol Influence on Drivers Excessive amounts of alcohol and drugs deprive the driver of conscious control over the vehicle, leading to catastrophic consequences.
• Therapeutic Drug Monitoring (TDM) Assays Therapeutic drug monitoring (TDM) refers to the measurement of chemical or biochemical parameters in the lab to inform drug prescribing procedures.
• Ilaris(R)-Drug Usage in U.S. and Australia Ilaris(R) has been approved for use in humans by the Food and Drug Administration (US) and The Pharmaceutical Benefits Scheme (Australia).
• Monopoly Drugs Versus Generic Drugs When a pharmaceutical company creates a new drug it may apply for and be granted a patent that is a legal protection that shelters an invention from being used, copied, or traded without permission.
• The Crisis of Drug Addiction This essay will focus on the crisis of drug addiction in general. It will also include some factors that lead to drug abuse. The paper will cover the dynamics of drug addiction in the USA.
• Drug Errors: Enhancing Care Quality and Safety Though numerous new technologies have been developed to improve healthcare delivery, drug errors continue to be an issue in the United States.
• Drugs: Myths and Misconceptions Starting from the very beginning of the twentieth century and ending even today, drugs as a topic have been surrounded by a mass of myths and misconceptions.
• Psychotropic Drugs Usage, Effects, Consequences Numerous aspects determine the effectiveness of drug therapy with psychotropic medication, for example, the appropriateness of the choice of pills for the disease.
• Drugs and Social Life in Iceland The nature of drug use in Iceland can be described as experimental — young people see something new in them and decide to try it out.
• Drug Addiction: A Choice or a Medical Disease? This article examines two opposing points of view on the problem of drug addiction – does a person have a choice to be a drug addict or is drug addiction a medical disease?
• Drug Testing Problem Reflection The paper discusses a need for the maintenance of a drug test policy. In the present world, this issue is further exacerbated by the legalization of marijuana in all states.
• Juvenile Drug Abuse Problems Analysis This essay describes the problem of juvenile drug use and applies the relevant delinquency theory. Additionally, the interventions or programs to fix the issue will be highlighted.
• Psychotherapy and Counseling for Drug Abuse Treatment Drugs are the biggest vice of humanity, along with the mental and moral deviations, horrible diseases of modern times, social neglect and abuse it causes and goes along with.
• How Can Illegal Drugs Be Prevented From Entering Prison?
• Can Economic Aid Make a Difference in the Flow of Drugs?
• Are Novel Drugs Riskier for Patients Than Less Novel Drugs?
• Can the Drugs Problem Be Tackled Primarily Through Legal Enforcement?
• Do Drugs Are Barriers to Our Future?
• Are Anabolic Steroids Really Pernicious Deleterious Drugs?
• How Can Kids Best Be Convinced Not for Do Drugs?
• Have Newer Cardiovascular Drugs Reduced Hospitalization?
• Are Illegal Drugs Inferior Goods in the U.S.?
• How Dangerous Are Drugs?
• Are Psychotherapeutic Drugs Overprescribed for Treating Mental Illness?
• How Dangerous Are Drugs and What Can We Do About the Drug Problem?
• Are Drugs Taking Away the Excitement in Sports?
• How Antidepressant Drugs Work Effect Us?
• Does Medicaid Pay Too Much for Prescription Drugs?
• Are Drugs More Detrimental to Educational Attainment?
• Are Diet Drugs Are Safe for People?
• Can Pharmacogenomics Improve Drugs Safely?
• Does Price Reveal Poor-Quality Drugs?
• How Are Biosimilar Drugs More Extensive Than Those of Generic?
• Are Illegal Drugs Inferior Goods?
• Does Previous Marijuana Use Increase the Use of Other Drugs?
• How Are Drugs and Alcohol Affecting the Teenagers?
• Are Any Drugs Derived From the Ocean Presently Approved?
• Are the More Educated More Likely to Use New Drugs?
• Does Coffee Contain Drugs?
• Has the Time Come to Legalize Drugs?
• How Cost-Effective Are New Cancer Drugs in the U.S.?
• Are Adolescents With Abusive Parents at a Greater Risk of Abusing Drugs?
• Can Production and Trafficking of Illicit Drugs Be Reduced?
• Performance Enhancing Drugs Legalization in Sports The question that was going to be answered through various arguments in this paper was whether these drugs should be legalized.
• Shoppers Drug Mart: History, Founder, SWOT Analysis This paper aims to provide a full review of Shoppers Drug Mart’s internal and external operations. The author examines the history of the company and its founder, Murray Koffler.
• Adderall Drug’s Impact on Cognitive Performance By exploring the effects of Adderall on cognitive performance, this research will contribute to an understanding of how this drug affects the brain and behavior.
• Leadership in Drug Abuse Program Development Within the context of a potential intervention for drug abuse, the roles and competencies of leaders are the primary emphasis of this paper.
• Drug Addiction: A Disease or a Choice? Drug addiction remains a serious health concern for contemporary society. The problem of whether drug addiction can be viewed as a disease or a choice remains topical.
• Drug Abuse and Its Impact on Creativity The boosting effect of drugs on creativity is a myth because changes in thinking are a brain reaction to a narcotic that is temporary yet severe.
• Drug Misuse, Abuse, and Their Factors Addiction is a recurrent, chronic disorder characterized by compulsive substance seeking and use despite harmful consequences.
• Drug Dependency: Construction of a Rehabilitation Center Creating a program that would act as a foundation to help drug addicts recover from drug usage would help lessen drug dependency.
• Cause and Effect of Drug Addiction As a result of drug misuse, there are changes in the functioning of neurological pathways in the human brain, with the associated physical; and mental health deterioration.
• Mandatory Drug Tests for Nursing Students Nursing schools have therefore tried to address this issue and one of the most commonly used tools is the mandatory drug test.
• The Drug Trafficking as Organized Crime Drug trafficking is among the recently organized crimes, and it has a direct influence on the economy as it earns a lot of money.
• The Link Between Drug Abuse and Corruption This paper discusses that drug abuse and corruption deserve attention. It introduces causes and reasons for drug abuse and corruption.
• Drug Trade. “Crack” Book by David Farber The purpose of the book “Crack” by David Farber is to study what influenced the development of the drug trade industry and how this process took place.
• Drug Addiction: The Problem of Xanax Abuse and Its Consequences Xanax as a drug can be very addictive and difficult to stop and it is very important for anyone using the drug to be cautious and follow the instructions that are provided.
• Apis Mellifica as a Homeopathic Drug for Headaches Homeopathy is one of the systems of alternative medicine. The paper investigates the effectiveness of using a homeopathic drug to address headaches.
• Shoppers Drug Mart Company’s Retail Networks The paper presents the analysis of business concept applications on the example of the Shoppers Drug Mart company. It suggests ways to maintain the market share of retail networks.
• Drug Addiction among Nurses The United States of America has one of the best healthcare systems in the world. Drug abuse among nurses is a serious problem that threatens the quality care that is offered.
• The Phenomenon of The Use of Prescription Drugs The need to have a prescription before the drugs are acquired is usually applied in order to prevent illegal distribution, and effective use of such medicine.
• Drug Criminalization: Causes and Effects A comparison of the points made by opponents and proponents of drug decriminalization shows the differences between their overviews of the causes of drug crimes.
• The Business Ethics Workshop: Sex and Drugs at Work Employees should not sleep with their bosses to get promotions and pay raises because it does not conform to honesty and fairness.
• Drug and Prostitution Issues in the Local Community The present scenario concerns a patrol officer assigned to a truck stop near a major highway encountering crime and disorder problems.
• What Are the Costs of Drug Addiction to Society? The essay will explore the overwhelming economic and social costs of drug addiction to society and outline how can confront and reduce the costs of drug addiction.
• The Drug Legalization Debate: A Complex Issue With Compelling Arguments Numerous social issues and concerns require close attention from the American government, including the problem of drug legalization.
• The Aspects of the Drug Use and Media The paper states that it is true when the media portrays drug and alcohol use in a glamorous light or when characters do not experience negative consequences.
• Drug Abuse in Pregnant Women: Effective Ways to Combat Several policies have been proposed to tackle the problem, namely financial support for therapy, voluntary sterilization, and criminal persecution.
• Monitoring Analysis of Drug Courts: The Value of Drug Courts The value of drug courts is expressed in their positive impact on drug-related crime statistics in the first years after completion of a drug treatment program.
• Solutions to Drug Misuse in the United States Drug abuse is a major cause of concern in the United States, with a consequential impact on people’s health and societal psychosocial and socioeconomic problems.
• Drug Abuse and Alcohol-Related Crimes in Adolescents The current paper focuses on the topic of drug abuse and alcohol-related crimes among teenagers, showing that substances remain the most notable factor in juvenile crime.
• The Issue of Misuse of Prescription Drugs The paper discusses the growing problem of prescription drug abuse in the United States, its consequences such as addiction and overdose, and possible solutions.
• Drug Abuse During Pregnancy: Policy Options Heated discussions on whether or not drug abuse during pregnancy should be illegal due to the potential risks to the developing fetus or child persist.
• Disclosure and Nondisclosure in Drugs Prescription The case focuses on the ethical and legal implications of prescribing new medication currently in the development stage for a child under the age of 12.
• Illegal Drug Use in Nurses: Discussion There are reasons why nurses are at risk of developing a drug addiction, which means that there is a high chance for practitioners to work with nurses who illegally use drugs.
• Drugs and Violence Go Hand in Hand From the point of view of American researchers, substance abuse increases the chances of subjects being drawn into conflict relationships.
• Alcohol in the Drugs and Behavior Context It is no secret that alcohol and human health are incompatible things. The most significant influence of alcohol falls on the cerebral cortex.
• Alcohol and Drug Foundation’s Public Relations The campaign conducted by Alcohol and Drug Foundation is a vivid example of how the theories and practices of PR can help alter people’s behavior.
• Illegal Drugs: Types and Influences Illegal drugs include substances that affect the body and the brain of a person. They are divided into several groups, depending on the method of use and the impact on the brain.
• Wellbutrin and Lexapro: Drugs Affecting Neurotransmitters Wellbutrin and Lexapro are effective drugs in the fight against depressive disorder. However, the drugs are addictive.
• Drugs and Behavior: History of Alcohol in America The ordinary colonial American drank roughly twice as much alcohol in 1770 as it does today—about three and a half gallons annually.
• Incretin Mimetic Drugs for Type 2 Diabetes In patients with type 2 diabetes, there is a significant decrease in the incretin effect and a decrease in insulin secretion in response to an oral load.
• Drug Addiction: The Brain Disease Drug addiction acts similarly to neurological diseases. Substances directly affected the brain, with addiction being the most acute phase of substance use disorder.
• The legalization of recreational marijuana: pros and cons.
• Should drug users be criminalized or treated?
• Are drug companies liable for the opioid crisis?
• Are safe injection sites effective in preventing drug overdoses?
• The gateway drug theory: reality or a myth?
• Are mandatory minimum sentences for drug offenses justified?
• The impact of zero tolerance drug policies in schools.
• The therapeutic potential of psychedelic substances.
• Why is drug testing essential in the workplace?
• Should drug education programs be mandatory in schools?
• Random Drug Testing at the Workplace Employees in law enforcement, public health and safety, and national security should all be subjected to random drug testing.
• Drug Repurposing in Cancer Treatment This article examines the concept of drug repurposing in the context of pharmaceutical companies’ innovation policy: the methods and economic feasibility of repurposing drugs.
• Ethics of Using Experimental Drugs It is necessary to examine whether terminal patients have a moral right to the experimental treatment and suggest possible outcomes for this type of cure.
• Public Policies Related to Drug Addiction Public policies related to drug addiction need to be enforced in a compassionate manner that pays attention to the unique needs of American society.
• Economic Evaluation: Prevention of Suicide and Drug Overdose The economic evaluation of the provided scenario was conducted in four dimensions: cost-of-illness, programmatic, benefit-cost, and cost-effectiveness analyses.
• The War on Drugs in the United States The United States government’s combat with substance abuse is called the “War on Drugs,” addressing the campaign initiated by President Nixon.
• Zero Discrimination for People Who Use Drugs From all of the above, it follows that HIV-infected prisoners should have the same access to timely and high-quality medical care as the population.
• The Drug Abuse Problem in Indiana Drug usage is one of Indiana’s most serious societal problems, affecting the state’s health, economy, behavioral, and criminal elements.
• The Effect of an Antimicrobial Drug on Gene Expression This paper critically evaluates methods and techniques that can be used to assess the effect of an antimicrobial drug on global gene expression.
• Drug Addiction as Moral Failure The paper shows that drug abuse cannot be viewed as a moral failure. Kuhar’s scientific examinations made him come to that conclusion.
• Sexually Transmitted Diseases Transmission Involving Drug Use Preventive techniques need to target drug addicts and sex workers to combat the STD epidemic and offer interventions to reduce risky sexual behaviors and drug use.
• The Problems of Drug Misuse and Abuse and Their Management This research aims to determine the best ways to prescript drugs, the importance of drug interactions, and the potential dangers of drug abuse.
• The Anti-Drug Programs in Boston The history of drug abuse across the US has been a challenge for decades. There were various anti-drug programs introduced in Boston to curb the spread of its use in the city.
• Drug Prescription Issues and Abuse This paper aims to determine the best ways to prescript drugs, the importance of drug interactions, and the potential dangers of drug abuse.
• History of Drug Use in Incarceration The history of drug use in prisons go beyond 2008 with some documents indicating a steady rise in drug use between 1980 and 2008.
• Rohypnol and Illegal Drugs in Clinical Trials The current paper discusses Rohypnol. It is a generic drug known as flunitrazepam which contains lorazepam, diazepam, and alprazolam.
• Media Misinformation About Drug Use The United States is one of the countries with the strictest policies, rules, and regulations against the peddling and abuse of illicit drugs.
• A Spontaneous Reporting System for Drug Safety Surveillance Post-marketing in clinical trials uses a spontaneous reporting system for drug safety surveillance where potential AEs induced by the drugs are detected.
• Drug Abuse Demographics in Prisons Drug abuse, including alcohol, is a big problem for the people contained in prisons, both in the United States and worldwide.
• Drug-Resistant Mycobacterium Tuberculosis Strains As with any other infectious disease, TB exhibits specific signs and symptoms that help distinguish it from other illnesses.
• Correlation of HIV, AIDS in White Males Who Are Injection Drug Users The testable hypothesis for this work states that socioeconomic status is correlated with HIV/AIDS in white males who are injection drug users.
• Assessment and Therapeutic Approaches for Drug Addiction Clients The paper uses various drug addiction assessment methods to examine the severity, give clinicians insight into the problem and assist in psychotherapy.
• COVID-19 Epidemic and Alcohol and Drug Addiction The sudden life changes during the COVID-19 epidemic make it difficult for people who suffer from alcohol and drug dependence to fight their addictions.
• High-Level Drug Trafficking in Australia Media articles explain the problem of narcotics trafficking across the Australian border. Australia is an effective participant in international drug trafficking organizations.
• Drug Addiction and Stigmatization The horrifying nature of stigmatization is one of the perplexing factors of drug addiction, so society should understand the role of mental and physical help for such people.
• Drug Addiction: Analysis of Goeders and Guerin Research Goeders & Guerin (1994) point out that anxiety and stress may be involved in drug use and increased risk of dependency, as these are involved in the etiology of cocaine use.
• COVID-19 and Drugs at Schools as Public Health Issues This paper discusses two articles on community and public health issues, specifically, concerning COVID vaccination and drugs at schools.
• Drugs for Neglected Disease Initiative There is a significant unmet need for the treatment of many neglected diseases, as well as for patient groups impacted by these.
• Negative Effects of Drugs on Voice The essay explores the influence of drug intake on the singer’s voice and illustrate the importance of the topic for the singer’s vocal cords maintenance.
• Drug Abuse at the Workplace and a Policy to Address It In this proposal, a policy to address worker substance abuse and addiction, will be discussed, with both its major goals and potential benefits being outlines.
• Drug and Substance Abuse: Sociological Causes and Explanations It is normal to think that drug and substance abuse affects only consumers. However, it also affects various aspects of society.
• Drug Legalization: Arguments For and Against Some people would say that the U.S. should stop the war on drugs because this war caused enormous imprisonment of small-time drug dealers.
• Act Liability for Price-Fixing of Generic Drugs The United States Department of Justice reported that Apotex Corporation, among other drug manufacturers, paid over $400 to settle violations of the False Claims Act.
• The Emergence of Drug-Resistant Pathogens The drug-resistant pathogens phenomenon has endangered the efficacy of drugs such as antibiotics which have helped transform modern medicine and saved countless lives.
• Non-Performance Enhancing Drugs in Sports The use of drugs is prohibited in professional sports. As for the drugs that do not improve performance, they also require control.
• The Adverse Consequences of Substance Use Tool and the Psychoactive Drug History The patient is a 25-years old White male, homosexual, currently single. He has a medical history of having a severe case of psoriasis and psoriatic arthritis, clinical depression.
• Vaccine and Antiviral Drug Supply and Distribution Problem Once the cause of the vaccine and antiviral drugs supply and distribution problem is established, it becomes possible to offer a solution.
• The Mexican Drug War and “Queen of the South” The purpose of this paper is to explore how the Mexican drug war and cartels and their influences on Hispanic culture are reflected in this Netflix series.
• Improving Drug Administration in Healthcare Facility The improvement plan consists of consecutive steps to be followed by a medical facility to ensure drug administration safety.
• Decriminalizing the Simple Possession of Illegal Drugs The decriminalization of illicit drugs has been mentioned as one of the most effective ways of dealing with the crisis in America.
• The war on drugs: the causes of its failures.
• The impact of the war on drugs on minorities.
• The link between the war on drugs and mass incarceration.
• Alternatives to the war on drugs.
• The war on drugs and human rights violations.
• The economic costs of the war on drugs.
• The effects of the war on drugs on drug prices and availability.
• The impact of drug prohibition on drug use patterns.
• The influence of the war on drugs on drug-producing countries.
• Unintended adverse effects of the war on drugs.
• National Association for Alcoholism and Drug Abuse Counselors This paper will consider the fourth principle of the organization’s ethical code, which reads: “Working in a culturally diverse world.”
• Law Enforcement of Drug Business on the Demand Side Law enforcement of the drug business on the demand side would not be an effective method of reducing the market.
• Evaluating Harm Reduction Program for Drug Users The target population of this quantitative study includes substance users with a focus on drug addicts. Harm reduction program addresses the needs of drug addicts who seek help.
• Drug Cartels in Mexico: Definition, Background, Mexican War on Drugs Mexican drug cartels, as one of the most powerful and well-known internationally, present the primary focus of interest in the research paper.
• Causes and Consequences of Alcohol and Drug Addiction Drug addiction is a psychological and physical disorder that affects the brain of an individual. It is caused by dependence on drugs, alcohol, and specific behaviors.
• The Food and Drug Administration (FDA) and Globalization The paper explains why the FDA has created a global strategy for fulfilling its mission and what are the costs and benefits to society of a more globalized food market.
• Six Stages of Change: Treatment Approaches for Drug Addiction Recovery from addiction leads to lifestyle change. Individuals whose loved ones undergo the recovery process may feel long when they have doubtful expectations.
• Types of Drugs and Types of Domestic Abuse Correlation Understanding that the consumption of particular drugs causes physical changes is essential in ascertaining the probability of a specific type of domestic violence.
• Drug Production During Crisis: The Case of COVID-19 The essay argues that the US healthcare system is not suited to properly address crises as COVID-19 has illustrated.
• High U.S. Drug Prices: Health Policy Log This paper presents a health policy log on why are U.S. drug prices so high, including a brief summary of the topic discussed, and an analysis of the health policy issue.
• Why Adolescents Take Drugs: Human Development Delinquent and irresponsible behaviors such as substance abuse, violence, and unsafe safe practices produce serious social and health implications.
• Prescription Drug Abuse Problem Providing access to prescription drugs is among the key tasks that the modern healthcare system should fulfill to increase recovery rates.
• The Influence of Drugs and Social Media Limitless online resources are used to search for helpful information and to harass, torment anonymously, or provoke others.
• War on Drugs: Causes and Problems Ever since a declaration on the war on drugs was made a few decades ago, arguments have not been far off. Top on the list of these disputes has been the issue of drug legalization.
• Drug War in Border Cities: Causes and Consequences This paper examines three topics: the situation in border cities, the consequences of drug wars, and the question of whether legalization can solve the problem.
• Consumption of Illicit Drugs in the United States Tackling the drug problem in America requires a two-pronged strategy that focuses on the demand and supply side of the problem.
• Court Decisions on Drug Offenders The research entails an investigation into the variables that influence the sentencing decisions of judges in drug offenders’ cases.
• Drug Testing in Pharmacology The aim of this paper is to analyze and review drug tests within the population of third-world countries and define whether these trials are ethical.
• Support for the Legalization of the Drug Consumption The appropriate use of drugs is everyone’s responsibility, and whether legalized or illegalized by the government may not reduce its abuse.
• Drug and Alcohol Addiction Treatment Program Successful addiction treatment is comprised of three aspects, constructing the addiction treatment: body, mind, and soul.
• Analysis of Drugs in American Society by E. Goode According to Goode, a number of scholars state that abuse is the use of drugs without a related medical prescription.
• Drugs and Substance Abuse in College: Effects and Treatments The paper will give a review of a treatment approach to drug abuse and describe the effects of substance abuse on a person who is in college.
• Male Health Drugs:Overview and Effects Adverse effects of androgenic drugs could be observed in livers in the form of blood-filled spaces known as peliosis of the liver.
• Alcohol and Other Drug Use Among the Aboriginal and Torres Islander People The paper evaluates the patterns of alcohol and other drug usage among the Aboriginal and Torres Strait Islanders, and drug-related harms.
• The Problem of Legalizing Drugs The problem of drugs legalization is a topic for debate in many countries where politicians, sociologists, philosophers, and other experts try to address the consequences of using drugs.
• The Effect of Prohibition Alcohol and Drug Use Although Prohibition reduced consumption in the initial period, it does not imply that it realized success; neither did it make the community better.
• Escalating Drug Prices: Solution to the Problem The healthcare system relies on the supply of drugs to prescribe and deliver treatment. If the government can not procure enough medications, the overall healthcare will suffer.
• How Liquid Chromatography and Mass Spectrometry is Used in Drug Screening Drugs like glucocorticosteroids are tested using LC/MS method. The paper has two different examples of how LC-MS is used in drug screening to understand better.
• Random Drug Testing: Pros and Cons Random drug testing (RDT) is becoming a common practice in many industries. This type of testing involves the analysis of urine or blood samples of existing employees randomly.
• Drugs in the Modern Sports Athletes can do almost anything to better their abilities, whether it is putting in extra hours in the gym, eating healthy, or experimenting with different workout routines.
• Patient Rights to Experimental Drugs The paper discusses why patients should have the right to decide if they would like to use drugs that have not been proven effective when there are no other treatment options.
• Drug Issues in Watertown, New York Every day, people smuggle drugs to the city to profit from peddling lethal drugs, calling a need for effective initiatives to root out drug trafficking in the area.
• Racism, Racial Profiling and Bias in the War on Drugs Racial profiling occurs when law enforcement bases their criminal investigations on race, ethnicity, or religion, which in the process undermines human rights and freedom.
• Variables That Impact Sentencing Decision of Judges in Drug Offender Cases In research, the statistical model used evaluates the proportionality, consistency, and non-discrimination in the judicial sentencing decisions.
• The Effectiveness of Drugs in Medicine The paper include buprenorphine and methadone which are regarded as replacement therapies; others are naltrexone, neurontine /gabapentin, baclofen, nicotine replacement.
• Doctors’ Knowledge on Drug Prescription The reason why doctors have little knowledge of the drugs they prescribe is misplaced priorities during clinical trials.
• Drug Trafficking and Terrorism in the Middle East Terrorism and drug trafficking are the major wars that the world has been trying to fight for several centuries.
• Drugs and Crime Committed Under the Influence It would be prudent to differentiate between two types of drug-related crimes. There are instances of drug-related crimes and psychopharmacological crimes.
• Combating the Local Drug Distribution in Missouri The article is devoted to the fight against drug trafficking in Missouri: the author shares his thoughts on how to cope with the problem.
• Colombian and Mexican Drug Cartels and Their Impact in the U.S. Thus this paper seeks to examine the two key sources of illicit drugs and the challenges they pose to the federal and states government in their campaign against them.
• Prescription Drug Abuse as a Community Health Issue
• Crime Trends: Drug Abuse in Adults and Juveniles
• Substance Abuse: Alcohol and Drugs in the Movie “Ray”
• Trade and Usage Control: Drug Enforcement Administration
• The Practice of Nursing Research: Drug Round Tabards
• “Addicts Who Survived” by David Courtwright: American Addiction to Narcotics Problem and Anti-drug Policies
• The Interrelationship Among a Bacterial Pathogen and Antimicrobial Drugs
• Should All or Certain Drugs Be Legalized?
• Drug Release: Ethical Dilemma in Pharmaceutics
• Drug Abuse in Correction Facilities
• Distribution of Fake Drugs: Analysis of a Criminal Case
• An Overview of Drug Addiction
• Medication Safety and Drug Therapy Process
• Reducing the Number of Adverse Drug Events Among Older Adults: An Action Plan
• A Study of Drug Allergy, Iron Poisoning and Abnormal Bone Mineral Metabolism
• Federal Food, Drug, and Cosmetic Act Amendment
• The Role of Forensics in the War on Drugs
• The Effects of Drugs on a Man’s Reproductive System
• Schizophrenia Treatment With Approved Drug
• Drugs and Crime Description: Federal Drug Statutes
• Patients Receiving Antipsychotic Drugs: Neuroleptic Syndrome
• Reducing Adverse Drug Events Among Older Adults
• Drug Abuse in Homeless Community
• The U.S. Drug Prices Assessment
• Drug Abuse in the United States’ Social Context
• The Drug Courts: The Question of Drug Abuse
• Judicial Process in Drug Offender Cases: Research Design
• Drugs for Treating Schizophrenia and Mood Disorders
• The Importation of Drugs into the United States
• Drug Courts and Criminal Courts Compared
• Regulation of Drug Compounding
• Community Health: Prescription Drug Abuse
• The Concept of the “War on Drugs”
• Two Acts on Drug Law Comparison
• Quality Patient Care: Drug Errors and Nurses
• Drug Addiction: Elimination of Incarcerations
• Health Issue Analysis: Prescription Drug Abuse
• Juveniles and Drugs in the US
• Carl Hart’s Talk on Racism, Poverty, and Drugs
• The Control the Availability of Illicit Drugs
• “Addicts Who Survived” by David Courtwright: Crucial Work on Drug Addiction
• Why Government Needs Drug Control Policy?
• War on Drugs: Fighting the Way We Are Not Likely to Win
• Pharmacogenomics Impact on Individual Drug Effectiveness
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Drug addiction: from bench to bedside

