Exploration has special value early-on in a learning process; thus, it seems prudent in the context of psychedelic therapy that it be given consideration now, rather than further down the development path, when sub-optimal parameters begin to undergo regulatory ‘lock-in’. Rectifying this matter now may help mitigate risks associated with a too hasty scale-up of access. To achieve this, however, buy-in from multiple stake holders will be needed, including the public, policy makers and those in between, e.g. scientists, clinicians and investors.There are signs that modern psychiatry is ripe for a radical ‘new’ treatment model, and psychedelic therapy offers a multilevel paradigm-challenge. Assumptions challenged by it include those pertaining to: theoretical frameworks in mental health, models of therapeutic action, selection of sufficiently sensitive and specific assessment scales, trial design and clinical practice, plus drug, economic and social policy. Here we propose that pragmatic trials, data registries and electronic data capture will aid advances in psychedelic medicine by catalysing our understanding of best practice, which includes, but is not limited to, identifying and mitigating risks. Pragmatic trials, data registries and digital and biometric data collection can interface well with so-called ‘n = 1 trials’ ,pipp horticulture racks cost where individuals and/or prescribing doctors assess, prospectively, the impact of introducing a time-limited intervention in single-case studies.
In contrast to large-scale observational cohort studies that allow for the modelling and prediction of response across wide demographics at the cost of experimental control , single-subject designs assess the effectiveness of an intervention experimentally, thus representing a scientifically rigorous alternative to RCTs . When participants serve as their own comparison , confounding variables such as age, gender or socioeconomic status are automatically controlled for, thereby decreasing the number of participants required to determine the likelihood of a causal relationship between intervention and outcome, and ultimately, research costs . Single-case approaches also bear relevance to ‘citizen-science’ initiatives, in which individuals’ willingness to engage in the scientific process is harnessed. For example, individuals may be invited to increase the rigour of their ‘self-experimentation’ by, for example, completing assessments, wearing biometric sensor devices or even engaging in a self-blinding placebo-controlled protocol, as was done recently for psychedelic ‘microdosing’ . As implied by some recent studies of ours , there is appetite for citizen-science-type engagement among users of psychedelics. Specifically, we foresee value in the use of smartphone apps to collect data pertaining to psychedelic use in a convenient and efficient way . For example, the combination of single-case trial designs and remote digital assessments could enable the collection of scientifically rigorous efficacy data on self-medicative psychedelic use in small or difficult to access patient populations , the potential utility of which is particularly salient considering the significant challenges that COVID-19 has posed on clinical and research psychiatry, including psychedelic trials .
Data from n = 1 experiments can be aggregated and analysed using Bayesian statistics and multi-level regression and post-stratification analyses to identify meaningful relationships within potentially rich datasets that could ultimately inform effective future care strategies. Idiographic high-frequency time-series data collected through such methods could enable more ecologically valid and nuanced modelling of change than conventional study designs . Zooming-out, the highlighted approach should not be interpreted as implying relaxed standards of screening or scientific rigour in psychedelic research. We are not, for example, advocating that researchers relax contraindication-based exclusion criteria intended to mitigate risks of adverse responses. Some might feel it premature to propose pragmatic trials for psychedelic therapy, as these are typically reserved for treatments that are already incorporated into clinical practice. However, we believe that it is right to begin such trials now, as policy changes are already afoot and could ‘get ahead of the data’, as occurred with cannabis, for example. There is presently insufficient data on which to recommend specific treatment parameters for specific populations and indications, as well as ‘no go’ criteria at screening, and big data pools would likely change this. Indeed, large-scale datasets from naturalistic sampling could have considerable harm reduction potential, by helping identify those most and least suitable for psychedelic therapy. Progressive policy changes on psychedelic medicine will likely have trickle down effects on research, innovation and investment in psychedelic medicine, particularly in the implicated geographical locations. Given the considerable cost-implications of a multi-site pragmatic research programme, health care payers and/or industry buy-in would likely be required to fund it, and the relevant parties would need to be incentivised to do so. Digital data collection could lessen this burden, however, particularly if individual end-users feel sufficiently incentivised to engage directly, e.g. via inputting data via a phone app . Mainstream, institutional-level funding has still not come into psychedelic science; philanthropy and now commercial investment have been its main drivers. Increasing demand for psychedelic therapy is poised to synergise with an upswell in initiatives to meet this, potentially jeopardising standards of safety and professionalism if corners are cut.
