Commentary on Methods for Addressing Functional Unblinding and Mechanistic Uncertainty in Clinical Trials of Psychedelic-Assisted Treatments

Suicide is the second leading cause of death for adolescents. Whereas school-based prevention programs are effective, obtaining active consent for youth participation in public health programming concerning sensitive topics is challenging. We explored several active consent procedures for improving participation rates. Five active consent methods (in-person, students taking forms home, mailing, mailing preceded by primers, mailing followed by reminder calls) were compared against passive consent procedures to evaluate recruitment success, as determined by participation (proportion who responded yes) and response (proportion who returned any response) rates. Participation acceptance rates ranged from 38 to 100% depending on consent method implemented. Compared with passive consent, active consent procedures were more variable in response and participation rates. In-person methods provided higher rates than less interpersonal methods, such as mailing or students taking consents home. Mailed primers before or reminder calls after consent forms were mailed increased response but not participation rates. Students taking consents home resulted in the lowest rates. Although passive consent produces the highest student participation, these methods are not always appropriate for programs addressing sensitive topics in schools. In-person active consent procedures may be the best option when prioritizing balance between parental awareness and successful student recruitment.

Researchers face considerable ambiguity and controversy regarding the issue of informed consent. Decisions about consent procedures can affect study participation rates and prevalence estimates among specific populations. Changing from passive to active parental consent procedures was examined in a case study with an anonymous survey of sixth- through eighth-grade students' substance use. Four types of procedures for obtaining parental consent were examined. Results suggest that certain types of consent procedures can yield high levels of participation. This study also demonstrates that low participation rates with some active consent procedures can cause biases in sample characteristics and outcome data.

Active parental consent in survey research poses ethical and practical concerns. One common argument against the requirement of active consent procedures is its effect on participation rates. There is additional concern that higher risk groups may be underrepresented in the final sample. Empirical support of differential attrition, however, is lacking. In the current multisite longitudinal study, passive consent procedures were approved for the collection of pretest data. For subsequent years of data collection, active parental consent procedures were required. In this article, we use the pretest data to examine demographic, attitudinal, and behavioral differences between those students for whom active consent was provided and those for whom active consent was either denied or for whom no response was received. The results indicate that active consent procedures produce deleterious effects on participation rates and lead to an underrepresentation of at-risk youth in the sample.

Previous studies have shown that active consent procedures result in sampling bias in surveys dealing with adolescent risk behaviors such as cigarette smoking and illicit drug use. To examine sampling bias from active consent procedures when the survey topic pertains to childhood obesity and associated health behaviors, the authors pair data obtained from both active and passive consent procedures. The authors find that parents of children who are overweight or at risk for being overweight are significantly less likely to give active consent. In addition, parents of children enrolled in lower grades are more reluctant to consent to participate.

The Effects of Requiring Parental Consent for Research on Adolescents' Risk Behaviors: A Meta-analysis

Current treatment options for major depressive disorder (MDD) have limited efficacy and are associated with adverse effects. Recent studies investigating the antidepressant effect of serotonergic psychedelics-also known as classic psychedelics-have promising preliminary results with large effect sizes. In this context, we conducted a review of the putative neurobiological underpinnings of the mechanism of antidepressant action of these drugs. A narrative review was conducted using PubMed to identify published articles evaluating the antidepressant mechanism of action of serotonergic psychedelics. Serotonergic psychedelics have serotonin (5HT)2A agonist or partial agonist effects. Their rapid antidepressant effects may be mediated-in part-by their potent 5HT2A agonism, leading to rapid receptor downregulation. In addition, these psychedelics impact brain derived neurotrophic factor and immunomodulatory responses, both of which may play a role in their antidepressant effect. Several neuroimaging and neurophysiology studies evaluating mechanistic change from a network perspective can help us to further understand their mechanism of action. Some, but not all, data suggest that psychedelics may exert their effects, in part, by disrupting the activity of the default mode network, which is involved in both introspection and self-referential thinking and is over-active in MDD. The mechanisms of action underlying the antidepressant effect of serotonergic psychedelics remains an active area of research. Several competing theories are being evaluated and more research is needed to determine which ones are supported by the most robust evidence.

