While new agents for the treatment of depression and schizophrenia have helped some patients who have not had success with other agents, the dissociative side effects and other events have raised concerns about appropriate patient selection, patient consent, and the risk of abuse, said Sharon Mates, co-founder, chair, and chief executive officer of Intracellular Therapies.
Paul Appelbaum, the Elizabeth K. Dollard Professor of Psychiatry, Medicine, and Law and director of the Center for Law, Ethics, and Psychiatry at the Vagelos College of Physicians and Surgeons at Columbia University, agreed. He added that the use of psychoactive drugs1 like ketamine and brexanolone raises ethical concerns that differ in extent and sometimes in nature from those used in conventional psychopharmacologic treatment. However, given the potential for greater effectiveness for intractable and treatment-refractory conditions, he suggested that rather than abandoning the use of these treatments, systematic and proactive approaches should be developed and implemented to ensure their appropriate use.
TRANSLATING ETHICAL PRINCIPLES TO THE CLINICAL USE OF PSYCHOACTIVE DRUGS
Translating the general ethical principles that apply to all aspects of medical practice—beneficence, non-maleficence, respect for persons, and
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1 NIDA defines psychoactive drugs as drugs that act on the central nervous system and alter its normal, everyday activity, causing changes in mood, awareness, and behavior. These include depressants like alcohol and sleeping pills; stimulants like nicotine and ecstasy; opioids like heroin and pain medications; and hallucinogens like LSD (Bellum, 2010).
distributive justice—to the clinical use of psychoactive drugs presents many challenges, said Appelbaum. These ethical challenges, he said, should be seen not as roadblocks but as speed bumps, signaling the need to slow down and develop thoughtful approaches and policies. He summarized six of these challenges and offered suggestions for how they might be addressed.
Ensuring Likely Benefits Outweigh Risks for Individual Patients
As mentioned earlier, clinical trials frequently exclude the very categories of patients commonly seen in clinical practice, said Appelbaum. For example, the esketamine trials had an exclusion criterion of suicidal behavior in the past year or suicidal ideation with some intent to act in the previous 6 months. Patients with a history of substance abuse are also typically excluded from clinical studies, especially for drugs with the potential for abuse. While these exclusion criteria are used in trials of nearly all new medications, Appelbaum suggested that they are particularly salient for psychoactive drugs because issues like intractable suicidality are exactly why patients seek clinical care and are what motivates clinicians to look beyond standard treatments to something such as ketamine. Moreover, he said, the differential impact of a drug on people with substance abuse histories may be more important for drugs with abuse potential. Thus, excluding patients in either of these two subgroups makes it less likely that the trial will be able to accurately ascertain either the benefits or the risks associated with the drug among these typical patients.
To ensure that benefits outweigh the risks for high-risk groups, Appelbaum suggested that clinical trials be required to include patients with conditions likely to be found in the target population. This does not mean that acutely suicidal people or those with histories of abuse should be included in the first trials of a new medication, he added, but only after some evidence of efficacy has been demonstrated.
Obtaining Meaningful Informed Consent
To obtain truly informed consent, the risks and benefits of treatment must be conveyed to patients in terms that are understood and meaningful. However, this may be particularly difficult for psychoactive medications, said Appelbaum. For example, dissociative experiences were the most commonly seen severe side effects in the esketamine trials, yet are difficult to describe to someone who has never experienced dissociation, he said. It also may be difficult to explain to a patient that although treatment may provide relief from the severe psychic pain associated with treatment-resistant depression, adjusting to a life without depression presents other significant challenges that may need further treatment and therapy, said Appelbaum.
He suggested further research to better understand how to convey inherently alien experiences like dissociation or recovery from chronic depression. Whether dissociative experiences are integral to obtaining efficacy or a side effect of the drug, people need to understand the risk even if it is a low-incidence risk, he said. Paper-based consent forms may not be sufficient, he said, suggesting that creativity and new technologies such as virtual reality may be needed. Lessons may also be learned from the advertising industry, which knows how to communicate concepts concisely and in engaging ways, he said.
Ashley Clayton, whose personal experiences with ketamine treatment for treatment-resistant depression were described in Chapter 2, suggested leveraging the patient experience to improve the process of informed consent for experiences that may be difficult to articulate. When considering ECT, for example, she noted that reading the scientific literature and talking to her physician failed to give her the insight she obtained from reading patient narratives.
Ensuring Competent Consent
Patients with severe or intractable conditions such as treatment-resistant depression or PPD may also have diminished competence to consent to treatment, said Appelbaum. Moreover, their desperation to receive treatment may lead them to underestimate the risks and overestimate the likelihood of benefits. He suggested that new approaches may be needed to systematically assess patients’ capacity for consent to treatment for severe and disabling conditions.