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• Molecular neuroscience

Drug addiction is responsible for millions of deaths per year around the world. Still, its management as a chronic disease is shadowed by misconceptions from the general public. Indeed, drug consumers are often labelled as “weak”, “immoral” or “depraved”. Consequently, drug addiction is often perceived as an individual problem and not societal. In technical terms, drug addiction is defined as a chronic, relapsing disease resulting from sustained effects of drugs on the brain. Through a better characterisation of the cerebral circuits involved, and the long-term modifications of the brain induced by addictive drugs administrations, first, we might be able to change the way the general public see the patient who is suffering from drug addiction, and second, we might be able to find new treatments to normalise the altered brain homeostasis. In this review, we synthetise the contribution of fundamental research to the understanding drug addiction and its contribution to potential novel therapeutics. Mostly based on drug-induced modifications of synaptic plasticity and epigenetic mechanisms (and their behavioural correlates) and after demonstration of their reversibility, we tried to highlight promising therapeutics. We also underline the specific temporal dynamics and psychosocial aspects of this complex psychiatric disease adding parameters to be considered in clinical trials and paving the way to test new therapeutic venues.

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Introduction.

Drug addiction including smoking, alcohol and illicit drug use is indirectly or directly responsible for 11.8 million deaths each year in the world [ 1 ]. According to the Global Burden of Disease study, this number is higher than deaths from cancer and accounts for a fifth of all deaths around the world [ 1 ].

Drug addiction is defined as a chronic, relapsing disease that results from the prolonged effects of drugs on the brain. Similarly to other neuropsychiatric diseases, drug addiction is intermingled with behavioural and social aspects that are equally important parts of the disease, complicating the overall therapeutic approach. Actually, it is only recently, in the beginning of the 21st century, that we started to see “the drug-addict” as someone suffering from a disease and whose brain has been altered fundamentally by drugs [ 2 ]. Therefore, the most effective treatment approaches include biological, behavioural and social-context components. Based on the latest scientific advances, treatment and management of drug addiction patients point towards a personalised strategy [ 3 ]. However, there are very few objective and effective strategies for treating drug addiction. Without the mandatory mechanistic basic knowledge on drug addiction, the development of new therapeutic strategies is postponed.

The neurobiological circuits and mechanisms that support compulsive seeking and consumption of drugs with addictive potential are partially known. They comprise a progressive shift in the involvement of ventral to dorsal and medial to lateral striatal circuitry [ 4 , 5 ], along with molecular and cellular adaptations to drugs of abuse exposure. They include neuronal and synaptic plasticity and modifications in gene expression, in part through epigenetic mechanisms [ 6 ]. Notably, drug-induced neuronal modifications can also occur in non-pathological processes, underlying the fact that drugs of abuse hijack normal adaptive changes in the brain [ 7 ]. Indeed, laboratory and clinical observations suggest that addiction is driven by the usurpation of neuronal processes that normally serve reward-related learning and memory. Most of the modifications that have been shown to be involved in a state of addiction (modified gene transcription, epigenetics, neuronal plasticity and neurotrophic mechanisms) are also associated with physiological forms of behavioural memory in murine model such as spatial memory, fear conditioning and operant conditioning [ 7 , 8 ].

We know that only a proportion of individuals (depending of the drug type) will develop drug addiction after several exposures [ 9 ]. This individual vulnerability is probably linked to both genetic and environmental factors [ 10 ]. Drug addiction is highly polygenic, as hundreds of genetic variations combined result in variable vulnerability [ 11 , 12 ]. Several types of environmental factors have been characterised and interact with an individual genetic background [ 12 , 13 ]. Psychosocial stress is one of the factors, but the most important one, is by far, the exposure to drugs of abuse. Usually, drug abuse starts with a ‘gateway’ drug (mostly socially driven) catapulting the individual vulnerability to other drugs of abuse [ 14 ].

During the last three decades, combine effort has been dedicated to identify brain regions and molecular pathways involved in the development of addiction to drugs of abuse. Here, we will focus on experimental approaches that helped to provide a clearer picture on the physiopathology of drug addiction guiding therapeutic opportunities.

Converging actions on brain reward pathway elicit its remodelling

The circuit at the centre of the disease is the mesolimbic pathway, also referred as the reward pathway (Fig. 1 ). The mesolimbic pathway includes dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAc), a major component of the ventral striatum. The GABA medium-sized spiny neurons (MSNs, ~95% of striatal neurons), which are targets of glutamatergic and dopaminergic inputs, form two pathways [ 15 ]. The dopamine D1 receptor–positive (D1R) striatonigral MSNs project to the medial globus pallidus and substantia nigra pars reticulata (direct pathway) and coexpress dopamine D1 receptors and substance P, whereas D2R striatopallidal MSNs project to the lateral globus pallidus (indirect pathway) and coexpress dopamine D2 receptor, adenosine A2A receptor and enkephalin [ 16 , 17 ]. Through different initial mechanisms, drugs of abuse increase the release of dopamine in the NAc from the VTA [ 18 , 19 , 20 ]. This VTA-NAc pathway could be seen as primum movens for the acute rewarding effects of all drugs of abuse. Regardless that drugs of abuse have distinct protein targets and mechanisms of action, in the end, the main addiction-related modifications are common to nearly all drugs of abuse and converge on the VTA and NAc with common acute functional effects [ 21 ]. It is schematically conjectured, that when stimulated by dopamine, cells in the NAc produce feelings of reward and satisfaction [ 22 ]. The physiological function of this response is to facilitate the motivation for basic biological goal-directed behaviours as survival, social interaction and reproduction. By artificially causing a build-up of dopamine in the NAc, drugs of abuse generate an artificial reward effect [ 22 ]. As all drugs of abuse increase dopaminergic transmission to the NAc after acute administration, they also produce shared modifications in the mesolimbic system after chronic exposure. They include (i) hypofunction of the dopamine pathway that is seen as a major contributor to the negative emotional symptoms associated to drug withdrawal, leading to drug craving and relapse, and (ii) drug-induced adaptations in glutamatergic afferents to the NAc [ 23 , 24 ]. Clearly, these modifications in the mesolimbic system after the exposure to drugs of abuse is oversimplified. The hypofunction of dopaminergic system hypothesis is self-fulfilling in that research work has principally focused on dopamine to the exclusion of other neurotransmitters. Actually, some drug of abuse reinforcement appears to be independent of the mesocorticolimbic dopamine system (e.g. opioids [ 25 ], nicotine [ 26 ]), but support self-administration by imitating the effect of dopamine in the nucleus accumbens [ 21 , 27 , 28 ].

Addictive drugs of different types have a common effect of increasing levels of dopamine released by neurons projecting from the ventral tegmental area (VTA). This effect is central for initial drug reinforcement. Notably, drug taking with initial reinforcement involves a potentiation of the projection from prefrontal cortex (PFC) to nucleus accumbens (NAc), while other glutamatergic projections are mostly involved in craving, like basolateral amygdala (BLA)-NAc projection, or in withdrawal/negative symptoms, like paraventricular thalamus (PVT)-NAc projection. With increasing administration of drugs of abuse and progressive shift toward compulsive abuse, the dorsal (dorso-lateral) striatum seems more and more implicated, with dopaminergic cells involved shifting progressively from the VTA to the substantia nigra pars compacta (SNc) [ 4 ]. Recently, data acquired through optogenetic dopamine neuron self-stimulation suggested prominent synaptic strengthening of the orbitofrontal cortex (OFC) to dorsal (dorso-medial) striatum projection in compulsive mice [ 31 ].

