Journal Article Assignment

Target Article

An Ethical Exploration of Barriers to Research on Controlled Drugs

Michael H. Andreae, Albert Einstein College of Medicine Evelyn Rhodes, Icahn School of Medicine at Mount Sinai Tyler Bourgoise, Icahn School of Medicine at Mount Sinai

George M. Carter, Foundation for Integrative AIDS Research Robert S. White, Weill Cornell Medical Center

Debbie Indyk, Icahn School of Medicine at Mount Sinai Henry Sacks, Icahn School of Medicine at Mount Sinai

Rosamond Rhodes, Icahn School of Medicine at Mount Sinai

We examine the ethical, social, and regulatory barriers that may hinder research on therapeutic potential of certain controversial controlled substances like marijuana, heroin, or ketamine. Hazards for individuals and society and potential adverse effects on communities may be good reasons for limiting access and justify careful monitoring of these substances. Overly strict regulations, fear of legal consequences, stigma associated with abuse and populations using illicit drugs, and lack of funding may, however, limit research on their considerable therapeutic potential. We review the surprisingly sparse literature and address the particular ethical concerns pertinent to research with illicit and addictive substances, such as undue inducement, informed consent, therapeutic misconception, and risk to participants, researchers, and institutions. We consider the perspectives of key research stakeholders and explore whether they may be infected with bias. We conclude by proposing an empirical research agenda to provide an evidentiary basis for ethical reasoning.

Keywords: biomedical research, confidentiality and privacy, human subjects research, informed consent, institutional review board, research ethics

Federal and state agencies have powerful and impor- tant justifications for controlling access to substances that are potentially dangerous. The U.S. Drug Enforce- ment Agency (DEA) controls drugs associated with a high risk of abuse (DEA 2007). Certain drugs can cause addiction and may induce or exacerbate underlying mental illness. These hazards for individuals and soci- ety, and their potential adverse effects on communities, are good reasons for limiting access and justify careful monitoring of their use. At the same time, the absence of studies on therapeutic uses of these controlled drugs suggests that strict regulations, fear of legal consequen- ces, stigma associated with abuse and populations using illicit drugs, and lack of funding may hinder research on their therapeutic potential. These impedi- ments can create barriers to developing effective medi- cations to alleviate chronic suffering and exploring harm reduction (Abrams 1998). They could obstruct research that might advance the treatment of chronic

conditions or possibly have an impact on the disease itself.

For the purpose of explaining the issues, we focus on HIV as our illustrative example because it shows the com- plexity of designing ethical approaches for research on controlled substances. For HIVC populations, the risks associated with drug use also include the spread of infec- tion through shared syringes, interactions with prescribed medicines (Harrington 1999), and side effects such as depression (Kousik, Napier, and Carvey 2012). Psychotro- pic drugs can diminish decisional capacity and lead to increased risk-taking, which in turn can lead to HIV trans- mission (Klitzman 2006).

Chronic pain for people living with HIV is frequent, devastating, and potentially difficult to treat. Chronic pain affects one-third of the HIVC population and amounts to a significant disease burden (Ghosh, Chanddran, and Jansen 2012). Heroin, marijuana, and many other illegal drugs are effective analgesics, some prescribed routinely in Europe

Address correspondence to Michael H. Andreae, MD, Department of Anesthesiology, Montefiore Medical Center Moses Division, Albert Einstein College of Medicine, 111 East 210th Street, Bronx, NY 10467. E-mail: [email protected]

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The American Journal of Bioethics, 16(4): 36–47, 2016

Copyright © Taylor & Francis Group, LLC ISSN: 1526-5161 print / 1536-0075 online

DOI: 10.1080/15265161.2016.1145282

(Wee et al. 2014). We tabulate their current routine clinical and the supporting clinical evidence (Table 1 Therapeutic potential of certain controlled substances). For many people living with HIV, chronic pain persists despite attempts at management with opioids, nonsteroidal anti-inflammatory drugs (NSAIDs), anti-inflammatory agents, tricyclic antide- pressants, and pain-modifying therapies (Finnerup, Sindrup, and Jensen 2010). In addition to pain, HIVC patients endure multiple chronic systemic, neurological, oral, respiratory, musculoskeletal, ophthalmological, der- matological, genitourinary, and psychological symptoms (Robertson et al. 2014; Giles and Workman 2009). Taken together, we are sympathetic to the suffering of people liv- ing with these chronic symptoms, suffering that cries out for relief. For this reason, research on effective and compas- sionate management of HIV-related symptoms and anti- retroviral drug side effects should be a biomedical research priority, even if the potential treatment agents include con- trolled substances.

Drug use and HIV transmission are intimately con- nected, because of the high prevalence of drug use in some high-risk HIVC subpopulations, and it is impor- tant to address the negative effects associated with

illicit drug use (Degenhardt and Hall 2012). Developing effective treatments for pain and other symptoms asso- ciated with chronic HIV could reduce the problematic use of less effective and illicit drugs, and reduce the associated harm of HIV transmission.

