Proposals to equalize these limits would likely spur greater tax revenue collection in certain parts of the state. Thus far, beyond funds earmarked for school construction, marijuana revenue has financed the regulatory apparatus necessary to oversee the state’s growing recreational and medical marijuana marketplace. Marijuana revenue has also been allocated to youth drug prevention, public safety, and public education. State officials have launched several advertising campaigns to inform residents and tourists about marijuana laws and regulations regarding its use. To date, more than $5 million has been spent on these public awareness campaigns with more to come. The amount the state is permitted to spend may depend on whether voters collectively decide to let it keep revenues in excess of TABOR limits. Close to one billion people are affected by mental illness and substance misuse worldwide. In many developed countries, mental illness ranks top for burden of disease , is more common, impactful and costly than other health conditions, and is a core component of overall health. The total cost of mental illness in the USA is estimated to be $2.5 trillion , the global antidepressant market is worth over $13.5billion and the wellness sector is estimated to be worth over $4.5 trillion . Despite record increases in psychiatric medication prescription rates, the prevalence of mental illness is not reducing and may well be increasing in certain populations,flood tables for greenhouse such as the young . There are indications that rates of mental illness have increased during the coronavirus disease 2019 pandemic .
Evidence indicates that the efficacy of leading drug and psychological interventions is modest, and there is scope for improved tolerability and access . Most mental health interventions are reactive. Effective prophylactic intervention would be hugely valuable . Relatedly, early life trauma and mental illness are reliable predictors of future morbidity. There is a legacy of division between the biological and psychological arms of mental health care and research. A notable initiative towards innovation in biomedical psychiatry is the Research Domain Criteria . The main principle of RDoC is that, since diagnostic criteria are a product of clinical expediency, transdiagnostically relevant pathological mechanisms and treatment targets may have been overlooked. Relatedly, there is now good evidence for genetic overlap between psychiatric disorders . RDoC is primarily a biological initiative that aims to translate mental illness into ‘brain illness’, for the purpose of discovering candidate brain biomarkers and treatment targets . Notable initiatives towards innovation in psychological health care include efforts to improve the cost-effectiveness of , access to and reach of psychotherapy – e.g. through utilising technological advances and social and familial networks . So-called ‘third wave’ psychotherapeutic approaches have gained traction, e.g. with a spike in the popularity of mindfulness and growing interest in – and evidence for – acceptance and commitment therapy . Bearing in mind relevance to RDoC, one important characteristic of these approaches is their alleged transdiagnostic relevance, i.e. that they seek to identify and target a common pathological mechanism, but more work is needed to link the relevant psychological constructs, such as ‘psychological flexibility’, with biological processes. There are promising signs of confluence between psychiatry’s biological and psychological divisions however, including a growing appreciation of the value of both psychological and neurobiological accounts of mental illness and its aetiology, as well as how environment, mind, brain and body interface and interact – consistent with the ‘biopsychosocial’ model .
Specific examples of biopsychosocial research in psychiatry include studying: gene × environment and drug × environment interactions – of which drugassisted psychotherapy can be considered an example , neurophenomenology and the biological mechanisms of psychological interventions . Into this arena comes psychedelic therapy, a quintessentially biopsychosocial intervention. Evidence indicates that psychedelic therapy is a particularly promising and progressive mental health care solution . Classic serotonergic psychedelics can be most precisely defined by their pharmacology, i.e. agonist action at the serotonin 2A receptor, which, if blocked, effectively abolishes their signature psychological effects . Psychedelic therapy is defined here as psychologically supported classic psychedelic drug experiences – although we recognise that psychotherapy alongside experiences induced by certain other psychoactive substances, e.g. MDMA and ketamine, bears relation to classic psychedelic therapy. Psychedelic therapy has shown promise for a range of different mental health conditions, including: depression , end-of-life anxiety , addiction and obsessive compulsive disorder . Indirect evidence also supports its potential for treating eating disorders and chronic pain . See Andersen et al. for a review. The Food and Drug Administration has granted ‘breakthrough therapy’ status to two independent multi-site double-blind randomised controlled trials , aiming to bring psilocybin therapy to marketing authorisation for depression, while related work is currently underway across Europe. Population and controlled studies , as well as large retrospective and prospective surveys , are generating evidence for improved mental well-being across a large demographic, potentially opening psychedelic therapy up to a sizeable wellness market. The successful initiative to legalise psilocybin therapy in Oregon, USA, intentionally included access for healthy individuals. In addition to its putative transdiagnostic utility, other reasons to feel optimistic about psychedelic therapy include: its novel action , and rapid and enduring therapeutic impact . Unlike traditional psychiatric drugs, positive effects have been observed for several months after just one or two doses. In terms of safety, psychedelics such as psilocybin have a favourable toxicity profile and therapeutic index, and negligible addiction potential .