Drug addiction is conceptually defined as a three-stages cycle: (1) consumption/binge/intoxication, (2) withdrawal with its negative affect and (3) craving stage (Fig. 2 ) [ 27 ]. Animal models and human imaging studies have exposed the different brain areas involved in each of these stages. Briefly, the VTA-NAc (for reinforcement) and dorsal striatum (for stimulus-response habits) are important for the consumption/binge/intoxication stage, the extended amygdala with the hypothalamus and the brainstem in the withdrawal stage and cortical areas, the dorsal striatum, the hippocampus and the basolateral amygdala in the craving stage (Fig. 2 ).

Progression to addiction is defined as a transition between three consecutive phases [ 252 ]: (1) Recreational, sporadic drug taking, in which drug of abuse administration is occasional and one activity among many other distractions of the individual. (2) Intensified and sustained drug use, in which drug administration strengthens and becomes the principal recreational activity of the individual; at this phase drug taking becomes a habit. (3) Loss of control of drug use and addiction, in which drug seeking and taking are now the principal activity of the patient. The first phase can occur to every person as drugs of abuse hijack the same brain circuit as natural rewards. The second phase occurs only in vulnerable users. The phase of addiction seems to be due to a second vulnerable trait with loss of control and compulsivity. Three stages of addiction are described [ 27 ]: (1) Binge/intoxication stage: reinforcing effects of drugs may initially use mainly dopamine and opioid peptides in the nucleus accumbens (NAc) and involves the ventral tegmental area (VTA). Subsequently, cue–response habits develop and includes the substantia nigra pars compacta (SNc) and the dorsal striatum. (2) Withdrawal/negative affect stage: the negative emotional state of withdrawal may involve the extended amygdala with corticotropin-releasing factor (CRF), norepinephrine and dynorphin as key neurotransmitters. Main projections of the extended amygdala consist of the hypothalamus and brainstem. (3) Craving stage: this stage includes conditioned reinforcement in the basolateral amygdala (BLA) and contextual processes in the hippocampus. This is controlled by cortical areas (prefrontal cortex (PFC) and orbitofrontal cortex (OFC)). A key neurotransmitter involved in the craving stage is glutamate.

The progression of drug addiction begins with the first exposure, mostly when the drug is taken voluntarily for its recreational and hedonic effect, and progressively consolidates during repeated but still controlled drug use. While administration intensifies along with loss of control over drug intake, drug use becomes habitual and compulsive in vulnerable individuals [ 4 , 29 , 30 ] (Fig. 2 ). This progression from voluntary drug intake to habitual and compulsive use represents a progression from ventromedial to more dorsolateral regions of the striatum and from prefrontal cortex (PFC) to orbitofrontal (OFC) and more global cortical region [ 4 , 31 ] (Fig. 1 ).

Synaptic plasticity

Brain plasticity is a fascinating capacity allowing appropriate modification of the neural activity in response to new experiences and environmental stimuli [ 32 ]. Modifying the synaptic strength between neurons is widely assumed to be the mechanism by which memory is encoded and stored in the brain [ 7 ]. Hence, it is appealing to hypothesise that drugs of abuse cause long-term alterations on behaviour by changing synaptic plasticity in key brain circuits [ 4 , 7 , 32 ].

Drugs of abuse such as cocaine induce specific synaptic plasticity in the mesolimbic circuitry. One single injection of an addictive drug can already modify the excitatory synaptic strengths in the VTA. Indeed, it has been extensively shown that the AMPA/NMDA ratio is increased in VTA dopamine neurons after one dose of cocaine and that some glutamate AMPA receptor 2 (GluA2)-containing AMPA receptors (AMPARs) are exchanged for GluA2-lacking ones [ 33 , 34 ]. At the same time, NMDA receptor (NMDAR) function decreases. All these elements cause an impairment in eliciting long-term potentiation (LTP). Different types of synaptic plasticity in VTA dopamine neurons induced by rewarding and aversive experiences are comprehensively reviewed by Pignatelli and Bonci [ 35 ]. Midbrain dopamine neurons are central in the mesolimbic circuitry for both natural rewards and drugs of abuse [ 18 , 36 ]. The VTA is known to be a central hub integrating numerous inhibitory inputs as GABAergic synapses represents 50–80% of all synapses onto VTA dopamine neurons [ 37 , 38 , 39 ]. GABAergic inhibition of dopamine neurons is mediated by both fast ionotropic GABA A receptors and slow metabotropic GABA B receptors [ 40 ].

In 2017, Edwards et al. [ 41 ] showed that the principal monosynaptic projection to VTA dopamine neurons arising from the NAc [ 42 ] inhibits the firing of dopamine neurons via activation of GABA B receptors, whereas local VTA inhibitory interneurons inhibits dopamine neurons through GABA A receptors. Today, it is well established that pharmacological activation of GABA B receptors (e.g. by baclofen) reduces cue-associated cocaine craving as well as reduce cocaine use in humans [ 43 , 44 , 45 ] and it reduces rewarding and reinforcing effects of cocaine on animal models [ 46 , 47 , 48 , 49 ]. Edwards et al. report [ 41 ] indicates that the therapeutic effects of baclofen might pass through VTA dopamine neurons’ GABA B receptors. Intrathecal Baclofen is an effective and safe long-term treatment used worldwide to treat severe spasticity [ 50 , 51 ]. Oral baclofen is less effective and has significant rates of side effects, like sedation, somnolence, vertigo and headache especially when prescribed off-label for drug addiction (because higher doses are commonly used) [ 51 , 52 ] . . Indeed, contrasting results on the effect of baclofen in reducing alcohol craving [ 53 , 54 , 55 ] and cocaine dependence [ 43 , 56 ] were probably due to different severity of alcohol dependence of the enroled patients. This is way higher dose are tested and often prescribed off-label for drug addiction [ 55 ]. Thus, self-poisoning that could lead to severe toxicity and death represents one the major concern of baclofen use in drug addiction. Therefore, baclofen should be prescribed with caution and close monitoring [ 52 , 57 ].

Together with drug of abuse-induced LTP at excitatory synapses, plasticity of GABAergic inhibitory synapse in the VTA also have an impact on the firing rate of VTA neurons, at least following opioid [ 58 ] and cocaine administration [ 59 ]. Normally, NMDA activation, during excitatory LTP (induced by high-frequency stimulation), leads to the release of NO that will activate guanylate cyclase in adjacent GABAergic terminals, which in turn, leads to increase in GABA release. This presynaptic NMDA receptor-dependent GABAergic LTP heterosynaptic plasticity, is named LTP GABA . Nugent el al. [ 58 ] showed that opioids blocks LTP GABA through a disruption of the coupling between nitric oxide (NO) and guanylate cyclase. The incapability of GABAergic synapses to potentiate after morphine or cocaine administration may promote LTP of glutamatergic synapses [ 58 , 59 ]. The early loss of inhibitory control combined with potentiation of glutamatergic synapses on dopaminergic neurons might represent adaptations that increase vulnerability to addiction [ 58 , 59 ]. Furthermore, GABA A receptor modulators modify the addictive drugs effects [ 60 , 61 ], and targeting these receptors might be seen as an effective therapeutic strategy but precluded by many side effects among which dependence itself [ 62 , 63 , 64 ].

In addition to the discovery of LTP GABA , Nugent’s group showed that morphine is also able to modulate a form of postsynaptic LTD (LTD GABA ) at GABAergic synapses onto VTA dopamine neurons. Remarkably, after a single administration of morphine, LTD GABA was absent in slices from morphine-treated rats while unaffected in slices from saline-treated rats, indicating a bidirectional control of morphine on GABAergic synaptic plasticity in the VTA [ 65 ]. This absence of LTD GABA is suggested to result from an occlusion effect due to prior morphine-induced decrease in GABAergic synaptic strength through potentiation of glutamatergic transmission and mediated by endocannabinoid signalling [ 66 ]. It is also possible that morphine alters the ability of synapses to exhibit evoked LTP or LTD in the VTA. Previous experiences such as exposure to drugs of abuse, stress, visual or sensory deprivation can change the ability of synapses to undergo subsequent plasticity in response to LTP and LTD induction protocols. This concept of modification of plasticity capability is referred as metaplasticity [ 67 ].

In the NAc, chronic exposure to addictive drugs induces specific synaptic changes that are different from those of the VTA, including a decrease of the AMPA/NMDA ratio as some AMPARs are endocytosed. This leads to a depressed synapse (sometimes referred as long-term depression (LTD) like state), where NMDAR-dependent LTD is reduced or, in some experiments, abolished [ 68 , 69 ]. Highlighting the importance of temporal aspects, studies of withdrawal period after chronic administration of cocaine, showed that synaptic AMPAR levels increase during the first week of withdrawal and persist elevated for weeks [ 70 , 71 , 72 ]. It is established that cocaine challenge transiently decreases AMPAR surface expression, while AMPARs recover back to upregulated levels within a week, with a continuous increase during what is known to be the incubation of craving stage [ 73 ].

The abstinence period after withdrawal is of particular interest considering the classical progression of the disease, the chance of relapse and the opportunity for new therapeutic targets. A seemingly counterintuitive concept named ‘incubation of cocaine craving’ was introduced by Grimm et al. [ 74 ] who modelled cocaine-craving behaviour by using rats trained to press a lever to receive an injection of cocaine and were then forced in a withdrawal period where cocaine reward was no longer given. This concept of ‘incubation’ did not originate in drug addiction research but came from a four-stage model of the creative process proposed by Graham Wallas in 1926 [ 75 ]. Consistent with clinical observations in humans [ 76 , 77 , 78 ], they showed that relapse was progressively stronger over 2 months of cocaine withdrawal and suggest that a craving syndrome progresses or ‘incubates’ during the first 2 months of cocaine abstinence, and probably lasts for longer [ 74 ]. Subsequently, it was shown that this increase was due to the addition of new AMPARs lacking GluA2 and that these new receptors mediate the ‘incubation of cocaine craving’ [ 72 ]. Conrad et al. [ 72 ] showed that after extended withdrawal from cocaine, addition of synaptic AMPARs together with the increased conductance of GluA2-lacking AMPARs triggers higher sensitivity of NAc neurons to cocaine-related cues, leading to a strengthening of drug craving syndrome and relapse. In line with these results, it was suggested that as soon as abstinence is reached, the risk of relapse might be reduced if GluA2-lacking AMPARs were inactivated or removed from NAc synapses. It was thus proposed that GluA2-lacking AMPARs could be a new target for drug development for the treatment of cocaine addiction. While these calcium permeable AMPARs are also critical for the pathogenesis of numerous other neurological disorders (including epilepsy [ 79 ], fragile X syndrome [ 80 ], amyotrophic lateral sclerosis [ 81 ], Parkinson’s [ 82 ] and Alzheimer’s [ 83 ] diseases), developing drugs that specifically target them and not calcium-impermeable AMPARs, which are critical for normal CNS function, is challenging [ 84 ] (Fig. 3 ).

DNA is packaged inside nuclei with the help of histones. These are positively charged proteins that strongly adhere to negatively charged DNA and form complexes called nucleosomes. Each nucleosome is composed of DNA wound around histone octomers (H2A, H2B, H3 and H4). Nucleosomes fold up to form chromatin fibre, which forms loops compressed and folded to produce fibres, which are coiled into the chromatid of a chromosome. Only by loosening compacted chromatin, the DNA of a specific gene can be made accessible to transcription. Some of these drug-induced modifications at the chromatin level are extremely stable and sustain the drug of abuse-induced long-term behaviours. Among them, histone post-translational modifications (PTMs) are known to be causally involved in drug-induced behaviours [ 194 ]. PTMs include acetylation (Ac), methylation (Me), phosphorylation (P), ADP ribosylation (PolyADP-R) and dopaminylation (DA), among a growing list of newly discovered modifications [ 162 , 172 ]. For example, while ubiquitylation (Ub) of H2A is known to be a key interactor of H3 methylation [ 253 ], its supposed role in drug addiction is still unknown. At this epigenetic level, some drugs were demonstrated to have an influence on drug-induces behaviours such as histone deacetylase (HDAC), bromodomain and DNA methyltransferase inhibitors. Locus-specific epigenome editing is now encouraging as a new field of investigation as it might help to the discovery of new specific and causal drug of abuse targets. Overview of the tetrapartite glutamatergic synapse composed of a medium spiny neuron (MSN), a glutamatergic projection, a glial cell and the extracellular matrix (ECM). Here, we focused on synaptic potentiation after drug of abuse administration with the addition at the post-synaptic membrane of glutamate AMPA receptor 2 (GluA2) lacking AMPA receptors (AMPARs). This mechanism might be reduced by metabotropic glutamate receptor 1 (mGluR1) positive allosteric modulator or more directly by GluA2-lacking AMPARs antagonists. In the same way, it was also shown that presynaptic mGluR2 agonists can potentially abolish drug seeking and impair craving incubation. Optogenetically-inspired 12 Hz deep brain stimulation (DBS) in the nucleus accumbens can also be a promising novel therapeutic for addiction. Finally, ceftriaxone, N-acetylcysteine, and inhibitor of matrix metalloproteases 9 (MMP-9), mainly through their action on glial cell and the ECM, are very interesting molecules that may be added in the addiction therapeutic arsenal.

Inspired by previous work performed in the VTA showing that metabotropic glutamate receptor 1 (mGluR1) LTD induces removal of GluA2-lacking AMPARs from synapses [ 33 , 34 ], Loweth et al. [ 85 ] demonstrated that synaptic GluA2-lacking AMPAR decrease could be accomplished by in vivo evoked mGluR1 LTD in the NAc. More importantly, their group showed that after prolonged cocaine or methamphetamine withdrawal, systemic injection of a mGluR1 positive allosteric modulator attenuated the expression of incubated craving by reducing GluA2-lacking AMPARs in the NAc [ 85 , 86 ]. These results suggest a strategy in which abstinent methamphetamine or cocaine users could use a systemically active compound to protect themselves against cue-induced relapse.

These latter studies were conducted without differentiating between D1 receptor D1R MSNs and D2R MSNs. In 2014, Pascoli et al. [ 87 ] demonstrated that this increase in the strength of excitatory afferents was exclusively related to D1R MSNs. Interestingly, the type of drug-evoked plasticity involved is also dependent on the input. It has been shown that even in the same D1R MSN a synapse connecting the PFC to the NAc increases its strength by inserting GluA2-lacking AMPARs whereas a synapse connecting the ventral hippocampus to the NAc increases the AMPA/NMDA ratio by inserting GluA2-containing AMPARs [ 87 ].

Besides operant self-administration, all these long-term synaptic modifications also underlie behavioural changes associated with drugs of abuse, such as locomotor sensitisation [ 88 , 89 ]. Locomotor sensitisation is a behavioural protocol used to model drug-induced behaviour [ 90 , 91 ]. In rodents, repeated cocaine injection induces gradually increased locomotor activity; after 5 days of consecutive injections, the locomotor response reaches a ceiling level. This state lasts for months after cocaine withdrawal [ 91 ]. As an experimental model, locomotor sensitisation is linked with increased tendency to self-administer psychostimulants [ 92 , 93 ] and with reinstatement of previously extinguished self-administration [ 94 , 95 ]. Whereas the existence of psychomotor sensitisation in humans is discussed [ 96 , 97 ], it is a key aspect of vulnerability to drug addiction and relapse, specifically drug craving or compulsive drug-seeking behaviour [ 91 , 98 , 99 ]. Still, locomotor sensitisation can be dissociated from the rewarding effect of a drug of abuse and conditioned place preference or self-administration are more appropriate experimental paradigms to test this aspect [ 100 , 101 , 102 ]. Even if drug-induced locomotor sensitisation is unclearly present in humans, as an animal model it offers a clear readout to understand the mechanisms by which drugs of abuse induce long-term brain modifications [ 91 ].

Furthermore, it has been elegantly demonstrated that optogenetic stimulation of the excitatory projections to the NAc is able to reverse cocaine and alcohol-evoked plasticity [ 87 , 88 , 89 ]. Briefly, applying a NMDAR or mGluR1-dependent LTD on cortico-accumbal glutamatergic synapses, before a drug of abuse administration, diminishes its effect. In another study, Luscher’s team took advantage of the knowledge, obtained from optogenetic in vivo experiment in rodents, to implement a novel deep brain stimulation (DBS) protocol that abolishes behavioural sensitization to cocaine (and thus that would be efficient during the relapse phase) [ 103 ]. Basically, the idea is to manipulate synaptic plasticity in the NAc to reverse pathological synaptic transmission and its associated behaviours following exposure to drugs of abuse. In this study, as a therapeutic use of optogenetic tools in humans is for now inapplicable [ 104 ], the authors reversed cocaine-evoked plasticity and thus drug-induced behaviours by using DBS instead of optogenetic. Indeed, DBS is routinely used in clinic and a new DBS protocol can easily be translationally implemented to the human therapeutics [ 105 , 106 ]. They refined the classical high-frequency DBS protocol (that has no sustained effect on cocaine sensitization, probably because it does not affect synaptic plasticity) by applying a low frequency stimulation (12 Hz to equal the one used in the optogenetic endocannabinoid- dependent LTD protocol) in the NAc together with the administration of a D1R antagonist necessary to unmask the mGluR-dependent LTD in D1R MSNs as demonstrated previously [ 107 ] (Fig. 3 , see section on clinical treatment for broader discussion on DBS).