Dealing with Abuse Potential
Appelbaum cited three possible ways that treatment with psychoactive medications may lead to abuse: (1) the psychoactive effect is experienced as pleasurable; (2) an incomplete treatment response may lead patients to seek drugs on the black market, believing that more frequent or higher doses would lead to a better outcome even though escalating doses could also increase the risk of adverse effects; and (3) incentives may exist to divert medication to the unregulated market, as has been seen with stimulants prescribed for attention deficit hyperactivity disorder that are widely spread on college campuses, for example. Research suggests that, at least for esketamine, abuse has been rare. Nonetheless, concerns remain, especially as the drug transitions to general clinical use with less strict regulatory oversight.
Appelbaum added that while FDA required a REMS for esketamine, more regular post-marketing monitoring of abuse of approved drugs may
also be needed. “This is probably the primary lesson that comes out of the opioid epidemic because of how long it took us to awaken to the reality of widespread abuse in the community,” he said.
Mitigating Risks Associated with Commercialization
When for-profit centers provide prescriptions for psychoactive medications, Appelbaum worried that there might be incentives for clinicians “to behave in a less than completely cautious way” by prescribing for less severely ill patients, those with less clearly defined diagnoses, or those who might respond to standard medication. He added that ketamine infusion centers are largely unregulated and can be easily accessed. These centers can offer inducements to patients, such as rebates for continued treatments that may not be needed, he said (Sisti et al., 2014).
Appelbaum suggested that intensive oversight may be needed to identify and restrict problematic practices. He added that it might be necessary to restrict direct-to-consumer marketing of drugs like ketamine.
Ensuring Fair Access to Medications
In Chapter 2, Ashley Clayton described her struggle to receive lifesaving ketamine treatments for treatment-resistant depression. She said that while she continues to rely on free access to ketamine, this could end if hospital administrators decide they can no longer absorb the cost of her care. Doctors can prescribe ketamine off-label, but reimbursement for treatment remains a huge barrier, she said. FDA’s approval of esketamine for treatment-resistant depression may help, but according to Clayton, “like most of mental health care, unequal access is a significant problem.”
A session of treatment with esketamine can cost more than $700, and a 60-hour infusion of brexanolone $34,000, said Appelbaum. Yet, whether insurers will cover these medications is not clear, and many patients lack health coverage. Fair access can only be achieved on a societal level, he said, by instituting policies such as those that regulate predatory pricing or encourage companies to create patient assistance programs.
Global access to these medications represents an additional ethical dilemma, added Ilina Singh, professor of neuroscience in society at the University of Oxford. Underlying this access issue are two challenges: (1) the lack of trial data from these populations, and (2) insufficient infrastructure for the delivery of care using these drugs. Singh advocated for further exploration of how to tackle these dual challenges in contexts where there is a significant lack of clinical services and personnel.
Safeguarding Patients While Expanding Access
Singh raised additional ethical issues that have implications for clinicians treating patients with antidepressants and antipsychotics. First, she said, is the philosophical question of how these treatments may affect a patient’s sense of authenticity or identity, and what the appropriate role is for the clinician in relation to this concept. For example, she recalled how Ashley Clayton described a dual kind of suffering she experienced from the depression itself, followed by the loss of the person who was briefly released from that suffering (see Chapter 2). Singh suggested that the rapid onset of the therapeutic effects can have the potential for harm when the medications cause revelatory highs followed by abrupt drops. These swings could disrupt the patient’s sense of authenticity, and more discussion is needed to understand and address this phenomenon, she said.
The second issue Singh raised relates to building an ethical framework around the regulation of these potentially lifesaving drugs that balances the need for good drug stewardship and the need to maximize access. She, along with research and clinical colleagues in the United Kingdom, published an article in 2017 that proposed an ethical framework around the regulation of ketamine (Singh et al., 2017). This framework argued that despite limited evidence, patient needs could outweigh uncertainty if certain precautionary conditions were put in place, such as restricted access to those with severe treatment-resistant depression and close monitoring by the clinician. They also suggested creating international registries to share trial information and data on safety and efficacy.
However, she also questioned whether this precautionary approach is inadvertently fueling the problem of lack of access to these medications. For example, she noted that more trial evidence is now available on the use of intranasal ketamine, which is regulated under a REMS, while at the same time, information in the lay literature is leading people to seek out ketamine in oral or intranasal form for depression. In cases like these, a shift may be needed in balancing patient access and suggested precautions, she said. She also noted the potential value of real-world data from black and grey market sources. There is no question that REMS is needed, she said, but parallel processes are needed that take into account what is happening outside the clinic and on the street, she said.