In anticipation of and, to some extent, already witnessing the beginning of a ‘hype-cycle’, we believe that innovative, pragmatic and exploratory research can play a vital role, helping safeguard the development of a particularly promising, yet vulnerable, approach to mental health care.Lifetime risks for alcohol-related blackouts in many surveys is >50% among drinkers . The high blood alcohol concentrations involved and the compromised cognitive processes inherent in ARBs increase risks for additional serious consequences, including accidents, unwanted sex, and exposure to other forms of violence . In addition to BACs>.20g/dl needed for most blackouts, ARBs are also associated with European American [EA] ancestry, female sex, and several genetically-influenced phenotypes related to heavier drinking, including a low level of response to alcohol, as described further below . However, the relationships among these characteristics and ARBs are complex and their potential interactions have not been adequately evaluated . The link of ethnicity to ARBs may relate to heavier drinking in EAs and, potentially, Hispanics, compared to other populations such as Asian individuals . Ethnic differences may also reflect divergent patterns of alcohol metabolizing enzymes, as Asians have higher rates of mutations in both aldehyde dehydrogenase and alcohol dehydrogenase that produce greater alcohol sensitivities and contribute to lower levels of heavier drinking with subsequent lower rates of ARBs . EAs, Asians, and Hispanics also differ on cultural-based proscriptions against heavy drinking, especially in women , have different rates of low LRs unrelated to alcohol metabolism ,mobile vertical grow racks and vary regarding typical body mass indices, with the latter likely to affect BACs per drink . One contributor to higher ARB rates in women may be their higher BACs per drink . This reflects women’s likely lower body weight, less first pass metabolism of alcohol, and higher body fat with corresponding less body water per pound. However, there is overlap between ethnic background and drinking patterns among women, and it is not clear if those two characteristics interact regarding ARBs. Both ethnicity and sex also relate to low LRs to alcohol . However, LR differences across EA, Hispanic, and Asian individuals , and across sexes raise questions about how LR interacts with ethnicity and sex to contribute to ARBs. A recent review highlighted the paucity of prospective studies evaluating how multiple risk factors interact in contributing to ARBs, while controlling for alcohol quantities . In response, the present analyses extracted information from a 55-week prospective study that evaluated educational approaches to preventing heavy drinking on campus . The data tested four hypotheses: Hypothesis 1 states that relationships of ethnicity to ARBs will remain even after controlling for the maximum number of drinks consumed, with the highest ARB prevalence in EA and Hispanic and the lowest rates in Asian students. Hypothesis 2 is that ARB rates will be higher in females, and that the ethnic differences will remain robust after considering sex and controlling for maximum drinks. Hypothesis 3 proposes that low LRs will relate to ARBs, and that ethnic differences will remain even after considering maximum drinks and LR. Hypothesis 4 states that ethnic group status will interact with sex and LR to predict rates of ARBs over 55 weeks. Following University of California, San Diego Human Protections Committee approval, in January, 2014, 18-year-old freshmen were selected from respondents to questionnaires emailed to UCSD students to solicit participants for a 55-week study of ways to diminish heavy drinking in college students . No student was selected because of current or past alcohol problems, and based on questions extracted from the Semi-Structured Assessment for the Genetics of Alcoholism interview , the protocol excluded nondrinkers, individuals with severe psychiatric diagnoses , students who ever met DSM-IV criteria for dependence on alcohol or illicit drugs , and Asian individuals who became physically ill after one standard drink . Five-hundred subjects were enrolled, half above and half below the median for the number of drinks required for effects the first five times of drinking using the Self Report of the Effects of Alcohol questionnaire.
The SRE determines the mean number of standard drinks needed across up to four possible alcohol effects actually experienced early in the drinking career. These included the drinks required to produce any effect, slurred speech, unsteady gait, and unwanted falling asleep. The SRE has Cronbach alphas and repeat reliabilities >.88 . This retrospective self-report measure was used rather than alcohol challenges because the latter are too expensive and time consuming for use in a large population . The overlap between SRE and alcohol challenge-based LRs in predicting heavy drinking and alcohol problems is 60%, and the measures produce similar results when used in different generations of the same families . High and low LR subjects were randomly assigned to three conditions: those who watched 5 videos regarding two different prevention approaches and no-intervention controls. The latter helped control for general-campus-related changes in drinking over time, and, reflecting the emphasis in the larger study on the impact of education groups, most students were assigned to active education. Using Survey Monkey, subjects reported drinking patterns and ARB experiences for the prior month at baseline , 1 month, 2 months, and each subsequent 1–3 months over 55 weeks. . At baseline, demographic and substance-related questions were extracted from the SSAGA interview . Of central interest to current analyses, alcohol related blackouts were evaluated by asking: “Have you had blackouts where you could not remember later what you have done while drinking alcohol? How many times last month?”. Baseline questions were repeated regarding drinking practices and numbers of prior month ARBs in: February, 2014 , March , May , June , August , November and February, 2015 . T4 evaluations occurred 18 days after a campus-wide day-long celebration known for heavy drinking Of 500 students enrolled, 462 of those in active education groups watched all videos, and to be included in analyses members of intervention and control groups had to complete >7 of 8 assessments. This high rate of cooperation was achieved by informing subjects of the importance of follow-ups at recruitment; through reminders via email, texts, and voice messages; and through prompt payment of $25 for each completed task. Considering our interest in relationships between ethnic group membership and ARB risk , current analyses focus on the 398 individuals in the three largest self-identified ethnic groups at UCSD: 159 EA, 76 white Hispanic and 163 Asian students. Sixty-four high and low LR individuals were not well matched on ethnicity because of a small pool of students of that ethnic background and were excluded from the analyses, including 25 students of Malaysian and/or Filipino heritage, 14 with Indian or Pakistani backgrounds, 11 with Middle Eastern or Persian heritage, 9 African Americans, 3 Native Americans, and 2 Pacific Islanders.The dependent variable was the number of ARBs the prior month at each assessment. Analyses began with data transformations based on distributional properties for numbers of ARBs and maximum drinks per occasion using inverse reflected and square root transformations, respectively. For the first set of analyses, to address Hypotheses 1–3, numbers of ARBs per assessment were compared across ethnic groups overall, ethnic groups among females and males separately, and ethnic groups among subjects with high and low LRs separately. As shown in Table 3 regarding each figure, at each assessment ethnic group differences were evaluated using two one-way ANOVAs, first presenting the F-value for differences in prior month ARBs across ethnic groups without controlling covariates, and again as F values controlling for maximum drinks consumed the prior month and for education group assignment .