Kalivas’ group showed in 2009 [ 108 ] that after extended withdrawal from chronic cocaine self-administration, cocaine-induced metaplasticity at the excitatory synapses in the NAc that impairs the ability of PFC stimulation to produce LTP or LTD in NAc MSNs. They also showed that N-acetylcysteine reverses cocaine-induced metaplasticity, allowing the induction of both LTP and LTD and that N-acetylcysteine decreases cocaine-relapse in a rodent model. We are currently awaiting the results of a randomised and control study that is testing newly detoxified (and therefore abstinent) hospitalised patients who received a 3–4 week course of treatment, in order determine if N-acetylcysteine can be a useful medication candidate to avoid relapse in patients with cocaine dependence (NCT03423667).

GABAergic D1R and D2R MSNs, equally compose and are mosaically intermingled throughout the striatum [ 109 ]. As explained above, D1R and D2R MSNs send axonal projections outside the striatum, forming the two main output pathways, respectively the direct and indirect pathways [ 16 , 17 ]. In a certainly oversimplified model, the activation of the D1R MSNs result in facilitation of locomotion, reward, and reinforcement while the activation of D2R MSNs result in opposing effects [ 110 , 111 , 112 , 113 ]. In addition to the long-range projections, these neurons form short-range synaptic connections with one another within the striatum, and because they consist of inhibitory collaterals, a mechanism known as lateral inhibition [ 114 , 115 , 116 , 117 ]. Interestingly, these connections are not symmetrical, with D2R MSNs forming more synaptic connections on D1R MSNs [ 115 , 117 ]. Through this previously understudied collateral transmission, Dobbs et al. [ 115 ] presented a novel mechanism by which cocaine exerts its stimulant effect: cocaine, by blocking DAT receptors enhance levels of dopamine and subsequently activating D2Rs, causes a suppression of lateral inhibition and thus disinhibition of D1R MSNs in the NAc which in turn promotes locomotion [ 115 ]. Furthermore, Alvarez’ group suggested that constitutive low D2R levels, through imbalanced lateral inhibition, might pre-sensitised D1R MSNs, facilitate behavioural plasticity to repeated cocaine and promotes an addiction vulnerable phenotype [ 116 ].

The characterisation of the role of glia and the extracellular matrix (ECM) in drug-induced synaptic plasticity is an exciting emerging field of drug addiction research as it comes with promising new therapeutic possibilitiess [ 118 , 119 , 120 ]. Mulholland et al. [ 118 ] summarised and emphasised the role of the ECM and of astroglial cells in the regulation of synaptic plasticity. Of great interest, restoring downregulated glutamate transporter 1 (EAAT2) with ceftriaxone reduces drug seeking in animal models [ 121 , 122 ]. Matrix metalloproteases (MMP) are important regulators of the ECM and contribute to synaptic plasticity [ 123 ]. Inhibiting their activity result in suppression of the reinstatement of cocaine conditioned place preference [ 124 ] and selectively inhibiting MMP-9 prevents cue- and cocaine-induced reinstatement of cocaine self-administration [ 119 ]; these results open additional therapeutic possibilities with the use of inhibitors of MMP-9 as an innovative targeted approach [ 119 , 124 , 125 ] (Fig. 3 ). Still, at our knowledge, there are no randomised controlled study currently investigating these ECM-related drugs.

Drugs of abuse-induced modifications in glutamatergic nuclei targeting the NAc, or the VTA and essential part of the reward circuit, are less studied than cortico-striatal synapses despite the fact that they play a crucial role in the development of drug addiction. Indeed, in the OFC and PFC, chronic alcohol exposure significantly increases LTP in pyramidal neurons [ 126 , 127 ]. Kazanetz et al. [ 128 ] showed that repeated cocaine injections impair endocannabinoid-LTD and mGluR2/3-LTD in the PFC. They postulated that this might mechanistically participate in the induction of a postsynaptic, observed LTP-like phenomenon with an enhanced AMPA/NMDA ratio. It was also demonstrated that neurons of the infralimbic cortex present a decrease in mGluR2 [ 129 ]. In addition, alcohol-dependent rats exhibit an escalation of ethanol seeking, which was abolished by restoring mGluR2 expression in the infralimbic cortex via viral-mediated gene transfer [ 129 ]. Notably, mGluR2 agonist was shown to impair the incubation of cocaine craving [ 130 ] and to attenuate reinstatement of cocaine-seeking [ 131 , 132 ](Fig. 3 ). Recently, Caprioli et al. [ 133 ] extensively reviewed preclinical studies on allosteric modulators of mGluRs on animal models of drug addiction and their potential translational implications. The results reviewed [ 133 ] indicate an remarkable effect of allosteric modulators of presynaptic mGluR2 and possibly mGluR7, supporting the idea that these compounds should be tested as potential medications for addiction treatments.

Besides the PFC, other brain regions appear to be key areas in drug addiction as the paraventricular thalamus (PVT) - a central hub for cortical, sensory and limbic information [ 134 , 135 , 136 , 137 , 138 , 139 , 140 ]. In 2016, Zhu et al. [ 141 ] showed that chronic morphine administration potentiates excitatory synapses between the PVT and D2R MSNs via insertion of GluA2-lacking AMPARs. Remarkably, in vivo optogenetic depotentiation at these synapses abolishes morphine withdrawal symptoms. In a recent paper, projections from the PVT to the NAc were shown to be critical for augmentation of heroin seeking in food-restricted rats [ 142 ] (Fig. 1 ). Actually, Otis et al. [ 143 ] demonstrated that the PVT is an integrative hub for reward seeking behaviour and that PVT-NAc neurons integrate different inputs from the PFC and the lateral hypothalamus to precisely guide reward seeking behaviour. In a recent review, De Groote et al. [ 140 ] focused on the new advances in the understanding of the roles of the PVT-NAc connections in motivated behaviours, highlighting their implications in drug addiction.

Drug addiction-related genes and transcriptomic regulation

Modifications in gene expression contribute to the long-lasting effect sustaining drug addiction; thanks to gene-expression arrays, RNA-sequencing and candidate gene approaches, the specific genes and their regulatory transcriptomic mechanisms involved in drug addiction development and maintenance are now better understood.

Drug addiction-related genes

For example, the use of conditional gene knockout in mice emphasises the importance of monoamine membrane transporters (dopamine transporter, and serotonin transporter) [ 144 , 145 ] and of mGluRs [ 146 , 147 ]. As new animal models of drug addiction, these approaches are also useful to better characterise fine-tuning of important pathways involved in addiction. For example, a scaffold protein known as Maged1 has been shown to be involved in cocaine reward and reinforcement [ 148 ]. We demonstrated that Maged1 inactivation impairs drug-evoked dopamine release and glutamatergic synaptic plasticity in the NAc. Inactivation of Maged1 in mice was able to abolish behavioural sensitization to cocaine as well as cocaine conditioned place preference and operant self-administration behaviours [ 148 ]. This sole genetic alteration, causally linked to a strong alteration of drug-induced behaviours, impairs (at least) two core neuronal mechanisms leading to addictive behaviours: (1) cocaine-evoked release of dopamine in the NAc and (2) NAc plasticity, with a reduced AMPA/NMDA ratio and a resistance to LTD. Actually, it seems that, after Maged1 inactivation, the excitatory synapses in the NAc shift to a depressed state. Our hypothesis is that, in line with the previously discussed in vivo optogenetic induced LTD, this impairment could be a key factor for the significant decrease in sensitization to psychostimulants [ 87 , 103 , 148 ]. Actually, it seems that placing neurons in a state of ‘presensitization’ is able to prevent drug-induced sensitization itself [ 148 , 149 ]. Our group is now trying to understand what are the cellular and molecular pathways directly altered by Maged1 inactivation and responsible for this strong anti-addictive drug phenotype. Remarkably, the promoter of Maged1 was found in a list of 213 promoters that co-precipitate with acetylated histones and with the activated form of cAMP response element binding protein (CREB) after chronic drug taking [ 150 ]. In line with this result, preliminary and unpublished results from our laboratory point out a specific epigenetic mechanism, in parallel with an alteration of synaptic plasticity in excitatory projection to the NAc, that would link Maged1 to its major effect on drug-induced behaviours. This selected gene approach is of great interest in refining our knowledge of pathways hijacked by addictive drugs. Using cell sorting of D1R MSNs and D2R MSNs as described previously [ 151 ], our group also identified the G-protein-regulated inducer of neurite outgrowth 3 (GPRIN3) in both MSN populations but strikingly more expressed in D2R MSNs [ 149 ]. The GPRIN family (GPRIN1, GPRIN2 and GPRIN3) are Gαi/o-regulated proteins suggested to intermediate the communication between GPCRs and the sequential intracellular target [ 152 ]. Indeed, GPRIN1 and GPRIN2 have been described as alternative (to adenylyl cyclase) mediators of GPCRs signalling but GPRIN3 had a much less defined role [ 152 , 153 ]. To understand the role of GPRIN3 in the pathophysiology of the D2R-indirect pathway, we induced a D2R-MSNs-specific knockdown (KD) of GPRIN3 using small hairpin RNA and lentiviruses [ 151 , 154 ]. We first observed a significant increase in distal branching, the points of convergence between glutamate and dopamine synapses in MSNs [ 155 ] and also key targets of cocaine, which itself promotes increase in distal branching in the NAc of mice [ 156 , 157 , 158 , 159 ]. Thus, we tested the cocaine acute effect and locomotor sensitization and observed a decrease in cocaine-induced hyperlocomotion after inactivation of GPRIN3 using a CRISP/Cas9 approach. The significant increase in distal branching in GPRIN3 D2R-MSNs KD corroborates our hypothesis that the lack of GPRIN3 induces a ‘presensitization process’, able to change the targets of cocaine and therefore altering its effects [ 149 ]. Finally, we provide the first evidence that GPRIN3 partners with D2R in the striatum and modulates cocaine-induced behaviours [ 149 ].

Transcriptomic and epigenetic regulations

Epigenetics is a broad field and has multiple definitions that comprise several biochemical mechanisms (including DNA methylation and histone modifications) sustaining modifications in gene expression throughout the lifecycle of an organism without mutations of the DNA itself [ 160 , 161 , 162 ]. Epigenetics can be considered as the process through which environment (and normal development) interacts with an individual’s genome to determine all phenotypic traits, in health and disease. Stable modifications in gene expression are also said to be ‘epigenetic’, because they are heritable in the short term (through mitosis) [ 160 ] and in some cases trans-generationally, thus, providing a potential mechanism for environmental influences to be passed from parents to offspring [ 163 , 164 , 165 ]. Handel and Romagopalan [ 163 ] mentioned that “epigenetics allows the peaceful co-existence of Darwinian and Lamarckian evolution”. Such trans-generational epigenetic inheritance of drug addiction vulnerability remains debatable [ 161 ], but has been increasingly studied for the last 20 years [ 166 , 167 ]. Some epigenetic changes are very stable, an thus mediate both drug addiction susceptibility and drug-induced brain alterations that underlie the development of drug addiction [ 161 ].

As the NAc is seen as the central hub of drug addiction, with the notion that chronic drug use induces long-lasting structural, electrophysiological and transcriptional changes in the NAc, researchers are mostly targeting epigenetic modifications in NAc cells. Still, considering initial reports of cocaine-induced epigenetic modifications [ 168 , 169 ], it might be relevant to study further epigenetic changes in other regions such as glutamatergic inputs to the NAc, and further in the VTA, as they are implicated in the physiopathology of drug addiction [ 170 , 171 ] as mentioned above.

To date, the three main epigenetic mechanisms consist of (1) DNA methylation, (2) action of the non-coding RNAs and (3) histone post-translational modifications (PTMs). As an illustrative example, we will focus here only on histone PTMs. PTMs of histone residues on their N-terminal tails, that protrude from the nucleosome core, control chromatin condensation and the switch between euchromatin and heterochromatin and thus DNA-accessibility and gene expressions. PTMs include acetylation, methylation, phosphorylation, ADP ribosylation, ubiquitylation and sumoylation, among a growing list of newly discovered modifications [ 162 , 172 ].

Among these PTMs, the most studied is the acetylation of H3 and H4, that is increased in the NAc after chronic exposure to drugs of abuse [ 150 , 173 , 174 ]. This increase in global acetylation levels is the result of drug-induced alterations in the balance of histone acetyltransferase and histone deacetylase (HDAC) function and is associated with gene activation. CREB-binding protein, a histone acetyltransferase critical to memory processes [ 175 ], is required for cocaine-induced increases in histone acetylation in the NAc [ 176 ].

Fifteen years ago, Tsankova et al. [ 177 ] showed that imipramine, a monoamine reuptake inhibitor used for decades to treat depression, was effective through histone remodelling in depression and highlight the therapeutic potential for chromatin regulation with histone methylation and deacetylation inhibitors in depression. Nevertheless, like with synaptic plasticity (see above), discovering a drug that would interfere with epigenetic mechanisms and thus decrease drugs of abuse effect faces temporal aspects issues [ 173 , 176 , 178 , 179 , 180 , 181 , 182 ]. Indeed, timing has a strong impact considering conflicting results obtained after experimental manipulations of histone acetylation. An acute administration of HDAC inhibitors systemically or directly into the NAc, promotes behavioural responses to the drugs. However, prolonged administration decreases cocaine behavioural effects. In 2013, adding a new layer of complexity, Kennedy et al. provided comprehension to this time-dependent regulation [ 183 ]. Remarkably, they showed that prolonged intraNAc administration (but not acute administration) of a HDAC inhibitor attenuated cocaine behavioural effects by inducing a form of repressive histone methylation. This study showed, for the first time, cross-talk among different types of histone modifications [ 183 ]. Besides cross-talk between different epigenetic modifications, multiple modifications work in parallel and there is often a decoupling between an observed modification at a specific locus and its final transcription [ 161 ]. Decoding these chromatin marks will be a future challenging field. Like with HDAC inhibitors, there are promising findings based on the use of DNA methyltransferases inhibitor [ 184 , 185 ] (Fig. 3 ). Though, the main issue with these new potential treatments for drug addiction is their lack of specificity. One of the key challenge for the pharmaceutical industry will be to generate small molecules with more specific targets [ 6 ].

While histone acetylation and methylation are increasingly studied, an important field of future investigation will be to understand the other drug-induced histone PTMs. It already seems that chronic cocaine alters levels of histone phosphorylation [ 174 , 186 , 187 ], and poly-ADP ribosylation [ 188 ]. Recently, an unexpected role for the intracellular dopamine in VTA has been revealed, showing that DA interacts with chromatin to initiate a new form of epigenetic regulation called dopaminylation [ 189 ] (see Table 1 for a summary of cocaine-related epigenetic modifications).

Further studies showed that histone PTMs that occur in the NAc after chronic drug administration are locus specific [ 150 , 190 , 191 ]. Even though, drugs of abuse alter global levels of multiple histone PTMs, such as increased histone acetylation or decreased methylation in the NAc, genome-wide studies have confirmed that a greater number of genomic sites show increased acetylation [ 150 ] or decreased methylation [ 190 , 191 ]. Conversely, hundreds of genes show opposite or no changes in these same PTMs after drug exposure. What defines whether, and in which direction, a specific gene is modified in the context of a global histone PTM is an intriguing and unsolved question [ 161 ]. These genome-wide studies (ChIp on chip or ChIpSeq) are nowadays fundamental to understand where PTMs and other epigenetic modifications are deposited. This will be fundamental to guide new therapeutics.

Actually, with new tools such as zinc finger proteins (ZFPs) DNA-binding domains and, more recently, RNA-guided CRISPR/dCas9 (drastically easier to design) [ 192 , 193 ], it is now possible to control epigenetic modifications at a single gene in a specific type of cell in a specific brain region [ 162 ]. Heller et al. demonstrated that gene-targeted epigenetic editing (targeted to the Fosb [ 194 ] and Cdk5 [ 195 ] locus with ZFP technology) can alter drug-related behaviours [ 194 , 195 ]. This represents crucial evidence that gene-specific changes to the epigenome are not simply correlated, but rather causal, in regulating transcriptional responses to drugs of abuse administrations. These new results of “causal epigenomics” are very encouraging as they open the way to precise translational therapeutic approaches for drug addiction and other CNS diseases.

Linking epigenetics and synaptic plasticity

Today, most studies investigate synaptic plasticity and epigenetic as two distinct fields and it is not clear how these research topics are connected to each other. Understanding how epigenetics is connected to synaptic plasticity is an emerging research issue [ 6 ].

Of course, bridging epigenetic mechanisms with synaptic plasticity is not limited to drug addiction field. For example, in 2011, Monsey et al. [ 196 ] elegantly demonstrated that DNA methylation and histone H3 acetylation regulate auditory fear conditioning and its related synaptic plasticity in the amygdala. In 2014, Massart et al. [ 197 ] suggested that sleep deprivation induces epigenetic modification (alteration in DNA methylation and hydroxymethylation) that triggers synaptic plasticity modifications by changing expression of plasticity related genes.

