Psychedelics for Medicinal Use: How Will This Alter the Collective Laboratory Consciousness?

The clinical evaluation of hallucinogens and other small molecules, conventionally termed psychedelics, has seen a dramatic increase in the past 5 years. Several key clinical trials recently demonstrated the potential efficacy of these compounds in treating a variety of mental health conditions including depression, anxiety, and substance use disorders. Concurrently, the business and patent landscape of hallucinogen derivatives from both conventional drug companies and emerging commercial entities is rapidly expanding. These 2 developments will require the clinical laboratory to rethink its approach to supporting this evolving area beyond the historic detection of these drugs in an abuse and/or overdose setting. For this Q&A, we invited a group of experts who are associated with psychedelic research, drug discovery, or drug approval to provide insight into this rapidly expanding field. The experts discuss what challenges are ahead for clinical adoption of psychedelic compounds and how this may impact the field of laboratory medicine. The opinions provided are those of the expert authors only and do not reflect opinions or outlooks for their respective institutions. How would US Food and Drug Administration (FDA)-approval of psychedelic compounds influence your career, research, or day-to-day focus? James Mullally: As a former regulator, an intriguing aspect of FDA approval of psychedelic drugs is how these approvals may impact other federal agencies. As part of my duties while working as Chief of the Toxicology Devices Branch at FDA, I was tasked with serving as an ex officio board member of the Substance Abuse and Mental Health Services Administration (SAMHSA) Drug Testing Advisory Board (DTAB). One of the functions of this board is to draft guidelines for federal workplace drug testing. A critical feature of federal workplace testing is Medical Review Officer (MRO) verification of prescriptions, medical records, and other medical information to determine whether a legitimate medical explanation exists for any positive drug test. Thus, FDA approval of new psychedelic drugs for prescription use may impact these guidelines, since the DTAB would need to consider (a) whether the new drug should be added to the classes of drugs subject to regulated testing, (b) whether the new drug could trigger false-positive results for any of the existing drugs of abuse tests, and (c) how legitimate prescriptions should be factored into MRO decisions. For example, when Epidiolex (cannabidiol) was recently approved by the FDA for prescription use, the DTAB had to consider the impact on federal workplace testing, and they subsequently published interpretation guidance for MROs stating that, since the active ingredient is cannabidiol only, Epidiolex should not cause a positive drug test (and therefore a valid Epidiolex prescription should not be a legitimate reason for a positive test result). By contrast, the active ingredient in the FDA-approved drug Marinol is delta-9-tetrahydrocannabinol (THC), and therefore evidence of a valid prescription should be factored into the MRO’s case determination. Frederick Barrett: For over 22 years, our group at Johns Hopkins University has been pioneering the study of the acute and enduring effects of classic and atypical psychedelic drugs in humans. To date, psilocybin is the psychedelic compound with the greatest amount of contemporary clinical data informing potential therapeutic use. Two multi-national Phase III registration trials have been approved by both the FDA and the European Medicines Agency (EMA) to study psilocybin, one for the treatment of major depressive disorder and the other for the treatment of treatment-resistant depression. The FDA has granted breakthrough therapy designation for each of these trials. Psilocybin is also being studied for the treatment of substance use disorders and a growing number of other psychiatric and neurological disorders. Final FDA approval of psilocybin as a medicine for depression would represent a tremendous milestone and validation for the field and would motivate continued investigation not only of the use of psilocybin to treat other indications, but also as a tool to better understand the etiology and effective mechanisms of action to treat both depression and other disorders. Current data point to the potential for psilocybin as a rapid and sustained treatment for mood and substance use disorders, with potential efficacy after as few as 1 or 2 discrete treatments. Understanding the mechanisms underlying this treatment effect may potentially inform our understanding of the development, maintenance, and eventual recovery from these disorders. Several additional psychedelic drugs, some with shorter duration of acute effects and others with seemingly different characteristics of acute effects, are also being investigated for therapeutic purposes. Approval of psilocybin would motivate further investigation of these and other psychedelic compounds as the field moves towards both a mechanistic understanding of these treatments, and optimization of these treatments. Alexander Sherwood: As a medicinal chemist engaged in psychedelic drug development at a non-profit, my efforts support our organization’s clinical trials and associated research by advancing our understanding of the pharmacological properties of psilocybin and related compounds. Psilocybin is a natural product that has been in the development pipeline for millennia, though it was clearly not discovered through traditional drug development efforts. Assuming adequate safety and efficacy is further supported in Phase III trials, psilocybin is poised to be the first classic psychedelic compound to attain FDA