Obtaining informed consent from individuals to participate in voluntary research studies is widely considered to be an ethical research practice. However, there is considerable debate over how consent should be obtained from subjects. Many researchers argue that active (opt-in) consent is the only type of consent that accurately reflects the true wishes of the subject and is closer to the informed consent ideal than passive (opt-out) consent procedures. Opponents of active consent procedures argue that such procedures harm study participation rates and increase the risk of self-selection bias to a greater extent than passive consent procedures. Empirical evaluations of these claims are rare, given the lack of studies that experimentally assign subjects to different consent procedures and utilize a control group (in which no consent is sought) to facilitate comparison. We report on an experiment that overcomes these issues in an study of consent to transfer contact data from a federal register to a third-party data collector for purposes of carrying out a telephone survey. Specifically, we evaluate the impact of requiring consent on survey participation rates, self-selection bias, and the resulting survey estimates. We find that the passive consent procedure does a better job of minimizing self-selection bias and maximizing the validity of the survey estimates (relative to the control group) compared with the active consent procedure. However, neither procedure is ideal: Both consent procedures increase the total self-selection bias and reduce the sample size. We conclude with a general discussion of the main findings and their practical implications.

1523 Background: Access to clinical trials is an important aspect of cancer care given rapidly changing treatment paradigms.Most patients with cancer including those belonging to racial/ethnic minoritized groups are treated in community oncology settings, but only a minority ( < 5%) of these patients are enrolled on clinical trials. Barriers to trial enrollment in community oncology settings have been well described at the patient, provider, and system levels. The National Cancer Institute Community Oncology Program (NCORP) aims to address these barriers- and improve equity in trial enrollment- by providing support and infrastructure for community oncology practices to conduct clinical trials. Kaiser Permanente Northern California (KPNC) is a large integrated health system comprising thirty cancer trial sites and is part of the Kaiser Permanente NCORP, one of the largest NCORP-designated sites. In this study, we compared sociodemographic characteristics of patients enrolled in interventional trials with the overall cancer population within KPNC. Methods: We evaluated all patients enrolled on interventional cancer clinical trials within KPNC between 1/1/2015-12/31/2022. We abstracted demographic and clinical characteristics from the KPNC cancer registry. We compared characteristics to the incident cancer population diagnosed over the study period across KPNC. We used Pearson chi squared tests (categorical), binomial tests (binary) and one-sample t tests (continuous) to compare sociodemographic characteristics. Results: We identified 1,341 patients who were enrolled onto interventional clinical trials and compared them to 97,764 patients diagnosed with cancer over the study period. Patients enrolled on interventional trials were younger (mean age 60.2 vs 62.9 years, p < 0.001), more likely to have Stage IV disease (22.7% vs 11.2%, p < 0.001), more likely to reside in high-socioeconomic status neighborhoods (27.7 vs 23.8%, p < 0.001), and less likely to speak a language other than English (4.7 vs 7.1%, p < 0.001). There were no differences in race, ethnicity or sex distributions between the trial population and overall population. Conclusions: Across a large NCORP-designated community oncology trials program, the racial and ethnic makeup of patients enrolled on trials was similar to the broader cancer population within KPNC. These findings suggest that the trial infrastructure provided by NCORP may surmount the structural barriers that drive low access to trials among racial/ethnic minorities. Small differences in enrollment based on age, language and socioeconomic factors persisted. Efforts to bolster clinical trial portfolios in community oncology settings may address existing barriers to enrollment.

Evaluations of school-based interventions and prevention programs typically require parental consent for students to participate. In school-based efforts, program evaluators may have limited access to parents and considerable effort is required to obtain signed consent. This issue is particularly salient when conducting research in under-resourced, urban schools, where parent involvement in the school setting may be somewhat limited. The aims of this article were to (a) examine the published school-based prevention and intervention literature to assess the state of the field in terms of consent procedures and participation rates; and (b) describe two examples of health promotion studies that used multi-component, partnership-based strategies in urban schools to encourage communication among children, their parents, and researchers. The purpose of the case studies was to generate hypotheses to advance the science related to school-based participant recruitment for research studies. Of nearly 500 studies reviewed, only 11.5% reported both consent procedures and participation rates. Studies using active consent procedures had a mean participation rate of 65.5% (range: 11-100%). This article highlights the need for researchers to report consent procedures and participation rates and describes partnership-based strategies used to enroll students into two urban, school-based health promotion studies.