THE THERAPEUTIC POTENTIAL OF CONTROLLED

DRUGS

The abuse potential of the strongest analgesics has led the federal government to tightly control certain drugs. The DEA defines a Schedule I drug as having “no cur- rently accepted medical use in treatment in the United States” (DEA 2007). Scheduled drugs include highly controversial, illicit, or tightly “controlled drugs” like cocaine (Schedule II) and ketamine (Schedule III), some of which may have considerable therapeutic potential. While any controlled drug can be dangerous, even the most abused and controversial drugs may have legiti- mate therapeutic indications. The decision to place a drug on any of these schedules is currently rather arbi- trary, which is why we include all controversial con- trolled drugs in our discussion but focus on the most

Table 1. Therapeutic potential of certain controlled substances.

Drug Schedule Clinical evidence supporting therapeutic use Routine clinical use

Diamorphine (a.k.a. heroin)

I (US) Labor pain (McInnes et al. 2004; Wee et al. 2011; Wee et al. 2014), pediatric acute pain (Gossop et al. 2005; Kendall et al. 2001; Mondzac 1984), pulmonary edema, myocardial infarct (Gossop et al. 2005)

United Kingdom

Ketamine (a.k.a. special K)

I (CAN) III (US) Anesthesia and analgesia for adults and children (Elia 2005; Roback et al. 2006), chronic pain (Sawynok 2014), major depression and other mental illnesses( Kavalali 2012; Li et al. 2011)

United States, Europe, and other jurisdictions

Ibogaine I (US) Addiction interrupter (Alper et al. 1999; Antonio et al. 2013; Koenig et al. 2014), depression (Bulling et al. 2012), anti-HIV (Silva et al. 2004)

None to date

Cocaine (a.k.a. snow)

II (US) Anesthesiology and ophthalmology (Fleming et al. 1990; Yau et al. 2011)

United States, Europe

Marijuana (a.k.a. cannabis)

I (US) Neuropathic pain (Abrams et al. 2007; Ellis et al. 2009; Iskedjian 2007; Lynch 2011; Ware et al. 2010; Wilsey et al. 2013), refractory epilepsy (Hamerle et al. 2014), MS related spasticity (Koppel et al. 2014), appetite stimulation (Kramer 2015; Lutge et al. 2013), dementia, diabetes, glaucoma, anti-HIV (Costantino et al. 2012)

Some U.S. states, Europe, and other jurisdictions

LSD, ecstasy, amphetamines

I (US) Trauma, depression and other psychological disorders (Greer 1986; Jacobson 2014; Parrott 2007; Ross 2012; Sessa 2007), addiction treatment (Castells et al. 2010; Nuijten et al. 2014)

None to date

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controversial substances.1 Their considerable therapeu- tic potential explains why many tightly controlled and controversial drugs are widely used in clinical practice inside and outside of the United States.

Heroin, marijuana, ketamine ,and cocaine have shown therapeutic benefit in randomized controlled trials (RCTs) and systematic reviews (Ellis et al. 2009; Kendall, Reeves, and Latter 2001; Koppel et al. 2014; McInnes et al. 2004; Roback et al. 2006; Ware et al. 2010; Wee et al. 2011; Wee et al. 2014). Randomized controlled trials and meta-analy- ses found smoked marijuana to be equally or more effec- tive for HIV-related chronic neuropathic pain than conventionally prescribed alternatives like gabapentin (Abrams et al. 2007;Ellis et al. 2009; Ware et al. 2010; Wil- sey et al. 2013). Marijuana may also have therapeutic uses in appetite stimulation and nausea reduction, symptoms frequently experienced by people living with HIV (Giles and Workman 2009). Marijuana may enhance appetite, reduce nausea, and prevent wasting (Kramer 2015), and may help in refractory epilepsy (Hamerle et al. 2014). Evi- dence from randomized trials suggest that ketamine is effective as an adjuvant therapy in the prevention and treatment of acute and chronic pain, and RCTs now also

support its use in children (Elia and Tram�er 2005; Roback et al. 2006; Sawynok 2014). Ketamine may also have thera- peutic use for major depression (Kavalali and Monteggia 2012; Li et al. 2011). Ibogaine and other serotonergic hallu- cinogens may act as addiction interrupters (Alper et al. 1999; Antonio et al. 2013; Donnelly 2011; Koenig et al. 2014), antidepressives (Bulling et al. 2012), and even as medication to eliminate HIV (Silva et al. 2004). Heroin is widely prescribed in the British National Health Service for pain associated with both acute and chronic conditions (Gossop et al. 2005), even in children and in women in labor (Kendall et al. 2001; McInnes et al. 2004; Mondzac 1984; Wee et al. 2011; Wee et al. 2014). Ecstasy and LSD may have therapeutic benefits for a wide range of condi- tions including trauma, depression, and other psychologi- cal disorders (Greer and Tolbert 1986; Parrott 2007; Sessa 2007; Sindicich et al. 2010); depression is common and insidious in the HIVC population (Giles and Workman 2009). The class of psychostimulant drugs may be effective in addiction interruption (Castells et al. 2010; Nuijten et al. 2014). Cocaine is routinely used in anesthesiology and ophthalmology (Fleming, Byck, and Barash 1990; Yau et al. 2011). There is laboratory evidence that ibogaine and can- nabinoid drugs can interfere with HIV replication (Silva et al. 2004; Costantino et al. 2012), motivating the Cochrane Collaboration to study the medical use of mari- juana for reducing morbidity and mortality in patients with HIV/AIDS (Lutge, Gray, and Siegfried 2013). These