Regarding drug addiction, some epigenetic marks seem fundamental and upstream as illustrated by HDAC inhibitors effect on drug-induced synaptic and behavioural modifications [ 178 , 198 , 199 , 200 ]. Additionally, Maze et al. [ 201 ] demonstrated morphological plasticity induced by cocaine through the histone methyltransferase G9a. Again advocating for causal epigenetic, Authement et al. [ 66 ] demonstrated that HDAC inhibition locally in the VTA is sufficient to reverse epigenetic modifications and synaptic plasticity changes after morphine administration.

Two transcription factors implicated in addiction exemplify this bridging attempt: CREB and ∆FosB (a truncated form of the FosB gene) are both activated by several drugs of abuse [ 202 ]. CREB activation occurs in both subtypes of NAc MSNs (D1R and D2R), while ∆FosB activation is limited to D1R MSNs in response to all drugs of abuse except for opioids, which remarkably induce the protein in both MSNs [ 203 ]. Expression of active CREB in NAc MSNs increases their excitability [ 204 ] and underlies drug-induced long-term synaptic plasticity and associated changes in dendritic spine plasticity [ 205 ]. ∆FosB is also linked to synaptic plasticity but evokes contrasting effects on the two MSN subtypes, with increased AMPA receptor function induced in D1R MSNs and decreased AMPA receptor function induced in D2R MSNs [ 206 ]. Renthal et al. [ 150 ] unravelled CREB and ∆FosB target genes and observed that these genes are mainly involved in neuronal excitability and synaptic function. Moreover, as already briefly discussed above, CREB and ∆FosB action have also been related to multiple epigenetic regulations, including histone acetylation and methylation [ 150 ]. Besides, a novel mechanism for bridging the gap between epigenetic control of transcription and synapse plasticity might be seen in microRNAs [ 207 ]. The most studied miRNA in the context of synaptic plasticity is miR-132 and is known to be CREB-dependent [ 208 ]. In the striatum, miR-212 targets the epigenetic regulator methyl CpG binding protein 2 (MeCP2). MeCP2 acts as a transcriptional repressor through recruitment of histone deacetylases to methylated DNA segments [ 209 , 210 ].

Clinical treatments for drug addiction

Besides psychosocial interventions [ 211 ] such as cognitive behavioural therapy, the most widely used treatment for drug addiction involves agonist-like medication, a solution inadequately called replacement or substitution therapy [ 212 ]. This type of treatment has been successfully implemented in the daily practice for opioid use disorder (e.g.: methadone, buprenorphine) [ 213 ] and tobacco use disorder (e.g.: nicotine patch or gum, varenicline) [ 214 ]. Currently, this agonist-like treatment is also promising for psychostimulant use disorder [ 215 ]. Still, considering the addictive drug-like effect, the risk of abuse, misuse and diversion, replacement therapy should be prescribed with caution [ 215 , 216 ].

Recently, a randomised and control study on a cocaine vaccine failed to show an effectiveness but instead raised an important issue: immunised subjects may have increased their cocaine use to overcome the competitive anti-cocaine antibody inhibition [ 217 ]. Even though significant improvements have been developed for immunopharmacotherapies for psychostimulant addiction over the last decade, very few candidates have been evaluated so far in clinical trials [ 218 ]. These considerations are some of the reasons why other treatments for drug addiction should emerge with the help of neurobiological research [ 219 ].

Following successful subthalamic nucleus DBS for Parkinson’s disease [ 220 , 221 , 222 ], DBS was investigated for diverse psychiatric diseases including depression [ 223 ], obsessive-compulsive disorder [ 224 ] and Tourette syndrome [ 225 ]. Today, indications for DBS are enlarging, with several positive case reports and small cases series that studied NAc DBS for drug addiction. The first studies showing potential positive effects on drug addiction were reports on application of NAc DBS primarily intended for other medication-refractory neuropsychiatric disorder where a comorbid drug addiction was unexpectedly resolved [ 226 , 227 ]. For DBS treatment in drug addiction, it seems that clinical empirical results led to further bench investigations and refinement [ 88 , 103 , 228 , 229 , 230 , 231 ], or at least, clinical and animal studies evolved in parallel with poor connectivity between the two.

Afterwards, many case reports and small cases series studied NAc DBS being used primarily for drug addiction, all showing encouraging decreases in drug use [ 232 , 233 , 234 , 235 , 236 , 237 ]. However, these studies are limited by their descriptive nature, inconstant follow-up, multiple publication bias, small patient numbers and lack of blinded stimulation and standardised outcome measures. At this stage, additional preclinical and clinical research are needed to clarify the role of DBS in the treatment of drug addiction [ 237 ]. Currently, randomised and control clinical studies are conducted (NCT01245075).

In a recent review, Sanna et al. [ 238 ] highlighted how repetitive transcranial magnetic stimulation (rTMS) confirms the hypodopaminergic hypothesis of drug addiction. While enhancing dopaminergic function through direct or indirect pharmacological approaches does not significantly alleviate symptoms, in numerous studies, and has not yielded a single FDA-approved medication [ 239 ], rTMS might indirectly modulate the dopaminergic system. Many rTMS studies stimulate the dorsolateral PFC [ 240 , 241 ] that projects to the VTA and thus induces an increase in dopamine release in the synaptic cleft in the NAc [ 55 , 242 , 243 ]. Nevertheless, considering the heterogeneity of methods used in rTMS studies during the last 10 years [ 238 ], protocols and guidelines, were recently suggested by an international network of experts in neuromodulation and addiction to improve homogeneity of studies [ 244 ]. From this report, it is clear that multiple technical details for optimal stimulation need further investigations that might be achieved through preclinical studies. For example, low frequency (but not high-frequency) rTMS before methamphetamine exposure in rats blocked drug-induced conditioned place preference [ 245 ]. Being non-invasive, with insignificant side effects, rTMS could be seen as a great opportunity for drug addiction treatment. We are currently waiting for the results of a randomised and control study that aims at determine if, in heavy alcohol users, a single session of TMS can lower a patient’s craving and brain response to alcohol cues (NCT02939313).

Interesting views of clinical treatments for drug addiction are discussed in some other reviews [ 212 , 215 , 216 , 219 ]. The clinical impact of new treatments also depends on their translation into clinical practice which is mainly promoted by the pharmaceutical industry [ 219 ]. Indeed, even when an effective treatment is identified through basic research, it is commonly challenging to translate it to clinical practice, as illustrated by naltrexone as a treatment of alcoholism [ 219 ]. Another example of problematic translation to clinic is illustrated by modafinil, a treatment that has been reported to attenuate cocaine euphoria but for which larger clinical randomised and controlled studies showed controversial results [ 246 , 247 ].

Future directions

Drug addiction is a brain disease strongly influenced by environment and psychosocial aspects. The psychosocial conditions in which it has developed are extremely important. Exposure to conditioned cues can be a central issue in causing drug cravings and relapses, even after successful treatment, and thus they have to be minimised [ 2 , 74 , 77 ]. The pathophysiological aspects are particularly unsteady. For instance, as discussed in this review and in other ones [ 73 , 248 ], synaptic plasticity is dynamically altered after psychostimulant administration, so that a treatment could have opposite effects depending on timing aspects of the administration protocol. In addition, a prolonged treatment may involve compensatory mechanisms, giving unexpected results (e.g.: when HDAC inhibitors and psychostimulants are both administered acutely, they have synergistic effects through hyperacetylation and thus transcriptional activation of psychostimulant-regulated target genes. Conversely, when a drug of abuse is given in the context of chronic HDAC inhibitor, compensatory mechanisms may promote acetylated histone to the promoters of genes responsible for inducing histone methylation and thus chromatin condensation and gene repression, all of which, in turn, gave opposite effect [ 183 ]). Thus, the evolution through the different stages of the disease has to be taken into account [ 249 ] and treatment must follow them. These two aspects have to be incorporated in a holistic treatment strategy. Besides, studying combination of different cutting-edge approaches, with animal models of addiction, such as targeted rTMS or DBS with more systemic epigenetic modulation might show a better restoration of altered synaptic transmission and decrease the probability of relapse in drug addiction. Basically, drug addiction is a disease that seems to be difficult to treat preventively but it is more conceivable to help patients that would be in an abstinence stage not to experience relapse of their disease. As addiction is chronic and relapsing, a good treatment outcome is a significant reduction of drug administration and long periods of withdrawal, with only sporadic relapses [ 2 ].

It is clear that the main issues for optimal therapeutic management of this specific psychiatric disease belong to its dynamic complexity, diverse temporal evolution and undeniably psychosocial aspects. In this review, we focused mostly on the effects of drugs of abuse on synaptic plasticity and epigenetic modifications. Nowadays, these two subfields are mostly studied separately and the understanding of how these two main addictive drug-induced brain modifications interact might be fundamental for addiction research [ 6 ]. Indeed, argument for clinical trials for new treatments emerge from fundamental behavioural studies that should be implemented in a global approach to the addicted patient.

Conclusions

Here, we highlight, from a vast fundamental literature (mainly based on rodent models), promising therapeutics that would potentially treat drug addiction. Based on effect, on synaptic plasticity and epigenetic mechanisms, treatments such as GluA2-lacking AMPAR antagonists [ 72 , 84 ], mGluR1 positive allosteric modulator [ 85 ], NAc 12Hz-DBS [ 103 ] (in line with other promising neuromodulation therapeutics such as rTMS or transcranial direct current stimulation [ 250 ]), N-acetylcysteine [ 108 ], HDAC inhibitors [ 183 ] or even (in very early stages of investigation) CRISPR/dCas9 epigenetic editing [ 194 , 195 ] could be potential candidates for human randomised clinical trials (Fig. 3 ).

Finally, it is fundamental to consider the specific clinical aspects of the disease that would help to develop a personalised-treatment strategy. Indeed, after going from the bench to the bedside it will also be essential to assess the reversed route.

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Acknowledgements

We thank Michele Zoli, Romain Icick and Daniel Rial for helpful comments and corrections on the manuscript. Julian Cheron is supported by a fellowship of the FRS-FNRS (Belgium). Alban de Kerchove d´Exaerde is a Research Director of the FRS-FNRS. FRS-FNRS (Belgium). Fondation Simone et Pierre Clerdent, Fondation ULB, supported this study.

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Cheron, J., Kerchove d’Exaerde, A.d. Drug addiction: from bench to bedside. Transl Psychiatry 11 , 424 (2021). https://doi.org/10.1038/s41398-021-01542-0

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Psychopharmacology (2022)

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Drug Addiction: Current Trends and Management

• November 2017
• International Journal of Indian Psychology 5(1):2348-5396
• 5(1):2348-5396

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Drug Addiction

From Basic Research to Therapy

• © 2008
• Rao S. Rapaka 0 ,
• Wolfgang Sadée 1

National Institute on Drug Abuse, Bethesda, USA

You can also search for this editor in PubMed   Google Scholar

College of Medicine and Public Health, Ohio State University, Columbus, USA

Provides a comprehensive overview of physiological, biochemical, and genetic pathways underlying drug addiction, and resultant efforts to develop novel treatment strategies dealing with drug addiction and other CNS disorders where the neurophysiological processes overlap, such as treatment of pain

Focuses on the translation of fundamental addiction research to a variety of treatments, bringing together scientists with widely ranging expertise in synthetic and computational chemistry, molecular biology, genetics, and neuroscience with researchers in drug discovery and development, drug targeting, and quantitative therapeutics

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Drug addiction: from bench to bedside

Drug addiction: a curable mental disorder?

• Cannabinoid
• amphetamine
• drugs of abuse

Table of contents (44 chapters)

Front matter, general topics, darpp-32 mediates the actions of multiple drugs of abuse.

• Per Svenningsson, Angus C. Nairn, Paul Greengard

Drug Discovery From Natural Sources

• Young-Won Chin, Marcy J. Balunas, Hee Byung Chai, A. Douglas Kinghorn

Computational Methods in Drug Design: Modeling G Protein-Coupled Receptor Monomers, Dimers, and Oligomers

• Patricia H. Reggio

Symbiotic Relationship of Pharmacogenetics and Drugs of Abuse

• Joni L. Rutter

Monoclonal Antibody Form and Function: Manufacturing the Right Antibodies for Treating Drug Abuse

• Eric Peterson, S. Michael Owens, Ralph L. Henry

Cocaine- and Amphetamine-Regulated Transcript Peptides Play a Role in Drug Abuse and Are Potential Therapeutic Targets

• Michael J. Kuhar, Jason N. Jaworski, George W. Hubert, Kelly B. Philpot, Geraldina Dominguez

RNAi-Directed Inhibition of DC-SIGN by Dendritic Cells: Prospects for HIV-1 Therapy

• Madhavan P. N. Nair, Jessica L. Reynolds, Supriya D. Mahajan, Stanley A. Schwartz, Ravikumar Aalinkeel, B. Bindukumar et al.

Viewing Chemokines as a Third Major System of Communication in the Brain

• Martin W. Adler, Ellen B. Geller, Xiaohong Chen, Thomas J. Rogers

Targeting the PDZ Domains of Molecular Scaffolds of Transmembrane Ion Channels

• Andrea Piserchio, Mark Spaller, Dale F. Mierke

Neuronal Nicotinic Acetylcholine Receptor Expression and Function on Nonneuronal Cells

• Lorise C. Gahring, Scott W. Rogers

Transporters & Stimulants & Hallucinogens

Role of monoamine transporters in mediating psychostimulant effects.

• Evan L. Riddle, Annette E. Fleckenstein, Glen R. Hanson

Development of the Dopamine Transporter Selective RTI-336 as a Pharmacotherapy for Cocaine Abuse

• F. Ivy Carroll, James L. Howard, Leonard L. Howell, Barbara S. Fox, Michael J. Kuhar

Serotonin Transporters: Implications for Antidepressant Drug Development

• Kellie J. White, Crystal C. Walline, Eric L. Barker

Recent Advances for the Treatment of Cocaine Abuse: Central Nervous System Immunopharmacotherapy

• Tobin J. Dickerson, Kim D. Janda

κ Opioids as Potential Treatments for Stimulant Dependence

• Thomas E. Prisinzano, Kevin Tidgewell, Wayne W. Harding

Regulation of Monoamine Transporters: Influence of Psychostimulants and Therapeutic Antidepressants

• Lankupalle D. Jayanthi, Sammanda Ramamoorthy

Hallucinogen Actions on 5-HT Receptors Reveal Distinct Mechanisms of Activation and Signaling by G Protein-Coupled Receptors

• Harel Weinstein

Recognition of Psychostimulants, Antidepressants, and Other Inhibitors of Synaptic Neurotransmitter Uptake by the Plasma Membrane Monoamine Transporters

• Christopher K. Surratt, Okechukwu T. Ukairo, Suneetha Ramanujapuram

Dual Dopamine/Serotonin Releasers as Potential Medications for Stimulant and Alcohol Addictions

• Richard B. Rothman, Bruce E. Blough, Michael H. Baumann

Editors and Affiliations

Rao S. Rapaka

Wolfgang Sadée

Bibliographic Information

Book Title : Drug Addiction

Book Subtitle : From Basic Research to Therapy

Editors : Rao S. Rapaka, Wolfgang Sadée

DOI : https://doi.org/10.1007/978-0-387-76678-2

Publisher : Springer New York, NY

eBook Packages : Biomedical and Life Sciences , Biomedical and Life Sciences (R0)

Copyright Information : Springer-Verlag New York 2008

Hardcover ISBN : 978-0-387-76677-5 Published: 07 July 2008

Softcover ISBN : 978-1-4419-2632-6 Published: 25 November 2010

eBook ISBN : 978-0-387-76678-2 Published: 19 June 2008

Edition Number : 1

Number of Pages : XXIII, 782

Number of Illustrations : 196 b/w illustrations, 1 illustrations in colour

Topics : Pharmacology/Toxicology

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108 Drug Abuse Essay Topic Ideas & Examples

🏆 best drug abuse topic ideas & essay examples, 👍 good essay topics on drug abuse, 💡 most interesting drug abuse topics to write about, ❓ drug abuse research questions.

Drug abuse essays are an excellent way to learn about the issue and its influence on various groups and populations while demonstrating your understanding.

Various substances, including alcohol, narcotics, and other mind-altering products, are a popular method for recreation in some communities.

However, they are prone to result in addiction, psychological as well as mental, and lead the person to pursue another dose before anything else.

In doing so, he or she can eventually ruin his or her life, which is why most drugs are currently banned around the world. This article will offer you some tips that will help you write an excellent essay and receive the top grade.

Youth is a major demographic that is affected by addiction issues due to drug consumption. Young people are impressionable and prone to search for new sensations. Drugs can offer a sense of novelty and provide an experience they have not had before, leading to considerable appeal.

Considering that young people are generally not wealthy and have to focus on work to succeed in life, essays on drug among youth can use a variety of excellent topics. You can offer your ideas on the reason for the phenomenon’s existence and ways in which it can be prevented.

However, remember that the purpose of the programs should be to help the people who are at risk.

There are many other drug abuse essay topics that you can explore, with poverty being a prominent example. Despite their conditions, many people turn to substance abuse to try and escape the unpleasant aspects of their life.

These population segments are more likely to suffer after acquiring a drug habit than young people because they generally receive less attention.

Furthermore, poor neighborhoods with relatively low amounts of surveillance by law enforcement are likely to house drug dealers who prey on vulnerable people.

You can discuss this topic or discuss a variety of other ones, as the relationship between poverty and poor outcomes has been researched deeply.