We read with interest the study of ketamine psychedelic and analgesic effects by Olofsen et al.1 and the accompanying editorial by Mashour.2 In both articles, the authors refer to the “dissociative” effects of ketamine. Corssen and Domino3 originally used the term “dissociative” in 1966 to describe “patients and subjects who, during recovery from CI-581 [ketamine], felt as though they were in outer space, or had no arms or legs.” This term has been used ever since, although we know considerably more about the subjective effects of ketamine than we did in the 1960s. Olofsen et al. measured the subjective effects of ketamine using a subset of items from a previously validated rating scale (Bowdle Visual Analogue Scale).1 We first used this rating scale in its entirety in 1998,4 along with the Hallucinogen Rating Scale,5 to establish the relationship between plasma concentrations and the subjective effects of ketamine. The Bowdle Visual Analogue Scale and the Hallucinogen Rating Scale are intended to measure the overall psychedelic effects, not specifically dissociative effects. We would suggest that the term “dissociative” may no longer be the best descriptor of the subjective effects of ketamine.Numerous terms have been used to describe the mind-altering effects of ketamine, including “dissociative,” “psychotomimetic,” “hallucinogenic,” “emergence reaction,” and “psychedelic.” Parsing these terms can be difficult because there is no universal agreement about their meaning. Dissociative experiences as described by Corssen and Domino can occur under the influence of a variety of psychedelic drugs and are not specific to ketamine. Psychotomimetic implies a psychotic state, lacking in insight; psychosis is not typical of psychedelic drug experiences because subjects are usually able to reflect on the nature of the experience. Hallucinogenic effects can occur under the influence of psychedelic drugs but are not an essential or universal element of the psychedelic experience. Emergence reaction refers to mind-altering experiences that occur after awakening from anesthesia with ketamine, and so does not apply to subanesthetic doses of ketamine. Psychedelic, meaning “mind manifesting,” was originally proposed by Osmond in 19576 to describe the effects of a variety of mind-altering drugs, including hashish. Subsequently, the term psychedelic has been applied to diverse mind-altering drugs, although some authors have used the term psychedelic more specifically to refer to lysergic acid diethylamide–like serotonergic receptor agonists.7,8Our current understanding of the psychedelic effects of ketamine and other psychedelic drugs comes primarily from narrative descriptions related by subjects who have experienced the effects, or from rating scales constructed to capture the experiences in a standardized fashion. Although scales are useful for measuring drug effects, the results depend on the nature of the items chosen for inclusion in them.Beyond ketamine, a small group of drugs that produce psychedelic experiences, analgesia, and anesthesia has been referred to as “dissociative anesthetics,” implying a similarity to ketamine. This group usually includes phencyclidine, ketamine analogues, dextromethorphan, salvinorin A (produced by the plant, Salvia divinorum),9 and nitrous oxide. The term “dissociative anesthetics” suggests that the mechanisms of action and the subjective experiences of these drugs are similar to ketamine, similar to each other, and different from other psychedelic drugs. In fact, the subjective experiences induced by dissociative anesthetics are not identical to each other and may be similar to nonanesthetic psychedelic drugs. Distortion of body image (a key feature of dissociation) is not confined to the dissociative anesthetics; other psychedelic drugs may induce a similar experience. For example, the subjective experience of ketamine, when assessed using the Hallucinogen Rating Scale, resembles that of the classic psychedelic serotonin receptor agonist dimethyltryptamine.4 The subjective experience of dextromethorphan assessed using a variety of rating scales resembles that of the classic psychedelic psilocybin.10The mechanism of action of these dissociative anesthetics is not identical. Phencyclidine, ketamine, and dextromethorphan (and its metabolite dextrorphan) are antagonists of the N-methyl-d-aspartate (NMDA) receptor. Salvinorin A is a highly selective κ opioid receptor agonist. The mechanism of action of nitrous oxide is uncertain but may involve antagonism of NMDA receptors11; the subjective effects of nitrous oxide have not been as well characterized as the other drugs.12 It is also worth noting that the recently discovered antidepressant effects of ketamine and other psychedelic drugs may or may not be related to the psychedelic effects, although this remains controversial.13We suggest that anesthetic drugs that also have psychedelic effects should no longer be referred to as dissociative anesthetics. Rather, it may be more useful to describe them primarily by their mechanism of action; for example, “the NMDA antagonist ketamine,” “the serotonin agonist psilocybin,” “the κ agonist salvinorin A.”Dr. Sackett declares a financial interest in Resa Health (Paradise Valley, Arizona). The other authors declare no competing interests.