Table 2. Barriers to investigator initiated drug research and development: Legal, regulatory, ethical and social barriers

Process Barrier

Pilot study to test a hypothesis about a new therapeutic application of a controlled substance and collect preliminary data for subsequent grant application and clinical trial

� Difficulty overcoming the scrutiny of the institutional review board in light of real and perceived concerns related to studying illegal substances

� Difficulty in legally procuring the study drug � Concern about stigmatization of investigator among their

peers and within the institution � Concern about the social risks to study volunteers

Obtaining a federal research grant to scale up research efforts and cover clinical trial expenses

� Conflict with federal and state legislation � Investigating the therapeutic benefits of controlled

substances is “not within NIDA’s mission” � Even applications that are ranked highly ranked by NIH peer reviewers may not be funded

Conducting a large-scale randomized clinical trial to provide evidence in support a hypothesis about a new therapeutic application of a controlled substance, and thereby demonstrate its safety and medical benefit

� Academic leadership may be concerned about institutional reputation

� Community may concern about effects on local crime � News media may scrutinize research on “gateway drugs”

1. We limit ourselves in this article to medical indications of con- troversial controlled substances and do not address issues regard- ing their recreational use.

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therapeutic effects should be studied more systematically and thoroughly. However, we can learn about the thera- peutic benefit of controlled drugs only if we study them.

BRIEF HISTORY OF HEROIN AND MARIJUANA

REGULATION IN THE ANGLO-SAXON WORLD

The legal status of marijuana is uncertain, in flux, and varies across the United States and sometimes varies even within a state or county (Bostwick 2012; Aggarwal et al. 2009). In the United States, drugs of abuse are currently regulated according to Title II of the Comprehensive Drug Abuse Prevention and Control Act (1970), known as the Controlled Substances Act (CSA) (DEA 2007). CSA out- lines federal guidelines for drug classification. Schedule I substances (including marijuana and heroin) are defined as having the “highest potential for abuse,” having “no currently accepted medical use,” and as not having “accepted safety for use under medical supervision” (DEA 2007). Classification under Schedule I is rarely based on scientific evidence alone (Cohen 2009a). Heroin and mari- juana policy are a case in point, and contrasting the history of heroin and marijuana regulation in the United States with the United Kingdom can be instructive (Berridge 2009; Aggarwal et al. 2009).

In the United States, very few clinical studies have investigated the therapeutic potential of heroin, while in the United Kingdom heroin’s therapeutic use has been and continues to be actively studied (Oviedo-Joekes et al. 2009; Wee et al. 2014). Early in the 20th century, as an unlisted ingredient in several effective over-the-counter medicines, heroin quickly became notorious for its addictive potential. It was then associated with leading middle-class Ameri- cans unwittingly to ruin (United States Congress 1980). In response, and as part of an international effort to control the flow of opium and also enhance Sino-American relations (McAllister 2004), the United States initiated measures to limit the manufacture, importation, and pre- scription of opium with the Harrison Narcotics Act of 1914. This act succeeded in removing heroin from the con- sumer market, but an uptick in violent street crime ensued and was ascribed to heroin’s thriving on the black market. In the wake of alcohol prohibition, Congress also passed a law prohibiting the importation of opium in 1924 (United States Congress 1980). Very little changed in U.S. drug pol- icy until the Controlled Substances Act was passed in 1970.

In contrast, the United Kingdom restricted and con- trolled access to heroin, but continued to allow its therapeu- tic use when prescribed by physicians (United States Congress 1980). In 1920, the British government passed the Dangerous Drugs Act, which, like the U.S. Harrison Nar- cotics Act of 1914, unilaterally restricted clinicians’ access to heroin by making it a crime to possess, import, export, or manufacture opium without a license (Zinberg and Robert- son 1972). Crucially, however, in 1926 the United Kingdom allowed narcotics, including heroin, to be prescribed as rou- tine therapy. Since then, and to this day, heroin (under the name of diamorphine) continues to be on the national