Here are some additional tips for your essay:

• Try to use examples to illustrate your points about various aspects of the issue. Drug addiction essay quotations from people who are affected by the condition or have overcome it can offer valuable insights. They also legitimize your findings by providing parallels with the real world.
• Alcohol essays are an excellent choice, as the substance is legal and available to everyone without much difficulty. Nevertheless, its effects can be devastating, especially if a person’s consumption is chronic.
• Try to write a drug abuse essay outline before starting work, as it will help you to organize the essay. Select some prominent ideas that you want to discuss and organize them in a manner that represents a logical progression. You do not have to discard all of the other concepts, as you can make them sub-headings under your main titles.
• Be sure to include a drug abuse essay introduction and conclusion in your work. They will help you provide a structure to the essay and make it easier for the reader to understand your ideas. The introduction should describe the topic and provide the thesis, and the conclusion should restate your main points.

Visit IvyPanda for drug abuse essay titles, and other useful samples on various subjects to help you with your writing work!

• Drug Trafficking and Drug Abuse Drug trafficking contributes to drug abuse in the society. Drug trafficking also contributes to increased criminal activities that affect the security of citizens.
• Drug and Alcohol Abuse For along time now, drug and alcohol abuse in the society has been a problem that affects the youth and the society at large. This paper highlights the problems of drug abuse and alcohol drinking […]
• Drug Abuse and Current Generation Drug abuse also breeds an array of behavioral problems among young people, which may affect their suitability to fit in the society.
• Drug Abuse & Its Effects on Families Focusing on the family seems to be by far, the most known and effective way of finding a solution with regards to the “war on drugs” since it more promising to end the vicious cycle […]
• Social Media Impact on Drug Abuse Thus, social media platforms definitely contribute to the misuse of various drugs by romanticizing their consumption and making “social drug use” acceptable among users.
• Drug and Substance Abuse Many experts consider addiction as a disease as it affects a specific part of the brain; the limbic system commonly referred to as the pleasure center.
• Consequences of Drug Abuse The endless stream of drugs, obtainable to the individuals with little or no restrictions, poses a serious inquiry. When assessing the advantages of using pharmaceutical drugs, it is essential to consider the severity of health […]
• Merton’s Argument of Deviance: The Case of Drug Abuse The most prominent example in support of Merton’s argument in relation to drug abuse is that cultural and social circumstances play a crucial role in defining people’s desire to engage in drug use.
• Prevention Research: The Fight Against Drug Abuse It is agreeable that US’s ‘War on Drugs’ has been an effective substance abuse prevention plan despite the hiccups that the program faces and its inability to attain some of its designated mandates within the […]
• Reasons Behind Youth’s Engagement to Drug Abuse in the 21st Century Although youths in the 21st century engage in drug abuse due to several factors, it suffices to declare factors such as the rising unemployment status, peer pressure, and their hiked tendency to copy their parents’ […]
• Drug Abuse. “Nine Years Under” Book by Sheri Booker The book is thought provoking and important because it allows representing the difficult social situation and the problems of gang violence and drugs in the United States from the personal point of view.
• “Cocaine: Abuse and Addiction” by National Institute on Drug Abuse The literature provides us with a report of a research that has been conducted in the US regarding the topic of cocaine and drug abuse.
• Substance Abuse: Prevention Strategies and National Benchmarks Still, this desire to get away from problems by means of substances instead of making effort to improve an individual’s environment contributed to the evolution of the challenge of substance abuse into a real public […]
• Youth Drug Abuse Among, Education, and Policies Although drug abuse encompasses improper use of drugs disregarding the prescriptions of medical practitioners, the principal challenges of drug abuse occasion from abuse of drugs such as cocaine, heroin, and marijuana.
• Drug Abuse Among the Youth Essentially, this case study will allow the evaluation of the prevailing cases of drug abuse among the youth. In this regard, the pain and peer pleasure cannot be persevered to allow an explicit cure of […]
• Drug Abuse, Aggression and Antisocial Behavior The use of abusive drugs can cause anger in people because of the effect they have on the brain. An example of how alcohol can cause aggression in a person is that it impairs an […]
• Prevention Programs: Drug Abuse Resistance Education This program focuses on handling peer pressure among youths, a crucial cause of drug abuse in the country. The program is also grounded on sound research, which offers the critical elements vital to handling the […]
• Drug Abuse Effects on Health and Nervous System These numerous damages severely affect the quality of the brains work and the health of the nervous system. While discussing the effects of drug addiction, it is essential to notice that it has a devastating […]
• Drug Abuse and Prevention Strategies When specialists deal with preventative factors, they pay attention to both mental and physical ways to resist the drug. The symbiosis of these procedures is exceptionally efficient in terms of the drug rehabilitation process when […]
• Drug Abuse in Adolescents and Its Causes Scientific research shows that the development factors for adolescent drug abuse are not limited to a set of three to five causes, but are usually linked to the integration of destructive environmental conditions.
• Drug Abuse and Its Psychological Effects The purpose of this paper is to explore in more depth the psychological effects of addiction on the family and inner circle of the addict.
• Policies for Pregnant Women With Drug Abuse Thus, out of all the offered policies, financial support for therapy is the best one, as it motivates prevention and treatment, which, in turn, causes the improvement of this situation.
• The Formative Evaluation: Program of Addressing Drug Abuse in Schools The proposed program sought to educate students about the challenges of drug abuse, its impacts on academic performance, and the best techniques to avoid the vice.
• Alcohol and Drug Abuse in Canada Therefore, it contributes as a central factor in the essence of the character, and it is crucial to understand the core definition and the elements that foster the ideology.
• Mitigating Drug Abuse in Pine View School The inclusion of professionals in the fields of health care, counseling, and drugs is expected to promote the delivery of desirable results.
• Drug Abuse and Its Negative Effects This paper aims to highlight what the field of psychology says about the negative effects of drugs and why people continue using despite the consequences. The main effect is that it creates a memory of […]
• Drug Abuse in Lake County, California The topic of drug abuse is essential for discussion due to the need to develop strategies to prevent and minimize the dangerous consequences of drug abuse in different regions.
• Drug Abuse Among Homeless Young Adults in New Jersey The reason why young adults in New Jersey get involved in drugs and alcohol after becoming homeless is to manage their situations in an attempt to attain the tentative pleasure of life despite their problems. […]
• Community Intervention Practices against Drug Abuse The key features that result in successful community-based intervention on drug abuse are integrated for effectiveness and efficiency. On the other hand, drug abuse refers to the consumption of substances that elicit particular feelings and […]
• Teenage Drug Abuse in the United States The problem of teenage drug abuse inflicts a threat to the future society and health state of the overall population in the United States.
• Alcoholism, Domestic Violence and Drug Abuse Kaur and Ajinkya researched to investigate the “psychological impact of adult alcoholism on spouses and children”. The work of Kaur and Ajinkya, reveals a link between chronic alcoholism and emotional problems on the spouse and […]
• Monitoring the Future: National Survey Results on Drug Use National survey results on drug use obtained by Monitoring the Future have a significant value to the development of various approaches with regard to the prevention of drug abuse.
• The Health Issues Associated With Drug Abuse It is therefore imperative to develop strategies for health promotion to reduce the number of teenagers, the most at-risk family member when it comes to drug abuse.
• Fentanyl – Drug Profile and Specific and Drug Abuse The drug has the effect of depressing the respiratory center, constricting the pupils, as well as depressing the cough reflex. The remainder 75% of fentanyl is swallowed and absorbed in G-tract.
• Cases of Drug Abuse Amongst Nursing Professionals It is noteworthy that at the top of the information, the date posted is Monday, February 14, 2011, yet against the information, the date is February 11, 2011.
• The Treatment of Drug Abuse Any medical practitioner treating a drug abuse patient has to be careful in many aspects, like: He has to be careful on the issue that if the addiction has effected the brain of the patient.
• Drug Courts and Detoxification: Approach to Drug Abuse Treatment However, since 1989, the US federal system has been providing the majority of drug abusers with proper treatment or education with the help of a drug court option.
• Drug Abuse in Adolescents Aged 15-19 Years Old: A Public Health Menace In addition, the objectives of the paper are as follows: the first aim is to analyze the collected data and produce a review of the information.
• Drug Abuse and Addiction Holimon has succeeded in reviving some of her family relations, and she is still putting a lot of effort to get ahead in this area to the fullest extent possible.
• Sports as a Solution to Youth Substance Abuse: Dr. Collingwood’s View His comments made me realize that it would be unwise by the end of the day for any parent to leave their children under the mercy of the media where they learned that doing drugs […]
• Drug Abuse in High School and College With respect to social work and the problem of substance abuse, research has been carried out in terms of investigating the relationship between drug abuse and poverty, the effects of drug abuse on the society.
• Critical Issues in Education: Drug Abuse and Alcoholism For this case, the ministry concerned has a very hard task of ensuring there are no critical issues that are left unsolved that relate to education, failure to which will affect the performance of students […]
• Biopsychosocial Experience in Drug Abuse Treatment There has to be a preventive strategy in every intervention procedure to avoid the occurrence of a disease. I find the course of treatment in this intervention beneficial for the creation of the needed preventive […]
• Addictive Behavior Programs and Drug Abuse Trends The involvement of stakeholders is an essential condition for the effectiveness of this model of work and its results, and all the roles should be allocated in accordance with the capabilities of the program’s participants.
• Substance Misuse in American Youth: A Socio-Cultural Analysis The paper analyzes studies regarding some of the most widespread types of substances, as well as discusses the role of the rap culture in the growing number of young addicts in the U.S.
• Social Behaviour as a Science: Drug Abuse in Youth Thus, the application of social psychology to the phenomenon of youth drug abuse helps to explain how social factors impact the prevalence of and risk for drug abuse.
• ACTIQ Prescription Drug Abuse The fast-acting characteristic of ACTIQ is a result of being absorbed in the mucosal lining of the mouth. ACTIQ is a synthetic drug that is available as lozenges/lollipops, which are designed to be sucked in […]
• Prescription Drug Abuse and Lebanon Students The first two authors are the representatives of the Department of Epidemiology and Population Health at the American University of Beirut, and Martins is from the Department of Mental Health, the John Hopkins University.
• Financial Planning for Drug Abuse Prevention in Virginia Estates Therefore, the first preferred sources for the program are the County Commission and the Alabama Department of Corrections. The program can be financed by the Montgomery County Commission in the short term and Alabama Department […]
• Addressing the Drug Abuse in Parolees and Probationers The aim of the program is to address the drug abuse in parolees and probationers during their probations and decrease the use of drugs in them.
• Problem of Drug Abuse in Schools The research worked on the hypothesis that the treatment would reduce or result in the total cessation of drug use, and better relations with family and friends.
• Prescription Drug Abuse in the United States The combination of Ibuprofen and acetaminophen are effective for the patients, who want to reduce and control the level of pain.
• Impact of Drug Abuse on Adolescent Development Therefore, it is important for counselors to consider these stages to help them address the issue of substance abuse among adolescents. In the habitual stage, most adolescents take drugs to help them modify their moods.
• Drug Abuse: Age, Gender and Addictive Susceptibility This incorporates the aspects of gender where males and females possess varying biological constitutions that might affect the prescribed treatments in the realms of addiction. It is important to consider the rapidity and susceptibility of […]
• Drug Abuse Prevention Programs Additionally, it is possible to prospect the success of the program in case the required readiness from the community can be unveiled prior to the program execution.
• The Cultural Context and Ethics of Prevention of Drug Abuse The first prevention strategy outlined in the document is the involvement of young people in all levels of the prevention program establishment. Concurrently, it is crucial to relate this technique with the subject of culture […]
• Use of Psychotropic Medications in the Treatment of Drug Abuse This is because the mental illness is, literally, the one that sustains the abuse of drugs and thus after it is healed; the patient will have no reason to continue abusing the drugs.
• Drug Abuse: Awareness Amongst the Youths This project is going to carry out a public awareness campaign with the aim of educating the young people on the hazards related to the vice of drug and substance abuse. The awareness campaign is […]
• A New Alcohol and Drug-Abuse Rehabilitation Center in Liverpool Hospital, Sydney The hospital, in response to this distress, has decided to bring help closer to the people of Liverpool by the construction of the annex facility.
• Spirituality Effect on Drug Abuse Treatment Programs The hypothesis of the study was that spirituality is appropriate in the formal treatment of addiction; the study confirmed this hypothesis.
• Drug Abuse and Religious Spirituality Concept Particularly, this high rate of relapses was determined by Olmstead et al.as a direct result of a degree of failure on the part of drug abuse treatment programs to sufficiently address the primary reason why […]
• The Extent of Drug Abuse Among People in America Toronto Mayor Rob Ford Said He Lied about Crack Cocaine Use Because He Was Embarrassed Mayor lied about the use of crack cocaine The article titled “Toronto Mayor Rob Ford said he lied about crack […]
• Drug Use and Abuse in America: Historical Analysis The new law was similar to the Boggs Act of 1951 in that it employed the same formula of using perceived increase in drug use in the country.
• Drug Abuse as an Ethical Issue On the side of duties and obligations, the societal norms stipulate that individuals should be caring to other members of the society especially the children and the old.
• Drug Abuse and Society Regardless of the many intervention measures that can be adopted to solve this problem of drug abuse, the most effective intervention measure is to create awareness to youths to enable them change their behaviors and […]
• Prescription Painkillers, the New Drug Abuse of Choice Studies attribute the recent increase in the misuse of prescription drugs to an increase in the use of the Internet, which facilitates the growth of illegitimate online drug stores and uncontrolled online prescription drug sales.
• Music Analysis: Drug Abuse in Music So in this song the artist is also lamenting the dangers of drugs and the theme of the music is one that advocates against tackling the problem with issues of drug abuse by arguing the […]
• Drug Abuse: Comprehensive Review The effects associated with drug abuse tend to vary depending on an individual’s age and the phase of drug abuse that the person is in.
• Drug Abuse as a Social Problem This poses as problem to the society because many of the people who are unemployed will resort to different ways of seeking money and pleasure.
• Adolescent’s Drug Abuse and Therapy Success When one accepts to put up with negative peer pressure, they end up giving up the personal trusts and values thus the pressure becomes a form of a negative force.”Does peer pressure affect the decision […]
• What Are Influences That Cause Drug Abuse on Youth?
• What Are Some Solutions to Drug Abuse?
• What Are the Primary Causes and Effects of Alcoholism and Drug Abuse Among Young People?
• What Causes Teenage Drug Abuse?
• What Does Drug Abuse Truly?
• Why Do Children Need to Be Educated About Drug Abuse?
• Why Has the American Government Not Managed to Stop Drug Abuse All These Years?
• How Does Drug Abuse Affect Personal Development of Hong Kong Teenagers?
• How Does Pericarditis Form Due to Drug Abuse?
• How Drug Abuse Ruins Families and Destroys Relationships?
• How Does Prescription Drug Abuse Affect Teens?
• Does the Drug Abuse Resistance Education Program Work?
• What Is the Drug of Abuse?
• What Are the Four Types of Drugs Abused?
• Which Is an Example of Drug Abuse?
• What Is the Leading Cause of Drug Abuse?
• What Are the Causes and Effects of Drug Abuse?
• What Are the Main Consequences of Drug Abuse?
• How Does Drug Abuse Affect Our Society?
• How Can We Prevent Drug Abuse?
• Why Is It Essential to Prevent Drugs?
• What Are the Ten Most Abused Drugs?
• How Do Drugs Affect Mental Health?
• What Are the Effects of Drug Abuse on Youths?
• What Is the Connection Between Adolescents From Divorced Families and Drug Abuse?
• Are Alcohol and Drug Abuse the Most Common Issues of Today?
• What Is Athletes’ Motivation for Performance-Enhancement Drug Abuse?
• What Is the Correlation Between Parietal and Adolescent Drug Abuse?
• How Is Dealing With Teenage Drug Abuse?
• What Is the Difference Between Drug Use and Drug Abuse?
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• Signs of Addiction

Addiction Research

Discover the latest in addiction research, from the neuroscience of substance use disorders to evidence-based treatment practices. reports, updates, case studies and white papers are available to you at hazelden betty ford’s butler center for research..

Why do people become addicted to alcohol and other drugs? How effective is addiction treatment? What makes certain substances so addictive? The Butler Center for Research at the Hazelden Betty Ford Foundation investigates these and other questions and publishes its scientific findings in a variety of alcohol and drug addiction research papers and reports. Research topics include:

• Evidence-based treatment practices
• Addiction treatment outcomes
• Addiction, psychiatry and the brain
• Addictive substances such as prescription opioids and heroin
• Substance abuse in youth/teens, older adults and other demographic groups such as health care or legal professionals

These research queries and findings are presented in the form of updates, white papers and case studies. In addition, the Butler Center for Research collaborates with the Recovery Advocacy team to study special-focus addiction research topics, summarized in monthly  Emerging Drug Trends  reports. Altogether, these studies provide the latest in addiction research for anyone interested in learning more about the neuroscience of addiction and how addiction affects individuals, families and society in general. The research also helps clinicians and health care professionals further understand, diagnose and treat drug and alcohol addiction. Learn more about each of the Butler Center's addiction research studies below.

Research Updates

Written by Butler Center for Research staff, our one-page, topic-specific summaries discuss current research on topics of interest within the drug abuse and addiction treatment field.