approval. This will almost certainly amplify efforts into the discovery of second- and third-generation psychedelics, perhaps better tuned toward specific clinical conditions. Regulatory approval will enable the refinement of clinical approaches to applying these compounds effectively in healing modalities, and possibly facilitate a better understanding of the underlying interplay between molecular pharmacology, systems neurobiology, and ultimately human behavior. While it is well established that the serotonin 2A receptor (5-HT2A) is central to mediating the effects of psychedelics, rational drug design is complicated by an inseparable and interdependent network of central nervous system (CNS) polypharmacology. With approval, I hope to see the advancement of better screening tools for assaying not only psychedelics, but also CNS-active compounds more broadly-new approaches that may help transcend a “one drug-one target” paradigm of drug discovery. Results from the clinic will ideally inform the parallel development of novel assay techniques toward the design of new and optimized chemical entities. Frank Wiegand: Having worked as a neurologist and then later as a drug developer in the psychiatric field for almost 30 years, I know firsthand how high the unmet medical need is for many patients suffering from neuropsychiatric conditions. New therapeutic options and medications that work through a different mode of action than currently available drugs are crucially needed to advance the field and improve the health of millions of people around the world. With that in mind, the regulatory approval of psychedelic medicines to address some of these conditions would be a huge step forward. Since I have the good fortune to be an active part of this development in my current capacity as Chief Medical Officer at Beckley Psytech (where I get to oversee the development of short-acting synthetic formulations of 5-methoxy-dimethyltryptamine [5-MeO-DMT] and psilocin for difficult-to-treat conditions), nothing would enrich my professional life more than being successful in bringing potentially paradigm-changing medicines to people in need. Laura Labay: As a forensic toxicologist in a CLIA-certified laboratory that provides routine testing for drugs of abuse and esoteric toxicology testing, FDA approval will likely result in a few key changes to laboratories. Even without FDA approval, one important part of our usual work is to evaluate emerging drugs and therapeutics for frequency of use with their potential to cause or contribute to death, produce impairment, or cause an adverse clinical event. This is done to ensure that the appropriate and relevant toxicology tests for each patient case or circumstance are available. This is a multi-step process that touches almost every working group within the laboratory. For example, test panels must be evaluated to determine if any reconfiguration is required. Should a particular psychedelic be added to the drug of abuse panels? If yes, are the analytical measurement ranges and quality control concentrations appropriately set to monitor concentrations that are expected following therapeutic use? Lastly, interpretive comments should also be reviewed and modified as needed to include any reference range data. Do you believe the media portrayal and attention given to psychedelic medicines will affect their regulatory future? If so, how? Alexander Sherwood: The portrayal of psychedelics in the media has ranged from dangerous illicit drugs to mental health panacea, with overstatements at both ends of these extremes. The reality is likely somewhere in the middle, and the interpretation of rigorous, objective scientific data is necessary to identify a signal in the noise. Recent scientific publications on psychedelics in mainstream journals have quickly topped “most read” rankings, which is certainly a major achievement; this was not happening 20 years ago. But with increased allure and attention, the impulse to move quickly may risk lowered research standards. A concerning observation is that scientific journals have been fast to publish psychedelic-related reports, especially those highlighting overly optimistic conclusions. Quick and painless peer-review processes are gratifying, but we should always welcome scrutiny. Considering the regulatory future of psychedelics, a challenging scenario is when weak science is published, and then misinterpreted and amplified by popular media. When weak science is amplified, unrelated significant findings in the same field may be dismissed by association; this results in setbacks for the whole field. A regulatory agency’s primary goal is the objective evaluation of a medication’s safety and effectiveness, and arguably media portrayal should have little influence. However, these agencies do not exist in a vacuum, and it is conceivably difficult to ignore the vast media attention given to psychedelics-good, bad, or misguided. James Mullally: In addition to reviewing objective data provided by drug manufacturers, the FDA also considers input from any and all relevant stakeholders when making regulatory decisions, so that they can fully consider the benefits and risks of a new drug for the target For example, the FDA has published guidance for how patient can provide data that can be in medical product development and regulatory it should not be that media could influence the understanding of the and of risk by psychedelic and that this understanding could a in FDA regulatory would therefore be for drug to this potential regulatory and to address it in their regulatory to the as of information to support the benefits and of risk Laura Labay: Substance drug and have increased over the is likely that the in drug use results from the need to the associated with the I patients