How can we really study addiction?
Written by: Jessica Karlovcec, MSc
Edited by: Fahad Hassan Shah
History of addiction studies in humans
Before the development and implementation of strict ethical guidelines for research in humans, much of the drug research conducted in humans was unstandardized and often conducted on vulnerable or captive populations, such as prisoners, racial minorities, and psychiatric patients (Resnik & Hofweber, n.d.). Furthermore, research was also frequently conducted without informing the participants or acquiring proper (or any) consent (Resnik & Hofweber, n.d.).
One of the most famous instances of questionable ethical treatment of human subjects in drug research is the existence of the “Narcotic Farm” that opened in Kentucky in 1935 (Institute for Research, Education & Training in Addictions [IRETA], 2014). The Narcotic Farm, often called “Narco”, was a prison for people who were addicted to drugs that also contained rehabilitation and research facilities (IRETA, 2014). While the research conducted at Narco resulted in a wealth of findings regarding the effects of various drugs of abuse, underlying factors contributing to addiction, and treatments for drug abuse and overdose, there are also significant ethical concerns with the research that was conducted there (IRETA, 2014). Firstly, the research was conducted on prisoners, a vulnerable population, and involved offering a person who was struggling with a substance use disorder (SUD) their chosen drug of abuse as a “payment” for their participation in studies (IRETA, 2014). Additionally, the methods used in experiments were questionable (IRETA, 2014). Ultimately, the research facility at Narco became involved in the CIA’s “MKUltra” program (which was created to develop mind control techniques) through its experiments on prisoners involving LSD (a hallucinogenic drug). This led to the facility being shut down in 1976 (IRETA, 2014; Resnik & Hofweber, n.d.).
Today, human research participants are protected by various codes and acts that have been enacted throughout history following various significant ethical violations (Resnik & Hofweber, n.d.). Examples include the Nuremberg Code, which advocates for informed consent and voluntary participation of subjects in research; the Declaration of Helsinki, a list of recommendations to guide biomedical research conducted in humans; and the Belmont Report, which describes three ethical principles (respect for persons, beneficence, and justice) for human research (University of Missouri-Kansas City, n.d.).
Considerations for drug research today
The ethical standards and regulations put in place to protect human subjects limit the scope or degree of what can be studied in humans. Firstly, the type of drug and its potential side effects or overdose risk must be carefully considered, and the type of research that can be conducted with a given drug depends significantly on the safety profile of the drug (Johansen et al., 2024). Additionally, to comply with ethical standards, participants recruited for drug-related research are usually people who already use drugs and are not currently seeking treatment for their drug use (Johansen et al., 2024). This represents a significant challenge in drug research, because we are unable to determine whether research findings from studies that use participants who already abuse drugs would differ in other populations of people- for example, people who have never used drugs before (Johansen et al., 2024). There are also a number of moral considerations for researchers studying addiction in humans. For example, when researchers are highly involved in the lives of people struggling with SUDs, they may feel a need to protect or help their research subjects or to report certain behaviours to authorities, which is beyond what is required by their research responsibilities (Fisher, 2011). Finally, human researchers are also limited in their ability to control participants’ environments or experiences, which can limit the scope of the research that can be conducted and/or introduce outside factors that can impact research results (American Physiological Society, n.d.).
Many of the ethical challenges that come with studying human participants can be overcome by studying drugs in animals instead. Rodent models such as rats and mice, and nonhuman primate models such as monkeys, make particularly good research subjects for neuroscience research because their brains are functionally and anatomically similar to the human brain (Suleiman, 2025). Using animal models allows researchers to study drugs that are not yet approved or are not safe to be used in humans while also tightly controlling the animal’s experiences and environment, allowing for an understanding of drug effects outside of the social factors at play in humans with SUDs (Institute of Medicine (US) Committee on Opportunities in Drug Abuse Research, 1996). In this way, researchers can easily manipulate factors such as drug doses, frequency and route of administration, and prior drug exposure. Additionally, researchers can induce addiction in animals to study its symptoms, underlying factors, progression, treatments, and more, which would not be ethical to do in human subjects (Harvard Medical School, n.d.). An animal’s genes can also be modified to help us understand how genetics play a role in factors underlying addiction onset and progression (Harvard Medical School, n.d.). Finally, researchers can collect tissue samples from animals at any point in an experiment to study how addiction impacts organs like the brain on a molecular or cellular level. In contrast, studying human tissues is much more complicated because tissues are typically donated postmortem and because of the need to consider a wealth of factors such as genetics, psychiatric and other diseases, drug use history, and more (Lull et al., 2010).
How can we study addiction in the laboratory today?