formulary of the United Kingdom. This policy has enabled physicians to exercise their clinical judgment in prescribing heroin and to explore its therapeutic potential (Gossop et al. 2005). Initially, indications in the United Kingdom were limited to treatment for narcotic addiction, pain relief after an attempt at cure has failed, and prescriptions for small doses to enable handicapped patients to perform tasks of daily living. Research has supported heroin’s expanded uses. In the United Kingdom today, heroin is routinely administered to control labor pain (McInnes et al. 2004; Wee et al. 2011; Wee et al. 2014) and for pain control after myocardial infarction; it is nasally administered in children to control acute pain (Kendall et al. 2001), and used for rou- tine pain control in critically ill adults, relief of pulmonary congestion, and symptom relief for shortness of breath for patients with pulmonary edema. In 1967 the British Parlia- ment amended the Dangerous Drug Act to include preven- tative measures against addiction, such as modifications in prescription writing practices and the establishment of punishment for physicians who violated these restrictions (Zinberg and Robertson 1972). Subsequently, those limita- tions were bolstered by the Misuse of Drugs Bill of 1971, which allowed the government to add or remove drugs in any class of the drug scheduling system. Through all of these legislative efforts, the United Kingdom approach has focused on facilitating safe, clinical use of heroin. Even though UK policy appears to be more informed by evidence than U.S. policy, it too has been criticized for grouping drugs in classes equivalent to U.S. Schedule I and hamper- ing therapeutic use and research (Berridge 2009).

A similar approach of blanket prohibition has charac- terized recent U.S. policy on marijuana. Marijuana was on the U.S. formulary until 1937 (Aggarwal et al. 2009). Throughout the 1930s, the Federal Bureau of Narcotics closely monitored marijuana use in public settings (Ran- som 1999), and newspaper articles dramatized the dangers of marijuana (Erleywine 2005). Federal Bureau of Narcotics Commissioner Harry J. Anslinger presented sensational- ized newspaper clippings as proof of the harms of mari- juana. Congress responded with the Marijuana Tax Act of 1937 (Erleywine 2005). The Tax Act required marijuana distributors, including physicians, to pay a prohibitively high tax on each of their transactions with the drug. At the time, the American Medical Association disapproved of the act, and in a statement before Congress, its consultant, Dr. William C. Woodward, testified against the inflamma- tory and dubious anecdotal evidence used to support the Marijuana Tax Act (Musto 1972). Woodward advocated unsuccessfully for the inclusion of marijuana under the Harrison Act of 1914 instead. Such a policy would have limited the use and production of the drug, while still making it possible for clinicians to prescribe it. The pas- sage of the Marijuana Tax Act was followed in 1951 by the Boggs Act, which imposed and increased minimum sen- tencing for all drug violations. The idea behind mandatory minimums was that imposing harsh punishment for the use or possession of mild “gateway” drugs like marijuana would discourage use of stronger drugs and thereby

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forestall addiction (Swartz 2012). During Lyndon Johnson’s presidency a special presidential committee was unable to confirm or refute the claim that marijuana use led to violence or heroin addiction (Erleywine 2005), but the regulations have remained in place and the Controlled Substances Act was passed in 1970. These views may incorporate attitudes toward racial minorities, our societ- y’s support of the “war on drugs,” fears of addiction, and stereotypes of people who inject drugs (PWID) or use rec- reational substances (Nahas and Greenwood 1974; Grins- poon, Bakalar, and Doblin 1995). In addition, enforcement of drug laws appears to target racial minorities and socially stigmatized groups (Alexander 2012).

THE CALL FOR REFORM

Since these regulations have been in place, scientists and journalists have repeatedly questioned the U.S. drug scheduling system. As recently as June 2014, investigators writing in the New England Journal of Medi- cine complained of a lack of data about the adverse effects of marijuana use (Volkow et al. 2014). We and they noted the “Catch-22” of U.S. drug policy, which defines marijuana as having no “accepted medical use” while obstructing efforts to investigate whether or not it actually has medical uses (Heuvel 2013; O’Keefe 2013). In the same vein, editors at Scientific American repeatedly called U.S. marijuana regulation policy “outdated” and pronounced that it “thwarts legitimate research” (Scientific American 2014), and editors at Nature implored researchers to “prioritize research on [marijuana]” (Nutt et al. 2013). Recently, a series of crit- ics have made similar points. Joseph S. Albert pointed out that “much of what we know about cannabis comes from folktales and limited clinical observation” (Elsev- ier Connect 2016). As part of an editorial series on mar- ijuana legalization, The New York Times cited “the clear consensus of science that marijuana is far less harmful to human health than other banned drugs” (Boffey 2014); the Gainesville Sun editorial board, in its editorial “Allow Pot Research,” wrote that “cannabis research is thin” due to “onerous federal restrictions” (Gainesville Sun 2015); and The Washington Post reported on U.S. veterans’ attempts to convince the Department of Veter- an’s Affairs of the legitimacy of marijuana as a treat- ment option (Wax-Thibodeaux 2014). All of these articles demanded evidenced-based evaluations of the benefits and harms of controlled substance regulations and the U.S. drug scheduling system itself. In sum, these critical assessments point out that across the United States people are talking about medical mari- juana, but nobody knows about its medical efficacy.