and will drugs to treat conditions and as mood disorders, and that have not well to other As psychedelics more some and will to media to their benefits while those with a more will publish case and analytical in the scientific I do not believe what is psychedelics in any media should affect the regulatory The to a drug for use should be evidence and clinical good therapeutic with risk to the Frederick Barrett: A amount of the media attention for psychedelic drugs has been with some media being attention has the potential for psychedelics as medicines to in To date, and of at the and the of have been and on with the to or psychedelic use as medicine or These have been at in by media portrayal and attention given to psychedelic in and have been to the and use of psychedelic These for a potential future of a more landscape of and of psychedelic drugs in a to but it is what effect this will have on federal The FDA has been in the evaluation of psychedelics as medicines in as of a as is with challenges the of how to or control clinical trials with of the challenges to psychedelics as it currently the future of federal of psychedelic drugs will from clinical trials data. Frank Wiegand: is a of attention being to the development of psychedelic medicines This is likely to a of the that these compounds are that they the that they are drugs of that is a associated with the they human a of following some of the their therapeutic One of the of is the that this can to in the in can in patients that in clinical This has the to impact the results which we need to as as As we to the future development and of the will be need to and evaluate the scientific evidence and should specific attention to clinical we have seen a few clinical trials over the few years that the therapeutic use of psychedelic compounds in many conditions major depressive disorder disorder and use disorder and provide a for how to future or with the increased adoption of psychedelic Laura Labay: are from a and laboratory a psychedelics, any other drug or can be of the psychedelic medicines may potentially the for new to drug toxicology have to with test to the and the rapid of novel including synthetic and drugs in the or may to more development, and is but can be challenging laboratory may be or at Alexander Sherwood: A is an of or on who In the same that is by experts within the of medical psychedelics are tools benefits are the and paradigm in clinical the around the is arguably more toward therapeutic efficacy than the psychedelic drug To this medicine may some growing in to the appropriate of drugs and will need to address the of especially the of I not that has guidance as to how psychedelics into our current or clinical and these will a of new experts to identify in the use of As therapeutic are to the properties of psychedelics, important is and of or through adequate to ensure that are in to Frank Wiegand: are a number of challenges by the development of psychedelic from and to use and is important to that many of these psychedelic compounds have a and and have been by for of years in the of healing for and and as or The on their research and use in the and a of that has scientific for many that is of the clinical development of these compounds is in its we do not have on how and will But the FDA approval of in provide a at an of how was approved as a therapy for treatment-resistant depression and in and not a this receptor is also a compound with use, given and subject to a risk and evaluation I believe that the approval of has demonstrated the of the to novel treatment which are being in clinical When psychedelic I in the field would be well to the and the risk and benefits of psychedelics as medicinal and the appropriate for how they can be for the patients at the in the medical and with the frequency and to effects and medical James Mullally: One of the likely of increased adoption of psychedelic medicines is potential for illicit use, in part to One regulatory that could is with to the of drugs of abuse and therapeutic in These are that have of to the of specific for small To the risk of results to this the FDA to evaluate the potential for and to other small that are to be in from in the use For drugs of abuse this testing all other illicit drugs that an illicit drug may to use and for therapeutic drug this testing other drugs that are likely to be with increased adoption of psychedelic should to relevant drugs in this into their validation Frederick Barrett: therapy with high of psychedelic drugs are likely to that require appropriate in approaches will in many of the that are necessary for of psychedelic drugs, but additional and may be necessary to provide a for patients psychedelic Understanding and the appropriate of and for patients in these will be necessary for the of patient of the of psychedelic will be However, for and of mental health in this have not been How should the field of laboratory medicine to this rapidly expanding field of Frederick Barrett: in capacity to and further the use and effects of psychedelic drugs is must also increase our of clinical trials data and increase the and of efforts to and evaluate the therapeutic effects of psychedelic understanding of the acute effects of psychedelic drugs and effective approaches to and will be psychedelic can be but these challenging can be effectively in with and understanding of the in which and is not or in which psychedelics a risk to patients in the potential case of will also be Laura Labay: with is need to know what drugs and must be in their testing they are of to the medical that are part of the laboratory medicine will also need to consider and that help with result For example, is the with therapeutic use? is the with abuse or a is likely that and reference in addition to