Psychedelic Drugs in Biomedicine

Looking beyond the opioid receptor: A desperate need for new treatments for opioid use disorder

Clinical trials play a critical role in the development of novel cancer therapies, and precise estimates of the frequency with which older adult patients with cancer participate in clinical trials are lacking. To estimate the proportion of older adult Medicare Fee-for-Service (FFS) beneficiaries with cancer who participate in interventional cancer clinical trials, using a novel population-based methodology. In this retrospective cohort study evaluating clinical trial participation among older adult patients with cancer from January 1, 2014, through June 30, 2020, claims data from Medicare FFS were linked with the ClinicalTrials.gov to determine trial participation through the unique National Clinical Trial (NCT) identifier. The proportion of patients with newly diagnosed or newly recurrent cancer in 2015 participating in an interventional clinical trial and receiving active cancer treatment from January 2014 to June 2020 was estimated. Data analysis was performed from November 18, 2020, to November 1, 2021. Patients with cancer aged 65 years or older with Medicare FFS insurance, with and without active cancer treatment. Enrollment in clinical trials among all patients with cancer 65 years and older and among patients receiving active cancer treatments as defined by the presence of at least 1 NCT identifier corresponding to an interventional cancer clinical trial in Medicare claims. Among 1 150 978 patients (mean [SD] age, 75.7 [8.4] years; 49.9% men and 50.1% women) with newly diagnosed or newly recurrent cancer in 2015, 12 028 (1.0%) patients had a billing claim with an NCT identifier indicating enrollment in an interventional cancer clinical trial between January 2014 and June 2020. In a subset of 429 343 patients with active cancer treatment, 8360 (1.9%) were enrolled in 1 or more interventional trials. Patients enrolled in a trial tended to be younger, male, a race other than Black, and residing in zip codes with high median incomes. Findings of this cohort study show that clinical trial enrollment among older adult patients with cancer remains low, with only 1.0% to 1.9% of patients with newly diagnosed or recurrent cancer in 2015 participating in an interventional cancer clinical trial as measured by the presence of NCT identifiers in Medicare claims. These data provide a contemporary estimate of trial enrollment, persistent disparities in trial participation, and only limited progress in trial access over the past 2 decades.

The acquisition of a random sample is one of the many methodological problems that arise when conducting research with adolescent populations. Frequently, due to ethical considerations associated with collecting data from adolescents, active parental consent procedures are required. The current study examined characteristics of parents who consented, refused consent, or did not respond to an active consent request for their children to participate in a large-scale study of adolescent lifestyle behaviors. Results indicated nonresponding-parents were more likely to be employed than consenting-parents. Further, differences were found for a number of attitudinal variables and about the importance of adolescent research. There were significant differences between refusing-parents, and consenting- and nonresponding-parents who were similar in their attitudes toward adolescent research. The findings suggest that nonresponding-parents are characteristically more similar to consenting-parents than to refusing-parents, which supports the use of passive consent procedures as a reasonable alternative to requiring active parental consent in adolescent research.

Issues associated with the use of active and passive parental consent procedures are reviewed. Active consent procedures satisfy legal and ethical requirements but include problems such as low response rates, nonrepresentative samples, and costly implementation. Passive consent, however, has been questioned regarding its ability to adequately inform parents. Factors associated with developing appropriate consent mechanisms are examined, and proposals for improving research in this area are made.