CATCH-22

The limited guidance on using regulated drugs for treat- ment of pain associated with HIV is typically not

evidence-based and often politically biased (Andreae et al. 2012; Bostwick 2012). The result is a classic Catch-22 situa- tion (Figure 1) (Diep 2011; Jacobson 2014). There is scant evidence on the therapeutic effectiveness of controlled sub- stances for the treatment of HIV symptoms, because there are few studies; there are few studies of the effectiveness of these drugs because they are tightly regulated and con- sidered to lack medical benefit.

Systematic and thorough research on controlled drugs has the potential to provide patients living with HIV with therapeutic benefit as treatment of chronic disease-related symptoms. Beyond this promise, studies can also produce significant harm reduction. Because many chronic pain patients self-medicate and self-manage their pain outside the health care system, information from studies would help to avoid overuse and misuse of ineffective drugs and the self-medication misuse of illicit drugs. Better preven- tion or treatment of addiction would curtail Nutt et al. 2013 secondary harm, including the spread of HIV disease. Increased knowledge about therapeutic benefit of substan- ces currently classified as Schedule I, II, or III could lead to improved treatment options for HIVC patients and thus reduce their abuse of inefficient or illegal alternatives.

Information from studies of these drugs could reduce cost burdens on the health care system by promoting the prescription of effective treatments, reducing inappropriate drug use, optimizing and integrating indicated administra- tion of controlled substances, and avoiding the untoward societal effects associated with illegal drug use. Some argue that many controlled drugs would be significantly cheaper if legal and more accessible for resource-poor populations (Kilmer et al. 2010; Blackstone 2012) Furthermore, scientific information on the effectiveness of controlled drugs as treatment could reduce the stigma associated with their use. That information could, in turn, reduce the stigmatiza- tion of those who use the drugs, and thereby enhance their opportunities for gainful employment and meaningful social participation (Bottorff et al. 2013).

SOCIAL AND ETHICAL BARRIERS TO STUDIES THAT

ADMINISTER CONTROLLED DRUGS

Many people in our society, including people who review studies, seem to have developed attitudes about substan- ces such as marijuana, ketamine, and heroin. These views may incorporate attitudes toward racial minorities, sup- port of the “war on drugs,” fears of addiction, and stereo- types of drug users and addicts. Such views expressed in laws, rules, and regulations may have the effect of imped- ing research on controlled drugs (Abrams 1998; Anderson et al. 2012b; Bernard 2011; Fleming et al. 1990; Bottorff et al. 2013; Bulling et al. 2012; Costantino et al. 2012; Ham- mer et al. 2012). More generally, biases and prejudices may be an impediment to valid research (Table 2).

Other barriers to research on these agents are both per- ceived and real (Kempner et al. 2005; Table 2). Some concern the fear of legal prosecution even in jurisdictions where medicinal or recreational use has been legalized. Others

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involve skepticism about the efficacy of agents that are defined as having “no currently accepted medical use in treatment” and create suspicion among institutional review board (IRB) members (Abrams 1998). Researchers, institu- tions, IRBs, and funding and regulatory agencies may also be concerned about their reputations. Such worries can deter people from undertaking studies on the effectiveness of these agents. Fear of running afoul of the law or harming one’s standing may also have an effect on the evaluation of studies that involve controlled drugs. These attitudes may affect fund- ing agencies’ decisions about projects; indeed, the National Institute on Drug Abuse (NIDA), the National Institutes of Health (NIH) institute tasked with funding research on drug addiction, is focused on investigating drug-related harms and abuse reduction, but not therapeutic benefits of of Schedule I drugs; in the words of its the director Nora Volkow, it is “not NIDA’s mission to study the medicinal use of marijuana” (Winter 2006).2

Selection of participants for these trials will present unique ethical challenges for those who evaluate study proposals. HIVC populations include current and former

users of controlled substances, as well as people who have never or rarely used controlled drugs. Consideration of these groups of potential study participants will compli- cate the evaluation of standard research ethics questions. For example, are current users, past users, or nonusers capable of providing informed consent for a study that involves their using a controlled drug (Carter and Hall 2008)? Is one group more vulnerable to addiction, abuse, or relapse and in more need of special protections than the others? Can “Certificates of Confidentiality” issued by the NIH adequately protect the confidentiality of participants’ potentially incriminating substance use (Check et al. 2014)? Does drug experience convey more or less capacity to assess the risks and benefits involved in a study that involves controlled drug? Are the risks to current users, past users, or nonusers more or less reasonable? Would the invitation to enroll in a study that provides controlled drugs constitute an “undue inducement”? Views on these questions may differ significantly between the various stakeholders in the research process (Bell and Salmon 2011; Anderson and DuBois 2012; Klitzman 2013), and they may vary significantly based on the hearsay reputa- tion associated with a particular drug (Grinspoon et al. 1995). Reviewers will need evidence-based guidance on how to respond to such questions when studies with con- trolled substances are proposed (Anderson and DuBois 2007). To date, the ethical factors involved in research using controlled drugs have not been well described, rec- ommendations have not been well developed, and there is

Figure 1. Catch 22 cartoon.