Not wishing to neglect rare cases of putative iatrogenesis, including those of so-called ‘hallucinogen persisting perceptual disorder’ , the main hazards of psilocybin therapy relate to the intensity of the psychological state produced by higher doses, and associated need for a carefully engineered contextual container, e.g. with effective psychological preparation, supervision and aftercare. The utilisation of a drug-induced period of heightened cortical plasticity is likely to be a core component of psychedelic therapy’s mechanism of action and candidate functional and anatomical biomarkers of this are already being examined. In the context of a predictive processing framework, the ability of psychedelic therapy to relax and recalibrate cognitive and behavioural biases may be a central part of its action – as may an accelerated learning rate . How can we best advance the science of psychedelic medicine? Here we advocate pragmatic considerations , the utilisation of ‘basket’ protocols , as well as digitally aided data registries. Distinguishing pragmatic from confirmatory trials, the former refers to the actual, realistic conditions under which a therapeutic intervention will be received , whereas confirmatory trials typically engineer experimental conditions to support strong scientific inferences, but these often poorly reflect real-world conditions. Basket protocols are defined as single protocols, approved by relevant research regulatory bodies, that allow for a single intervention to be tested for multiple different disorders or conditions, such as a single drug for different types of cancer. Developers may be right to adhere to convention in delivering confirmatory trials, but, if resources and conditions allow, considerable benefits could be gained from more explorative study designs. Such exploration may be best served by research that can address a greater range of questions of clinical and real world relevance. Similarly, whereas confirmatory trials may choose to constrain eligibility and treatment criteria, pragmatic trials may benefit from broadening them, while maintaining a sensibly high-bar for contraindication-related exclusion criteria. Easy to sample biometrics and behavioural sampling could accrue large pools of objective data with potential predictive value. If such studies and data registries are designed with careful consideration of data quality and fitness, pragmatic research could create significant value for various different stakeholders, e.g. scientists, clinicians, regulators, health care systems, payers and investors. As has been the case with medical cannabis,indoor growing trays treatment-seeking patients will look for guidance from clinicians who take theirs from scientific evidence. Liberal policy changes occurring prior to the conducting of sufficient research could create similar problems for clinicians as occurred with medical cannabis. Such imperfect clinical scenarios could, however, also represent opportunities for innovative pragmatic and observational research. The creation of electronic data registries, e.g. for prescribers of psilocybin therapy in regions legally permitting access , may be one appealing example, enabling the collection of valuable real-world data. Data registries and pragmatic trials will collect data from broad and diverse samples. Data on use among healthy individuals can be supplemented by data from individuals seeking psychedelic therapy treatment for depression, particularly as safety is being established in this population . An even more ambitious project would be to utilise a protocol to only exclude individuals where there are good reasons to suspect elevated risk and inadequate specialist support. Indeed, future psychedelic therapy clinics in areas supporting legal access and/or operating under a research mandate may support such a scenario. Moreover, utilising digital tools, such as cellphone apps , to track outcomes linked to psychedelic use could generate large data pools that could be mined to inform on such matters as patient screening and treatment optimisation. Whether via data registries annexed to legal-access psychedelic therapy or approved pragmatic research trials, or both, the proposed approaches can serve the agenda of identifying transdiagnostic treatment targets . The RDoC initiative pays selective attention to phenotypes associated with pathology, neglecting parameters associated with wellness, and this may be an oversight. Evidence of reliable and sustained improvements in well-being and lifestyle with psychedelic therapy, as well as the maintenance of psychological wellness , recognition of the bidirectional relationship between psychological and physical health, and awareness of the substantial costs required to implement any human drug study, let alone a clinical trial with a psychedelic, and combined with a need for greater safety data across a diverse demographic, particularly given the liberalising political climate surrounding psychedelics, are all good reasons to justify innovative and pragmatic approaches to researching psychedelic medicine.
Collecting large sample sizes will enable better prediction-of response modelling , which will help mitigate risk and inform the potential customisation of care. A multi-site ‘trial’ or centralised registry would help generate and store the large data needed for reliable prediction-of-response modelling, with the added benefit of being able to assess between site discrepancies and consistencies. Confirmatory trials constrain important treatment parameters such as dosage and frequency of interventions, whereas pragmatic psychedelic trials could exercise flexibility here, particularly given the nascent nature of the treatment model, where practitioners cannot confidently claim to know the best parameters for all individuals and indications. In the context of psychedelic therapy, what dosage, frequency-of-dosing, as well as frequency and nature of post-dosing psychotherapy sessions are optimal, and for which cases, are all key questions that may be best addressed via pragmatic research under a basket protocol – and/or via digital data collection. Upper limits on the number of dosing sessions and lower limits on the intervals between them may be set to reduce the risk of bad practice, but redosing in response to relapse and based on clinical judgement may be permitted, thereby reflecting the conditions of clinical practice post roll-out. Most modern trials of psychedelic therapy have employed just one or two fixed-dose treatment sessions for all participants within relatively small and homogeneous samples, not because of assumptions about best practice, but because of alignment with regulatory traditions and budget constraints. This article argues that carefully designed pragmatic trials implemented under a basket protocol could offer a powerfully progressive model for advancing our understanding of the safety, effectiveness, mechanisms, impact, best-use and pitfalls of a promising but vulnerable new treatment model in psychiatry. Progressive policy changes would likely be needed to actualise the proposed approach – but these are already occurring. For such policy changes to occur, a vision of the societal value of improved mental health care, and how this can be safely and effectively achieved via psychedelic therapy, will need to be well communicated to the public and policy makers. For the time being, DB-RCTs will continue to sway sceptical opinions and aid progress with regulators, who presently base pivotal licensing decisions on data derived from such trials. Our view, however, is that data derived from pragmatic trials may be able to teach us more about how best to deliver the treatment and how it could impact on the lives of a broad cross-section of people. To be clear, the argument here is for the complementary value of pragmatic trials, not for their superiority over DB-RCTs. At the same time, however, we do challenge, as others have previously, the hierarchical preeminence of DB-RCT derived evidence .