Self-Administration Procedures
The best method we have to study addiction in a lab setting is the drug self-administration procedure (SAP). Drug self-administration involves a research subject performing a response (such as pressing a button, a lever, or nose-poking in a certain area) in order to receive a dose of a drug (Panlilio & Goldberg, 2007). In this way, SAPs are the most direct comparison we have to drug-taking behaviours in a natural environment because the subject is choosing whether or not to administer the drug to themselves, and how often to do so (Panlilio & Goldberg, 2007). SAPs can be used to study addiction in both humans and animals and can be modified in countless ways to fit the specific research question a researcher has (Johansen et al., 2024; Panlilio & Goldberg, 2007).
The first way we can modify SAPs is through the use of different reinforcement schedules, which are formulas that determine how many responses a subject needs to perform in order to get each administration of the drug. A fixed ratio (FR) schedule is the simplest type of schedule, where a subject needs to respond a fixed number of times to receive an administration of the drug. For example, in an FR1 schedule, a subject must respond once to receive one administration of the drug, and in an FR5 schedule, they must respond five times to receive one administration of the drug. Variable ratio schedules can also be used, where the number of responses required to receive the drug varies each time the drug is received (Johansen et al., 2024). There are also fixed and variable interval schedules, where responses result in an administration of the drug after a fixed, or variable, amount of time has passed, respectively (Johansen et al., 2024). Another type of schedule that is commonly used to determine how motivated a subject is to receive a drug is called the progressive ratio (PR) schedule (Johansen et al., 2024). During SAPs with PR schedules, each drug administration requires an increasing number of responses; for example, the first administration requires one response, the second requires two responses, the third requires three responses, and so on (Johansen et al., 2024).
It is also possible to provide subjects with free access to self-administer a drug, where there are no schedules or responses required to receive the drug. It is available whenever the subject would like to use it (Johansen et al., 2024). SAPs can also include an element of choice; some studies may provide subjects with an option between a drug and some other reward, such as food or money, and some studies provide subjects with a choice between two different drugs (Johansen et al., 2024; Manzardo et al., 2002). Finally, the doses of drugs, route of drug administration, length of the SAP, frequency of the SAP, and more can be altered to address specific research questions (Panlilio & Goldberg, 2007). Importantly, changing these factors can allow researchers to study many aspects of addiction, including punishment resistance, withdrawal, abstinence, relapse, and more (Panlilio & Goldberg, 2007).
Place Conditioning Procedures
We can also study certain aspects of addiction using other procedures. For example, the place conditioning (PC) procedure, which can also be conducted in both human and animal subjects, can allow researchers to understand if a drug has rewarding properties (Krishnan, et al., 2023). PC procedures involve the use of a chamber or environment that has at least two separate rooms. In the simplest form of the PC procedure, a subject receives one drug in one room of the chamber and receives a placebo in the other room (Cunningham et al., 2011). These pairings are made numerous times before the subject’s behaviour is tested (Cunningham et al., 2011). In the test session, the subject is placed in the middle of the two rooms and is allowed to roam freely between the rooms (Cunningham et al., 2011).
If a subject spends more time in the room that was consistently paired with the drug, then it is said that this drug has conditioned a “place preference”, meaning that the subject now prefers the space that they associate with the drug (Krishnan et al., 2023). Researchers would then infer that this drug has rewarding properties (Cunningham et al., 2011). On the other hand, if a subject spends more time in the room that was not paired with the drug, it is then said that this drug has conditioned a “place aversion”, meaning that the subject now prefers the space that they associate with not getting the drug (Krishnan et al., 2023). Researchers would therefore infer that this drug has aversive, or negative, properties (Cunningham et al., 2011).
It is important to note that if a drug is determined to be rewarding, this does not automatically mean that it is addictive. Some drugs can produce rewarding effects without causing addiction, people can become addicted to drugs that are not strongly rewarding, and addiction can cause people to continue using a drug even when the rewarding effects of that drug have diminished (Robinson & Berridge, 2025; Volkow et al., 2019). Ultimately, PC procedures provide valuable information regarding a drug’s rewarding effects, but this only captures one aspect of its broader addictive potential. Therefore, it is important to interpret findings carefully and to combine these procedures with others in order to obtain a more complete understanding of a drug’s addictive properties.
Conclusion
Drug research has changed drastically over time as ethical standards for research involving human and animal subjects have evolved. These standards protect research subjects, but they also impact the type and scope of research that can be conducted. Today, researchers use a variety of techniques to better understand addiction, such as self-administration and place conditioning procedures. While no lab procedure can fully capture the complexity of addiction, these models allow researchers to investigate important aspects of the disorder. By continuing to ethically study addiction in research subjects, scientists hope to better understand addiction and to ultimately develop highly effective treatments for people struggling with substance use disorders.
References
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