2. We experienced this firsthand when our R01 NIH grant appli- cation was highly scored as exceptional to outstanding and better than 96% of all other applications in response to the PAR-12-244 on Ethical Issues in Research on HIV/AIDS and its Co-morbid- ities, but was not funded NIDA because investigating barriers to research on therapeutic benefits of controlled substances “doesn’t fit their priorities.”

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almost no evidence-based guidance on how to assess these factors and proceed.

Little has been published on attitudes that may consti- tute barriers to research on controlled drugs (Anderson and DuBois 2007). A few studies have surveyed physician atti- tudes toward prescribing Schedule I drugs. A 1984 paper reported variable and diverging attitudes toward heroin among researchers, clinicians, and authorities, while advo- cating for research on the drug’s pharmacological and clini- cal properties (Hamerle et al. 2014). A 1994 paper that explored attitudes on long-term opioid prescription for chronic pain found that concern about tolerance, depen- dence, and addiction varied significantly depending on specialty, prescribing habits, region, and regulatory pres- sure (Turk 1994). Gossop and colleagues surveyed practi- tioners in the United Kingdom (where heroin is on the national formulary) to elicit their concerns about prescrib- ing heroin (Gossop et al. 2005). He reported that the major- ity had no reservations about either prescribing or addiction. A 2011 Canadian focus-group study explored the views of women who use illegal drugs on decisional capacity, stigma, and undue inducement in the context of research. That study found that the views of the surveyed women differed from prevailing attitudes in IRBs (Bell and Salmon 2011). This minimal amount of evidence suggests that physicians‘, patients’, and regulatory bodies’ attitudes toward controlled drugs are not homogeneous, while the dearth of studies on the therapeutic use of controlled drugs suggests that there are barriers. Cohen reviewed the Con- trolled Substances Act and Food and Drug Adminstration (FDA) regulations related to research on medicinal uses of marijuana and proposed that “the ability of scientists to conduct impartial studies . . . [has been] greatly hampered by political considerations” (Cohen 2009a; Cohen 2009b; Cohen 2010). The Multidisciplinary Association for Psyche- delic Studies (MAPS) exposed barriers to research on Schedule I drugs in the United States (Publications.parlia- ment.uk. 2015.). Its memorandum maintains that the pro- cess for conducting research into the medical uses of marijuana is obstructed by federal agencies blocking the supply of marijuana for clinical research and by guidelines and requirements created by the Department of Health and Human Services that apply solely to marijuana research. Abrams reported on multiple barriers to research and the difficulties he had in procuring marijuana for a study of treatment for HIV neuropathy (Abrams 1998).

ETHICAL CONCERNS

Policymakers need to consider all of the harms and bene- fits that are likely to result from any regulation that limits access to and research on specific drugs. Among those harms and benefits, they need to reflect on whether and how the policy in question would limit liberty or dispro- portionally burden some individuals and thereby raise concerns about justice. Although the imposition of limita- tions on liberty and other societal burdens may be reason- able given the other benefits that they provide, policies

with such effects—such as those bearing on research with controlled drugs—require justification and, when possible, should be informed by empirical data. For example, are the restrictions on individual and institutional liberty posed by restrictive drug policies justified by their ben- efits? Do such policies impose burdens on some popula- tions more than others, thereby creating justice concerns?

Liberty

Considerations of liberty are involved in the political ques- tions of when and why some infringements on personal freedom are justified; we allow physicians broad freedom to administer drugs without recognized benefit, provided they obtained their patients’ informed consent. We allow patients the freedom to refuse even lifesaving interven- tions, as long as they have decisional capacity. Signifi- cantly, researchers typically have the liberty to question established truth; some indeed consider this their calling. In contrast, the U.S. Food and Drug Administration and other federal laws and agencies limit these liberties as well as manufacturers’ liberties in marketing drugs and require that substances be shown to be both safe and effective before they may be marketed and prescribed. FDA regula- tions are among federal regulations aiming at protecting and promoting health, promoting and maintaining well- being, and assuring that the public is protected from phar- maceutical products that are unsafe or ineffective, but by necessity do so at the expense of limiting research and commercial liberties. At the same time, these valuable reg- ulations limit the array of substances that may be used freely by individuals and thereby limit liberty.

Justice

The formal principle of justice requires treating like cases alike and different cases differently. This principle would be easy to satisfy if it were possible to tell which factors were ethically salient for determining that cases were alike and which differences were irrelevant and could be ignored. In drug research, questions of social justice can be subtle and difficult to sort out. Although some conditions may be alleviated by a Schedule II or III substances (e.g., morphine), other conditions may only respond to a sub- stance currently under Schedule I (e.g., marijuana). Is it just to allow research on a substance that may alleviate the pain of some patients and limit or prohibit research on a different substance that may alleviate the pain of other patients? When may research on a substance be limited, and why? Who will be affected by a limitation and will their share of burdens be fair?