View our most recent updates, or view the archive at the bottom of the page.

Patient Outcomes Study Results at Hazelden Betty Ford

Trends and Patterns in Cannabis Use across Different Age Groups

Alcohol and Tobacco Harm Reduction Interventions

Harm Reduction: History and Context

Racial and Ethnic Health Disparities and Addiction

Psychedelics as Therapeutic Treatment

Sexual and Gender Minority Youth and SUDs

Health Care Professionals and Mental Health

Grief and Addiction

Helping Families Cope with Addiction

Emerging Drug Trends Report and National Surveys

Shedding New Light on America’s No. 1 Health Problem

In collaboration with the University of Maryland School of Public Health and with support from the Butler Center for Research, the Recovery Advocacy team routinely issues research reports on emerging drug trends in America. Recovery Advocacy also commissions national surveys on attitudes, behaviors and perspectives related to substance use. From binge drinking and excessive alcohol use on college campuses, to marijuana potency concerns in an age of legalized marijuana, deeper analysis and understanding of emerging drug trends allows for greater opportunities to educate, inform and prevent misuse and deaths.

Each drug trends report explores the topic at hand, documenting the prevalence of the problem, relevant demographics, prevention and treatment options available, as well as providing insight and perspectives from thought leaders throughout the Hazelden Betty Ford Foundation.

View the latest  Emerging Drug Trends  Report:

Pediatricians First Responders for Preventing Substance Use

• Clearing Away the Confusion: Marijuana Is Not a Public Health Solution to the Opioid Crisis
• Does Socioeconomic Advantage Lessen the Risk of Adolescent Substance Use?
• The Collegiate Recovery Movement Is Gaining Strength
• Considerations for Policymakers Regarding Involuntary Commitment for Substance Use Disorders
• Widening the Lens on the Opioid Crisis
• Concerns Rising Over High-Potency Marijuana Use
• Beyond Binging: “High-Intensity Drinking”

View the latest  National Surveys :

• College Administrators See Problems As More Students View Marijuana As Safe

College Parents See Serious Problems From Campus Alcohol Use

• Youth Opioid Study: Attitudes and Usage

About Recovery Advocacy

Our mission is to provide a trusted national voice on all issues related to addiction prevention, treatment and recovery, and to facilitate conversation among those in recovery, those still suffering and society at large. We are committed to smashing stigma, shaping public policy and educating people everywhere about the problems of addiction and the promise of recovery. Learn more about recovery advocacy and how you can make a difference.

Evidence-Based Treatment Series

To help get consumers and clinicians on the same page, the Butler Center for Research has created a series of informational summaries describing:

• Evidence-based addiction treatment modalities
• Distinctive levels of substance use disorder treatment
• Specialized drug and alcohol treatment programs

Each evidence-based treatment series summary includes:

• A definition of the therapeutic approach, level of care or specialized program
• A discussion of applicability, usage and practice
• A description of outcomes and efficacy
• Research citations and related resources for more information

View the latest in this series:

Motivational Interviewing

Cognitive Behavioral Therapy

Case Studies and White Papers

Written by Hazelden Betty Ford Foundation researchers and clinicians, case studies and white papers presented by the Butler Center for Research provide invaluable insight into clinical processes and complex issues related to addiction prevention, treatment and recovery. These in-depth reports examine and chronicle clinical activities, initiatives and developments as a means of informing practitioners and continually improving the quality and delivery of substance use disorder services and related resources and initiatives.

• What does it really mean to be providing medication-assisted treatment for opioid addiction?

Adolescent Motivational Interviewing

Peer Recovery Support: Walking the Path Together

Addiction and Violence During COVID-19

The Brain Disease Model of Addiction

Healthcare Professionals and Compassion Fatigue

Moving to Trauma-Responsive Care

Virtual Intensive Outpatient Outcomes: Preliminary Findings

Driving Under the Influence of Cannabis

Vaping and E-Cigarettes

Using Telehealth for Addiction Treatment

Grandparents Raising Grandchildren

Substance Use Disorders Among Military Populations

Co-Occurring Mental Health and Substance Use Disorders

Women and Alcohol

Prescription Rates of Opioid Analgesics in Medical Treatment Settings

Applications of Positive Psychology to Substance Use Disorder

Substance Use Disorders Among Legal Professionals

Factors Impacting Early Alcohol and Drug Use Among Youths

Animal-Assisted Therapy for Substance Use Disorders

Prevalence of Adolescent Substance Misuse

Problem Drinking Behaviors Among College Students

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Substance Use Factors Among LGBTQ individuals

Prescription Opioids and Dependence

Alcohol Abuse Among Law Enforcement Officers

Helping Families Cope with Substance Dependence

The Social Norms Approach to Student Substance Abuse Prevention

Drug Abuse, Dopamine and the Brain's Reward System

Women and Substance Abuse

Substance Use in the Workplace

Health Care Professionals: Addiction and Treatment

Cognitive Improvement and Alcohol Recovery

Drug Use, Misuse and Dependence Among Older Adults

Emerging Drug Trends

Does Socioeconomic Advantage Lessen the Risk of Adolescent Substance Use

The Collegiate Recovery Movement is Gaining Strength

Involuntary Commitment for Substance Use Disorders

Widening the Lens of the Opioid Crisis

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Drug abuse and addiction research at johns hopkins institute of basic biomedical sciences.

IBBS researchers are studying how chronic drug use causes lasting changes in the brain that can lead to addiction. Their findings may aid in the development of more effective treatments for addiction.

Current addiction treatments use a combination of counseling and complete abstinence, slow weaning, or drug replacement that either substitutes for the drug or blocks withdrawal symptoms. Although these therapies control physical cravings, they don’t seem to reverse the lasting changes in the brain caused by drug abuse, and therefore may only provide a temporary fix.

During learning and memory formation, the brain’s neurons create new connections to strengthen or weaken communication routes between neighboring neurons. Similarly, chronic drug use modifies neuron connections, leading to permanent alterations in the brain’s circuitry. Taking drugs creates memories of objects, places or people that users associate with doing drugs, which triggers cravings and drug-seeking behavior when the user re-encounters those situations. Several IBBS neuroscientists study these molecular changes as they occur during learning, memory and chronic drug use.

Jay Baraban of the Solomon H. Snyder Department of Neuroscience studies how exposure to drugs such as cocaine or morphine triggers long-term adaptations in the brain that underlie addiction. Persistent changes in the strength of nerve connections encode memory and drug cravings. These adaptations are mediated by rapid synthesis of plasticity proteins that modify the strength of nerve connections. Baraban and colleagues have identified a pair of proteins that play a key role in driving rapid synthesis of synaptic proteins that change the efficacy of neuronal contacts and encode long-term memory. These researchers have engineered mice that lack these proteins in selected neuronal populations and are using these valuable tools to learn more about how this novel signaling pathway contributes to drug addiction.

Paul Worley , also from the neuroscience department, studies the molecular basis of specific forms of long-term learning and memory. His laboratory focuses on a class of proteins found at the interface between connecting neurons—synapses—that ramp up as the neurons engage in information processing and storage. These proteins directly modify the strength of the signals sent between neurons and are essential for information storage. Recent work reveals how molecules that regulate neuronal responses that signal reward, such as dopamine, can selectively strengthen communication across synapses, and implicates this process in addiction.

Mollie Meffert , a faculty member in the Department of Biological Chemistry and in the neuroscience department, investigates the formation of lasting memories. She focuses on growth factors in the hippocampus that turn on or off the particular genes involved in the growth of neurons and in establishing memories. Levels of these growth factors elevate during activity in the normal brain, and mice with lower-than-usual levels perform poorly on spatial memory tests such as navigating mazes. In addiction studies, researchers showed chronic drug use causes the release of brain-derived growth factors in rat brain areas involved in sensing the drug-associated “reward.” Meffert’s group studies how the brain-derived growth factors turn genes on or off to control long-lasting brain responses, such as those occurring in learning and memory, or addiction.  By investigating the regulation of these genes in healthy and diseased neurons, the Meffert lab uncovered the mechanism by which brain-derived growth factors rapidly and specifically alter these genes. These findings may one day help us understand and develop therapeutic targets for failures in memory and brain processing as they pertain to addiction.

Substance Use & Addiction Research at the UW

Interested in learning more about substance use and addiction research at the UW? We host annual Open Houses (virtual) that bring together different departments and programs at the UW to talk about the work they’re doing in the field and how you can get involved! Our latest one was in November 2023; watch the recording , download the slides , and view the contact list ! To get notified about our next Open House, you can follow us on Twitter or subscribe to our News & Events blog .

The University of Washington is a world leader in addiction research ranging in scope from molecular pharmacology, to prevention, treatment strategies, impacts on individuals and communities, to social policy. Sponsored research from NIH and other funders brings in tens of millions of dollars annually to support the work of collaborative centers, independent researchers, and graduate and postdoctoral education in addiction at the University.

UW Substance Use & Addiction Research Centers:

Addictions, Drug & Alcohol Institute (ADAI) Director: Susan M. Ferguson, PhD ADAI (formerly the Alcohol & Drug Abuse Institute) was established in 1973 as an independent, multidisciplinary research center at the UW. Its mission is to advance research, policy, and practice in order to improve the lives of individuals and communities affected by alcohol and drug use and addiction. Areas of special emphasis include: testing new addiction treatment options in community settings; opioid use and overdose prevention; cannabis research and education; alcohol and drug use by pregnant and parenting women; and workforce development for substance use disorder treatment and recovery professionals in Alaska, Idaho, Oregon, and Washington.

Addiction Psychiatry Residency Program Director: Jonathan Buchholz, MD Major goals of Addiction Psychiatry Residency Program training include developing clinical excellence in the diagnosis and treatment of individuals with substance use disorders, broadening scientific knowledge in Addiction Psychiatry, furthering research skills relevant to Addiction Psychiatry, and expanding expertise in teaching Addiction Psychiatry. Close work with a range of interdisciplinary treatment teams is a core aspect of the residency. The faculty consists of a diverse group of psychiatrists and psychologists who have many years of clinical and research experience in addictions.

Center for Cannabis Research (CCR) Chair: Nephi Stella, PhD The CCR was created in 2017 to represent a coordinated and centralized effort for cannabis research across disciplines. The CCR Board of Directors represent the School of Medicine; Addictions, Drug & Alcohol Institute; School of Social Work; School of Public Health; School of Law; and the College of Arts and Sciences.

Center for Novel Therapeutics in Addiction Psychiatry (NTAP) Directors: Nathan Sackett, MD, MS, and Darron T. Smith, PhD, PA-C. The mission of the UW Center for Novel Therapeutics in Addiction Psychiatry is to create powerful new ways of treating people struggling with alcohol, opioid, tobacco and other addictions by combining psychedelic compounds with evidence-based behavioral interventions.

Center for the Study of Health and Risk Behaviors (CSHRB) Director: Mary Larimer, PhD CSHRB is dedicated to cutting-edge, culturally-sensitive research and dissemination in which health and risk behaviors interact. It is focused on the etiology of risky behaviors and the development of empirically-based prevention and treatment for risk reduction.

Center of Excellence in Neurobiology of Addiction, Pain, and Emotion (NAPE) Director: Charles Chavkin, PhD The NAPE Center addresses the challenging interplay of chronic pain, drug addiction and depression, scientists in the UW departments of Pharmacology, Anesthesiology and Psychiatry are working together to understand how the nervous system processes sensory information and how that transmission is affected by chronic pain and mood disorders.

Chavkin Lab Director: Charles Chavkin, PhD Dr. Chavkin’s work focuses on the molecular basis of drug addiction.

Fetal Alcohol and Drug Unit (FADU) Director: Susan Stoner, PhD FADU conducts research and disseminates information on fetal alcohol and drug effects, provides consultation for persons thought to be affected by prenatal exposure, and provides training in human behavioral teratology. Since 2013 FADU has been a unit within the Addictions, Drug & Alcohol Institute .

Fetal Alcohol Syndrome Diagnostic and Prevention Networ k (FAS DPN) Director: Susan Astley, PhD FAS DPN is a network of five WA State community-based clinics linked by the core clinical/research/training clinic at the UW Center on Human Development and Disability. Its mission is FASD prevention through screening, diagnosis, intervention, research, and training.

Harm Reduction Research and Treatment Center (HaRRT Center) Directors: Susan E. Collins, PhD and Seema L. Clifasefi, PhD, MSW The HaRRT Center works collaboratively with substance users, community members and organizations to develop, conduct, evaluate and disseminate evidence-based interventions that help to reduce substance-related harm, improve quality of life, and promote social justice and racial equity for affected individuals and their communities.

Innovative Programs Research Group (IPRG) Director: Denise Walker, PhD IPRG conducts studies designed to achieve a greater knowledge of the characteristics and needs of underserved populations. Their projects assess the effectiveness of innovative means for reducing barriers to the delivery of effective social and mental health services.

Neumaier Lab Director: John Neumaier, MD, PhD This lab investigates the interface of pharmacology, molecular neuroscience, and behavior. It uses strategies that span several levels of organization from RNA regulation, protein translation, cellular plasticity, and neural circuit level analysis of complex behaviors relating to stress and addiction models. It uses rat and mouse behavioral models as well as in vitro cultures of cell lines and primary neurons to study components of intracellular signaling pathways.

Neuroscience of Addiction Director: Susan M. Ferguson, PhD This research lab at Seattle Children’s Center for Integrative Brain Research uses a multi-level approach, combining molecular biology, circuit-mapping and behavioral neuroscience, to understand the development of behaviors associated with drug reward and addiction, as well as in the processes that underlie decision-making, motivation and impulsivity. They also examine how environmental factors such as extended exposure to sensory stimulation during childhood and adolescence modulate the development of these behaviors.

Social Development Research Group (SDRG) Director: Margaret Kuklinski, PhD SDRG’s research seeks to promote achievement and success as well as prevent and treat health and behavior problems among young people. Drug use, delinquency, risky sexual behavior, violence, and school dropout are among the problems addressed.

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National Research Council (US) and Institute of Medicine (US) Committee on Immunotherapies and Sustained-Release Formulations for Treating Drug Addiction; Harwood HJ, Myers TG, editors. New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions. Washington (DC): National Academies Press (US); 2004.

New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions.

• Hardcopy Version at National Academies Press

1 Introduction and Background

Drug use is one of the nation's most expensive health problems, costing $109.8 billion in 1995 alone ( Harwood, Fountain, and Livermore, 1998 ). In addition to the financial costs, drug use also exacts a human cost with thousands of lives being damaged and forever changed by drug use and addiction. Prevention and treatment research, as well as clinical experience, have shown that it is often possible to intervene successfully in addiction. However, such interventions must be grounded solidly in research and must also provide long-term behavioral and sometimes pharmacological support to ultimately achieve abstinence.

As part of these research-based interventions, the National Institute on Drug Abuse (NIDA) is funding the development of new classes of medications to treat drug addiction. These medications include immunotherapies and sustained-release formulations. Immunotherapies involve products that are introduced into the body to stimulate an immune response either through active immunization (e.g., vaccines) or passive immunization (monoclonal antibodies). This immune response counteracts the effects of the target drug. Currently, immunotherapies are being developed to counteract the effects of cocaine (see Carerra et al., 2001 ; Fox et al., 1996 ; Kantak et al., 2001 ), methamphetamine (see Aoki, Hirose, and Kuroiwa, 1990 ); phencyclidine (“angel dust” or PCP) (see Proksch, Gentry, and Owens, 2000 ), and nicotine ( Hieda et al., 1997 ; Pentel et al., 2000 ; Tuncok et al., 2001 ). Sustained-release formulations, also known as depot medications, involve a slow, timed release of medications that counteract the effects of illicit drugs. Sustained-release preparations of naltrexone ( Kranzler, Modesto-Lowe, and Nuwayser, 1998 ) for opioid addiction and lofexidine ( Rawson et al., 2000 ) to treat nicotine addiction are currently being developed. All three therapies—vaccines, monoclonal antibodies, and sustained-release formulations—are long acting, but time limited, with durations from weeks to months.

The availability of these medications will raise a host of issues. Some of these issues will marry traditional vaccine concerns, such as establishing and monitoring safety, ensuring efficacy, and financing and distributing the medications, with traditional drug abuse treatment issues, such as ensuring patient adherence to treatment, using these therapies in a variety of settings, and dealing with coercive legal methods that are sometimes used to “motivate” treatment initiation. In addition, less traditional issues may also be raised, such as who should be immunized or treated with a depot medication and when, and who will decide.

• COMMITTEE CHARGE AND REPORT

NIDA requested the advice of the National Research Council and the Institute of Medicine of the National Academies about behavioral, ethical, legal, and social issues likely to arise as a result of research they are funding to develop immunotherapies and sustained-release formulations. The Committee on Immunotherapies and Sustained-Release Formulations for Treating Drug Addiction was formed to identify and define the behavioral, ethical, legal, and social questions that will be raised in determining who should be given these medications and under what circumstances, given the major issue of therapeutic safety. This study was not intended to be a safety review of immunotherapies and sustained-release formulations, which are still under development, but safety forms a necessary backdrop for all of the issues the committee considered. Morover, the committee was not asked to evaluate the actual or potential efficacy of immunotherapies and depot medications for treating drug addiction. These therapies are still under development, and none has even been submitted to the Food and Drug Administration (FDA) for approval.