may to increase their related to of the testing that may be expected to will also be the need to support research and clinical trials clinical are to provide testing of clinical research Alexander Sherwood: efforts in the drug discovery are from the of laboratory but the many psychedelics may for as the field the are psychedelics to produce a sustained after the drug is and from the to with this therapeutic a in has been the of To date, this has As more psychedelics clinical and of may new for the discovery of potential associated with psychedelic may also to consider a to a specific Recent evidence has that for changes at the receptor can and the in by different psychedelic The is that may to the same psychedelic a but effect disorder has been in a small of the as for or years after to a psychedelic it has been that a may be a the of is and screening techniques are available to an psychedelics as psilocybin and have a of so current clinical trials only as and to determine if a patient is in good However, as novel psychedelics clinical trials or popular the safety of classic psychedelics is not are psychedelics with at the of psychiatric and have been to their use, by adverse including and Considering testing for medicine and it will be important to quickly identify the by compounds and to better hope is that a understanding of the toxicology between and psilocybin may the design of To this it is not what should be optimized in new psychedelic medicines that are both and of a the is in for assay design and testing. In the information by the clinical laboratory could be to not only patient to psychedelic drugs, but also the in discovery efforts into optimized Frank Wiegand: As we are our compounds into and are how the of should be and which medical to are always for good data that can inform in this but of the current in the neuropsychiatric field have when it to the therapeutic This is further complicated by the that the field is psychedelics in with and support as which can not be in The that the is a good for the effects of new molecular entities and be a but not tool for the discovery of new molecular entities new data and can the therapeutic potential of novel and help to the therapeutic efficacy As a clinical I attention to these findings and hope that we will also in the development of clinical that can be to therapeutic or determine the and for therapeutic James Mullally: As I to prescription psychedelic medicines is likely to result in increased of illicit use. When drugs may a safety should who are to these drugs to or other that could are also risks to the including and adverse effects to use of Testing for illicit use can therefore be an effective to these for or to from or to identify a drug as the cause of to help ensure it will be the medical to and that are and of psychedelic do you will be the greatest of this new area of Frank Wiegand: I and that patients will be the of psychedelic But since many of the neuropsychiatric currently as depression, and substance abuse have a not only on patients but also on their and I believe that and as a whole will also from novel treatment As in my a huge unmet need for many of these conditions and existing treatment are and are an new paradigm for the first be an for a pharmacological medications will not have to be on a but could be or in an If this a then many patients not be to the effects of If we are to these compounds and the rapid effects and that Phase and some Phase III I believe we can tremendous suffering around the world. Frederick Barrett: hope is that people who are suffering from mood and substance use disorders, and psychiatric and all those who are not will to and effective that the they approach the and their within the world. this it that psychedelic drugs, the may but we must better understand the and the of these effects as well as the of these drugs, and for and what conditions they risks than is that, if approved as both and to to these medicines will be that will to only those with the greatest of that have been in this especially in the of and the to date, will be The regulatory of the of these drugs as medicines in the case of an drug safety as a and will need to be the safety and the of these drugs and their associated Alexander Sherwood: better approaches toward mental health a and that ultimately hope is that the adoption of psychedelics as medicine may not only suffering for those who have not been by current but also address in our by a new to better and perhaps the underlying of mental in this James Mullally: As is for medications that have been to be and effective for their by the FDA, patients will likely be the greatest of approvals for new psychedelic Laura Labay: The greatest should be patients with conditions that affect as anxiety, and depression. is that though mental health conditions can be as as some treatment and support from and of The and be is and the of these disorders. As new drugs in this are or for their demonstrated use in clinical will the need to further associated with these as well as the and treatment FDA, US Food and Drug Medical Review serotonin 2A in authors they have to the of this and have the following (a) significant to the and of or and interpretation of (b) or the for (c) approval of the published and to be for all of the that related to the or of any part of the are appropriately investigated and Frederick Frederick Laura James Alexander and Frank all authors the and/or potential of of Medical of Toxicology Advisory Board member for the in forensic toxicology of and The for and the member for is a of Beckley Psytech Medical Advisory for a study and board member on the Drug Testing Advisory Board from to The Johns Hopkins for and by from the and as well as and support for and/or from support for and/or from