Concerns of liberty and justice apply across morality. A number of additional issues specific to research ethics have, however, become key points for consideration in the review of protocols by funding agencies and IRBs. Several of these issues are likely to be especially complicated and controversial in the context of studies of controlled drugs on patients who are HIVC.

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Risks

Out of concern for protecting research subjects from unreasonable risk, studies are required to minimize risks and IRBs are charged with balancing the study risks and potential benefits so as to determine whether they are reasonable. The risk/benefit assessment in studies of controlled drugs on people who are HIVC will be especially difficult and complex. It is not clear when the risks of addiction and other harms associated with drug use are worth the potential benefit of allevi- ating burdensome symptoms. Furthermore, exaggerated risks (informed by media and urban legends) may dis- tort judgment of actual risks. It is also not obvious whether the risks for a drug user are greater or less than the risks to a former drug user or a nonuser. Legal risks also have to be added to the physical, psychologi- cal, social, and privacy concerns that are to be taken into account in the risk/benefit assessments. Decisions about the acceptability of a study should be informed by an accurate picture of potential legal consequences related to study participation, as well as the legal expo- sure of investigators and institutions.

Informed Consent

Informed consent is a critically important condition for the ethical conduct of research (Kavalali and Monteggia 2012). Yet it is not apparent whether patients who are currently or formerly using drugs are capable of providing informed consent (Carter and Hall 2008). Patients are deemed to lose capacity to consent to a change in their surgical procedure after mild sedation in the operating room. At the same time, heavily medicated women with labor pain are con- sidered capable of consenting to both research and inter- ventions, as are patients who chronically use anxiolytic and pain medication.

Thus, it is not clear whether the potential subjects in studies on therapeutic uses of controlled substances are capable of giving informed consent if they are using con- trolled substances. Are those who use drugs more like those who we consider intoxicated or those with an under- lying mental condition that does not impair their deci- sional capacity. Would people with a history of drug use be more or less informed because of their personal experi- ence with controlled drugs?3

Undue Inducements

In her 1981 paper, Ruth Macklin argued that offers of great benefits could overwhelm people’s decisional capacity and compromise their judgment of risks and benefits to such an extent as to render them incapable of providing informed consent (Macklin 1981). Macklin declared that such inducements are “undue” and should be prohibited. That position has been vigorously debated in subsequent

literature (Savulescu 2001; Largent et al. 2013; Klitzman 2013), and at least one study provides evidence that inducements do not impede judgment (Halpern et al. 2004). In the context of research on controlled drugs, we anticipate that the issue of undue inducement will be raised. Reviewers are likely to ponder whether the offer of drugs to drug users would constitute an undue induce- ment. Similar questions about the undue inducement of providing drugs to drug users in research were directly addressed in a case discussed by Louis Charland in a 2002 paper, “Cynthia’s Dilemma: Consenting to Heroin Pre- scription” (Charland 2002). Most, but not all (Rhodes 2002), of the numerous commentaries published along with the paper agreed with Charland that the inducement of providing clean needles and free heroin in that case was “undue” and that subjects could not provide consent.

To make appropriate ethical decisions about policy for conducting research with Schedule I substances, IRB mem- bers, researchers, potential participants, and funding agen- cies need a clear picture of how these issues are involved. Yet separating bias from fact is difficult. Research policy decisions are further complicated by thinking about the three groups of potential participants in a Schedule I sub- stance study. For example, are people who have had per- sonal experience using drugs better informed than others or are they incapable of making a decision involving drug use because their desire for the drug is irresistible? For someone who has never been a drug user, are the risks associated with participating in a trial of a controlled drug greater or less than they would be for a current user or a former user?4 And is someone who has no personal experi- ence with drug use and who does not personally know people who use drugs informed enough to make these judgments? Should cash incentives for participation in clinical trials be different for current, former, and drug- naive users? Evidence on whether and how bias affects judgments about these matters will be critical for the development of rational fact-based policies to guide research on controlled drugs.

MOVING FORWARD

Literature on how ethically to conduct studies of Schedule I substances is surprisingly sparse (Abrams 1998; Ander- son and DuBois 2007; Cohen 2009a; Cohen 2010; Hamerle et al. 2014). The marginal level of attention indicates that research is needed to provide an accurate basis for both policy and clinical use. In addition, because we have iden- tified only a single study that compares different stake- holder views on issues in research ethics (Cohen 2009b), more in-depth and systematic investigation is in order. Systematic and comprehensive studies would reveal whether and how the views of disparate groups differ: IRB

3. Vulnerability is a separate contentious issue, which we are not addressing in this article.

4. Could a comparison with analogous issues regarding inclu- sion of research subjects with a history of ethanol use be helpful? We doubt this, as the therapeutic potential of alcohol is limited to the treatment of acute methanol intoxication and disinfection.