The committee was not expected to achieve consensus about how all of the issues should be resolved. Rather, the committee was expected to achieve consensus about what the issues are likely to be and which are likely to be the most pressing Indeed, the committee was charged with anticipating issues that may or may not bear upon the assessment of safety and efficacy of these medications. The committee has attempted to forecast issues that may arise in the therapeutic use of these medications if and when they are approved by the FDA for use. The committee believes that the nature and importance of many of these issues are such that NIDA may wish to encourage research into these issues in parallel with—if not integrated into—clinical trials that are done in order to test and demonstrate the safety and efficacy of medications. The committee suggests that some or all of these issues be examined during the FDA approval process.

This report reviews the behavioral, ethical, legal, and social issues likely to arise if, and when, immunotherapies and sustained-release formulations become available for treating drug addiction. It identifies the relevant issues and lays out a research agenda for NIDA. Because these therapies are still early in development, no literature exists that the committee could analyze or synthesize as a way of identifying and defining the behavioral, ethical, legal, and social issues. Rather, the committee reviewed similar, but related, literatures to better understand the potential implications of these new medications. This process required some creative thinking and use of judgment and members' expertise about what the issues are likely to be and which of them are most pressing.

The rest of this chapter provides a basic description of both immunotherapies and sustained-release formulations. In Chapter 2 the committee lays out considerations for clinical trials, focusing in particular on issues that are generally considered outside the usual FDA process.

Chapter 3 then considers a range of treatment issues, including the organization and delivery of care in alternative treatment settings, privacy, financing, and costs. Finally, in Chapter 4 the committee looks at potential adverse behavioral responses to the use of immunotherapies and at the difficult practical, ethical, and legal issues of consent, particularly for vulnerable populations.

• MEDICAL BASIS OF IMMUNOTHERAPY

Vaccination (active immunization) for the prevention and treatment of human disease has a long and distinguished medical history dating back at least to the pioneering work of Jenner nearly 200 years ago. The World Health Organization (2003) suggests that clean water and vaccines have been the two greatest contributions to worldwide public health. Indeed, vaccines prevent illness or death in millions of individuals each year.

Vaccines work by stimulating an immune response to a disease-related organism or subunit(s). Over a period of weeks to months, immunization(s) lead(s) to the generation of protective antibodies in body fluids, which act as an early surveillance system to block or reduce the effects of an invading organism or substance, such as a toxin.

The next advance in immunotherapy came in the early 20th century. Before the advent of antibiotics, polyclonal antibodies in the form of a specific immune serum were used to treat infectious diseases. Although these antisera were highly effective in treating diseases, such as pneumococcal pneumonia and tetanus, they sometimes produce a serious adverse side effect called serum sickness ( Devi et al., 2002 ). This allergic reaction resulted from the administration of animal antisera to humans, so animal antisera could only be used as a last treatment option. Later, the technique of plasmapheresis and the development of specific vaccines provided the possibility of immunizing human donors and then collecting human immune globulin for the purpose of treatment ( Mallat and Ismail, 2002 ). Indeed, human immune globulins are still used under certain situations to treat hepatitis B, tetanus, and Varicella zoster (which causes chickenpox) ( Terada et al., 2002 ).

Advances in biotechnology and genetic engineering over the last 30 years have made it possible to generate the newest form of immunological medication, monoclonal antibodies. These antibodies are of uniform composition, well-characterized chemical properties (in terms of specificity, affinity, and amino acid composition) and can be produced by large-scale manufacturing techniques without the use of animals or animal proteins ( Smith, 1996 ; Demain, 2000 ). Because monoclonal antibodies are not produced from human blood, they do not carry the risk of transmission of human infectious agents, such as HIV and hepatitis B and C viruses, and so represent an intrinsically safer product in that regard.

The medical rational for using immunotherapies for treating or preventing drug abuse is similar in concept to more traditional immunological applications. However, the primary action of an antidrug antibody in the serum is to reduce drug levels in the brain by binding the drug before it enters the brain ( Pentel and Keyler, 2004 ). Because the drug binds with high affinity to the antibody, the rewarding as well as the medically harmful effects of the drug are reduced or blocked. And because these therapies target only the drug, they are potentially safer than treatment with small molecule drug agonists, which bind directly to important receptor systems in the brain and other organs (Pentel, this volume).

Current immunotherapies for drug abuse are of two types, active and passive. Although both treatments require highly specific, high-affinity antibodies, the medical use and the mechanisms of the therapies differ somewhat. In active immunizations, drug vaccines are used to stimulate the body to makes its own antibodies and to create a long-term immunological memory for a more rapid future response to the vaccine ( Kosten et al., 2002a , 2002b ) In passive immunotherapy, laboratory-generated antibodies (e.g., monoclonal antibodies) are injected: more antibody can be administered and the protection can be immediate, but it only lasts until the antibody is cleared, and there is no immunological memory against the drug ( Owens et al., 1988 ). Depot medications are variations of currently available medications that are designed to release a drug slowly, over a long period of time. They act by binding to the drug receptor (in the brain or elsewhere in the body), “locking out” the drug from the site of action.

In all cases, however, these medications only target the pharmacological effect of particular licit and illicit drugs. They do nothing to counteract the effects of craving and overlearned drug-seeking behavioral responses that frequently lead to relapse ( Robinson and Berridge, 2000 ; Berke and Hyman, 2000 ; O'Brien et al., 1998 ). Consequently, their use is expected to require the concomitant availability of psychosocial and behavioral treatment programs to maximize their effectiveness. We discuss these issues in more detail in Chapter 3 .

Active Immunotherapy

In active immunotherapy, a chemical derivative of the drug of abuse (called a hapten) is coupled to an antigenic protein carrier, which is then used as a vaccine (with or without an immune enhancing adjuvant) for immunization. Because stimulation of an immune response requires multiple interactions on the surface of an antibody-forming B lymphocyte, a single, small drug molecule (like cocaine or nicotine) cannot produce cross-linking of cell surface antibodies on a B cell to activate it to produce more antibodies. Consequently, drug haptens must be irreversibly bound to their large protein carriers for use as vaccines.

The molecular orientation and spacing of the drug haptens on the protein surface are critical factors that scientists must control for an optimal immune response. The antibody response will not increase if a vaccinated individual uses the small drug molecule itself; only the circulating antibody at the time of drug use will be protective. Because cross-linking of surface antibody on B cells is required to stimulate antibody production, the same drug hapten-protein vaccine must be used for boosting the immune response on later occasions. Periodic boosting with the vaccine is required to keep serum antibody levels high (Pentel, this volume).

The actual serum level of an antibody is affected by the quality of the drug-protein vaccine, the dose of the vaccine, the frequency of vaccinations, the time interval between immunizations, and poorly understood genetic variations among individuals (Pentel, this volume). On the basis of results from prior vaccine regimens, it is anticipated that the immune response will not be adequate for at least 3-6 weeks after the start of vaccination, and booster immunizations will be required every 1-6 months to maintain a sufficient level of drug-specific antibodies ( Cerny et al., 2002 ; Hieda et al., 2000 ; Byrnes-Blake et al., 2001 ; Kantak et al., 2001 ). Improper timing of vaccinations could result in a poor response or a significant reduction in the amount of circulating antibody. Thus, the timing and duration of vaccinations will need to be carefully coordinated with patient needs and other medical interventions, such as counseling or behavioral modification programs.

Passive Immunotherapy

In passive immunotherapy, rather than vaccinating an individual to stimulate his or her antibody response, preformed antidrug antibody medications are administered directly. Although this antibody medication could be a polyclonal serum or a purified immunoglobulin fraction from the serum of an individual who has been vaccinated against a drug of abuse, a monoclonal antibody is more likely to be used. Given today's technology for making and selecting monoclonal antibodies, it should be possible to make high-affinity antibodies to most drugs.

The monoclonal antibodies that have been safely used in humans are chimeric monoclonal antibodies (comprised of 34 percent mouse protein and 66 percent human protein), humanized monoclonal antibodies (comprised of more than 90 percent human protein), and fully human antibodies ( Villamor, 2003 ). All of these types of antibodies are currently made by advanced biotechnological techniques called antibody engineering. As of mid 2003 there are 10 FDA-approved therapeutic monoclonal antibodies and one FDA-approved monoclonal antibody approved. Of relevance to the therapeutic strategies for using immunotherapies for drugs of abuse is Synagis ® ( Simoes and Groothuis, 2002 ). This monoclonal antibody is approved for the prevention of serious lower respiratory disease caused by respiratory syncytial virus (RSV) in pediatric patients at high risk of the disease. This antibody is administered before and then monthly throughout the RSV season to maintain protective circulating antibody levels ( Simoes and Groothuis, 2002 ).

For treating drug abuse, monoclonal antibodies could be used in three clinical scenarios: to treat drug overdose, to prevent drug use relapse, or to protect certain at-risk populations who have not yet become drug dependent (e.g., adolescent children who have begun using cocaine). Other special populations, such as fetuses of drug-abusing mothers, might also warrant protective immunotherapy of the mother to prevent fetal exposure to the abused drug. Active vaccination could be used to prevent drug-use relapse or to protect at-risk individuals, though not for drug overdose. Depending on the particular situation, active vaccination or monoclonal antibody therapy (or a combination of the two) could be administered. For example, antibody fragments (of a size that would be cleared by the kidney) could be used to treat overdose so that not only would the antibody bind the drug and lower the amount in the brain, but also so the drug-antibody complexes would be cleared quickly from the body. In a drug abuse protection or relapse setting, where it would be desirable to have significant antibody present over a long period of time, one could envision administering a loading dose of an antibody medication with carefully timed periodic repeat doses to maintain the desired serum antibody concentrations. An example of a current successful medical therapy is Remicade ® for the treatment of rheumatoid arthritis ( Vizcarra, 2003 ). This chimeric monoclonal antibody is given at 0, 2, and 6 weeks as a loading dose and then every 8 weeks thereafter. Vaccinations with an antinicotine vaccine might be appropriate in patients who are attempting to stop cigarette smoking.

Advantages and Potential Disadvantages of the Therapies

Both active and passive immunotherapy require high-affinity antibody binding to be medically effective, and both have potential strengths and weaknesses.

• Antibodies target the drug, not the drug's sites of action in the brain.
• The binding of drug to antibody inactivates the drug.
• An antibody can be highly specific for a drug or drug class.
• Immunotherapies can complement conventional therapies (such as behavioral modification) for a more comprehensive medical approach.
• The use of immunotherapy would not necessarily preclude the use of chemical agonist or antagonist, but an important exception is the combined use of a nicotine agonist therapy and antinicotine antibodies.
• Immunotherapy has a different pattern of side effects (in theory, fewer) than treatment with chemical agonist or antagonist.
• Antibodies are not addictive, as are some chemical agonists.

Potential Disadvantages

• Monoclonal antibodies are time consuming and expensive to produce.
• The production of a high-affinity antidrug antibody is sometimes difficult.
• Vaccinations may lead to an inadequate response in some individuals.
• Vaccinations may not produce antibodies in a timely fashion for proper integration with other medical interventions (e.g., drug overdose).
• The beneficial effects of the therapy could be overcome by large amounts of drug.
• The immunotherapy could lead to allergic reactions.

There are other potential problems with the use of antidrug antibodies for the treatment of drug abuse. Because in some cases the drugs of abuse are closely related in structure to either neurochemicals or approved medications (e.g., nicotine replacement therapy for cigarette smoking), it is possible that the therapies could lead to unexpected adverse reactions or reduced effectiveness of other medications. Some of these possible outcomes can be avoided or anticipated by careful screening of the antibodies for cross reactivity against known drugs and neurochemicals before they are used in humans. It is also possible that immunological responses against an antidrug of abuse antibody binding site (called an anti-paratype response) could lead to a second generation of antibodies, which are complementary to the antibody binding site and are capable of being druglike, thus, able to activate receptor systems just like the drug of abuse. It is known that monoclonal antibodies and other protein therapeutics do stimulate an immune response to the product in some individuals; therefore, they may not be suitable for life-long or even extended use in all individuals. Vaccines comprised of the drug-protein conjugate might also lead to entirely unexpected allergic reactions. However, it is expected that most of these potential problems would be anticipated, tested for, and dealt with during the clinical trails of new medications and the FDA approval process.

Finally, there are ethical considerations, however remote, for the use of vaccines. Active vaccination can stimulate long-lasting immunologic memory that could serve as a marker of past immunization and could stigmatize an individual for extended periods of time, or even over their entire life if tests were available for detecting memory immune cells. Monoclonal antibodies, however, have a finite life span, and after some period of time following treatment would no longer be detectable. Depot medications would similarly be undetectable following treatment because of their finite life span.

Depot therapies for opioid addiction pose a different set of advantages and challenges. A great deal is already known about the therapeutic agent (naltrexone) that is being developed for depot use because it has been used in non-depot form for more than 20 years. Naltrexone is known to be very effective as well as safe when patients adhere to the medication. For the depot versions, extensive work has been done by companies seeking to develop and obtain FDA approval for their products. Their primary advantage is expected to be in greater adherence, since dosing will only be about once every 30 days, instead of daily. One noteworthy issue is that patients on depot therapies who need treatment for acute pain (e.g., due to trauma) will present problems because naltrexone blocks opioid analgesics as well as illicit opioids. Special protocols (medications, dosing) will be required to treat pain for patients on naltrexone.

This consideration of the medical basis for immunotherapy and sustained-release formulations for treating drug addiction has led to one major recommendation by the committee, but several recommendations in subsequent sections are also related to the medical basis for these therapies.

Recommendation 1 The National Institute on Drug Abuse should support basic immunology studies on increasing the stability and longevity of antibody blood levels and on developing combination therapies to simultaneously treat a variety of abused drugs.

• Cite this Page National Research Council (US) and Institute of Medicine (US) Committee on Immunotherapies and Sustained-Release Formulations for Treating Drug Addiction; Harwood HJ, Myers TG, editors. New Treatments for Addiction: Behavioral, Ethical, Legal, and Social Questions. Washington (DC): National Academies Press (US); 2004. 1, Introduction and Background.
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• 4 Boston Medical Center, 801 Massachusetts Ave Crosstown, Boston, MA, USA.
• 5 First Pavlov State Medical University of Saint Petersburg, 6-8 Lev Tolstoy Street, St. Petersburg, 197022, Russia; Bekhterev National Medical Research Center of Psychiatry and Neurology, 3 Bekhterev Street, Saint Petersburg, 192019, Russia.
• 6 First Pavlov State Medical University of Saint Petersburg, 6-8 Lev Tolstoy Street, St. Petersburg, 197022, Russia; Smorodintsev Research Institute of Influenza, Prof. Popov Street, 15/17, Saint Petersburg, 197376, Russia.
• 7 Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA; Boston Medical Center, 801 Massachusetts Ave Crosstown, Boston, MA, USA; Boston University School of Medicine, 72 E Concord Street, Boston, MA, 02118,USA.
• 8 Boston University School of Public Health, 715 Albany Street, Boston, MA, 02118, USA; Boston University School of Medicine, 72 E Concord Street, Boston, MA, 02118,USA.
• PMID: 35134598
• PMCID: PMC8960362
• DOI: 10.1016/j.drugpo.2022.103600

Background: HIV-positive people who inject drugs (PWID) are stigmatized and face more challenges in accessing ART. The natural course of stigma and its role on ART initiation in this population is unclear. We examined 1] whether HIV stigma changes over time and 2] whether HIV and substance use stigma are associated with ART initiation in a prospective cohort of HIV-positive PWID in St. Petersburg, Russia.

Methods: We used data from 165 HIV-positive PWID who were ART-naïve at enrollment andgeneralized estimating equations to assess changes in HIV stigma between baseline, 12- and 24-month study visits. Logistic regression estimated associations of HIV stigma and substance use stigma with ART initiation. All models were adjusted for gender, age, CD4 count, duration of HIV diagnosis, recent (past 30-day) drug use and depressive symptoms.

Results: Participants characteristics were the following: median age of 34 (Q1; Q3: 30; 37) years; 30% female; 28% with CD4 count <350; 44% reported recent drug use. During the study period, 31% initiated ART and the median time between HIV diagnosis and ART initiation was 8.5 years (Q1; Q3: 4.68; 13.61). HIV stigma scores decreased yearly by 0.57 (95% CI -1.36, 0.22). More than half (27/47 [57.4%]) of participants who were eligible for ART initiation per local ART guidelines did not initiate therapy. Total HIV stigma and substance use stigma scores were not associated with ART initiation (AOR 0.99, 95%CI 0.94-1.04; AOR 1.01, 95%CI 0.96-1.05, respectively).

Conclusion: In this Russian cohort of HIV-positive, ART-naïve PWID, stigma did not change over time and was not associated with ART initiation. Addressing stigma alone is unlikely to increase ART initiation rates in this population. Reducing further existing structural barriers, e.g., by promoting equal access to ART and the value of substance-use treatment for ART treatment success should complement stigma-reduction approaches.

Keywords: Antiretroviral therapy; Linkage to care; People who inject drugs; Russia; Stigma; Substance use disorders.

Copyright © 2022. Published by Elsevier B.V.

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Conflict of interest statement

Declarations of Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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