Although the European Medicines Agency approved intranasal esketamine for adults with treatment-resistant major depressive disorder in 2019, the United Kingdom’s National Institute for Clinical Excellence rejected it for use within the National Health Service (NHS), saying that it is not cost-effective, said Singh. Meanwhile, the Medicines and Healthcare Products Regulatory Agency has mandated a company registry that collects data on each treatment with intranasal esketamine, said Rupert McShane,
associate professor in psychiatry at the University of Oxford. McShane runs an off-label ketamine infusion clinic within the NHS, where a few patients (usually Americans) come seeking “ketamine top-ups” because they do not think they are getting enough relief from esketamine alone. The problem, said McShane, is that clinicians prescribing ketamine are not able to look at the registry to see if a person has been getting esketamine somewhere else. He suggested that a publicly funded registry with prescribing information on multiple drugs could mitigate this problem and protect both patients and clinicians from the dangers of overprescribing.
However, Mason Marks, assistant professor at the Gonzaga University School of Law, argued that increasing access rather than increasing restrictions is the best way to get these drugs to the people who need them. Prescription monitoring databases raise significant concerns about privacy, can stigmatize people, and can perpetuate systemic racism and bias, particularly if they are using artificial intelligence to formulate risk prediction scores, he said.
Appelbaum countered that easing access can contribute to more widespread abuse, as has been demonstrated with the opioid epidemic, where increasing the legitimate prescription of opioids failed to alleviate the oxycontin black market. In response, Marks raised the point that since opioid overdoses are predominately the result of illicit use, this is a good illustrative example of how restricting prescribing did not decrease overdoses, but instead had the unfortunate effect of limiting opiate medication access to patients with chronic pain and other conditions. He suggested that anonymous data collection is needed to estimate the extent of the problem with ketamine. Singh added that the therapeutic alliance, where patients and clinicians work cooperatively to manage the patient’s care, is key to solving the problem of potential abuse.
Nora Volkow, director of NIDA, said that evidence supports both sides of the argument: that better regulation and oversight can be protective, but can also have negative consequences. She added that the approval and increased use of ketamine for depression have increased awareness of the importance of research on substances that have addictive potential. Moreover, for drugs such as PCP and LSD, which do not have the addictive quality that dramatically destroys people’s lives, some people have very negative reactions to the drugs. Understanding how to use them in a way that will minimize these negative outcomes is crucial, she said, yet what she called “extremely draconian regulation” of Schedule I substances makes it difficult to conduct such research.
PSILOCYBIN THERAPY: CLINICAL USE AND LEGAL CHALLENGES
Psilocybin is a classic hallucinogen similar to LSD, which was discussed briefly in Chapter 5. It is a 5-HT2A receptor agonist that has been shown to produce sustained decreases in symptoms of depression and anxiety, said Marks. However, despite no clear evidence of physical or psychological dependence—unlike some other compounds such as ketamine and benzodiazepines, he continued—psilocybin is classified as a Schedule 1 controlled substance. Therefore, DEA holds the position that this compound has no currently accepted medical use, has a high potential for abuse, and has a lack of accepted safety for use under medical supervision (DEA, 2020). However, FDA has given psilocybin breakthrough therapy status for depression, and several clinical trials are underway in the United States and other countries. In this context, psilocybin may be administered orally under controlled, supervised conditions over an eight-hour period, he explained.
Marks noted that agricultural products containing psilocybin can be purchased over the counter in the Netherlands. Canada allows people at the end of life to access psilocybin through a compassionate use program. In the United States, advocates are working at the state level to relax restrictions on the medical use of psilocybin. Oregon passed a measure in November 2020 to set up a statewide industry for psilocybin therapy and will begin issuing licenses for manufacturers and facilitators in 2023. Other states have proposed similar bills or have taken more conservative approaches such as limiting its use to end-of-life care, creating task forces to explore the issue further, or developing bills to decriminalize psilocybin, he remarked.
Marks highlighted examples of issues and unresolved questions relating to psilocybin. Firstly, U.S. states are grappling with how to regulate the compound. Although several issues remain unresolved, states are moving forward to formulate regulations, said Marks. For example, the governor of Oregon is about to appoint a psilocybin advisory board that will recommend regulations and training guidelines for psilocybin therapy facilitators, he remarked. Secondly, he continued, a major open question asks what are the best practices for psilocybin research, psilocybin-assisted therapy, and clinical screening.