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members, researchers, clinicians, and people who are liv- ing with the conditions and symptoms that require atten- tion. Each group has its own expertise and perspective. Areas of difference as well as areas of consensus are likely to be instructive. The empirical data combined with an overview of the legal status quo would provide a sound basis for recommending policy changes that would facili- tate research on controlled drugs. It is instructive to exam- ine the issues discussed above in light recent work on the psychology of judgment and decision making by Daniel Kahneman and Amos Tversky (Kahneman and Tversky 2000), D. T. Gilbert (Gilbert and Ebert 2002) and T. D. Wil- son (Wilson et al. 2000). In their widely accepted work on normal human psychology, these psychologists have established a cognitive basis for common human errors and explained how frequently human judgment is infected with bias. We have only identified five papers that apply their robust findings to bioethics (Gligorov 2009; Halpern and Arnold 2008; Rhodes 2006; Rhodes and Stain 2008, 2009). None of these articles address issues in research ethics. Yet it may be especially important to be aware of distortions in judgment that reflect cognitive basis when formulating policy recommendations for research with Schedule I substances. If empirical studies identify contra- dictory stakeholder judgments, the views of at least one group may reflect bias. Inconsistent views could be com- pared to the scientific literature to discern which views have a basis in fact and which are likely to reflect a cogni- tive distortion. Such an innovative approach to resolving controversies in bioethics would be useful in guiding pol- icy recommendations.

Specifically, studies designed for guiding policy on research with Schedule I drugs should focus on answering the following questions:

1. Is there agreement or are there differences in the views of stakeholder groups on the potential subjects’ deci- sional capacity, ability to assess risks and benefits, vul- nerability, and susceptibility to inducement?

2. Is there agreement or are there differences in judgments regarding the acceptable degree of risk exposure for the three groups of possible subjects, namely, current drug users, former drug users, and nonusers?

3. Is there agreement or are there differences in judgments regarding the degree of risks and the overall acceptabil- ity of specific studies with respect to drugs that have different social connotations and drugs that differ in their addictive potential or health risks?

Study findings of a clear consensus on an issue of research ethics could offer a starting point for policy devel- opment. Scientific evidence that supports one of two oppos- ing views will provide evidence to support data-based recommendations. When the views of different groups dif- fer, there may not be empirical data to support one position or the other. In some cases the alignment of views (e.g., patients vs. professionals, or people with direct experience vs. those lacking direct experience) may be enlightening. In

other cases, after identifying the disparity in views, the only reasonable solution may be to call for more scientific inves- tigation. The key caveat for policymakers will be to remain mindful of these possibilities and careful to avoid drawing conclusions that the data do not support.

CONCLUSIONS

Social views about marijuana have been changing rapidly, its legal status is in flux, and views about its safety and effi- cacy will continue to evolve. The issues that we have iden- tified are certainly relevant to the need for research on the efficacy and safety of marijuana. Our point, however, is broader. It is likely that several drugs currently classified under Schedule I have important therapeutic potential for the relief of symptoms as well as for the management of the underlying chronic conditions. Without research, that potential cannot be detected or verified and the potential benefits cannot be dispersed. The Catch-22 of the status quo is that the classification of drugs as Schedule I amounts to an unsurmountable barrier to research.

As matters of liberty and justice, changes are needed in FDA and DEA policies so as to make research on substances currently classified as Schedule I more feasible and less restricted. At the same time, because the research will involve concerns about the ethical conduct of research, the specific issues related to such research need to be carefully identified and considered. And because views about issues related to drugs, drug users, and addiction are likely to be infected with bias, and because conflicts of interest are likely to affect the judgment of IRB members as well as clini- cians and researchers, policymakers need to hold fast to requiring evidence for guiding their recommendations and avoiding pronouncements that are not supported by data.

Policymakers should seek and employ study findings as the basis deciding how existing regulations should be revised and in offering their recommendations. Their clear goal must be to allow research to proceed on regulated drugs in accordance with the highest ethical standards and without being swayed by political agendas, preconceptions, or prejudices. IRBs that are responsible for reviewing stud- ies of Schedule I drugs, investigators who are interested in conducting studies, and funding institutes and agencies that sponsor such research should also be aware of the need for an evidentiary basis for grounding their decisions.

FUNDING

Drs. Sacks, Andreae, and Indyk were supported in part by grant 1R01AT005824-01 from the National Institutes of Health, National Center for Complementary and Alterna- tive Medicine. MHA was supported in part by the CTSA Grant 1 UL1 TR001073-01, UL1TR000067, 1 TL1 TR001072- 01, 1 KL2 TR001071-01, from the National Center for Advancing Translational Sciences (NCATS), a component of the National Institutes of Health (NIH). This work must adhere to the Public Access Policy. We also acknowledge Maud Dupuy for her support in preparing this article. &

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Barriers to Research on Controlled Drugs

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