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Experimental Therapeutics

Experimental therapeutics is the development of treatment strategies that more effectively and specifically treat human disease with less toxicity. Research in experimental therapeutics integrates multiple disciplines in order to understand the disease from the molecular to organismal levels and then strives to apply this knowledge to identify and validate targets, discover and develop interventions or drugs to manipulate these targets, and ultimately drive preclinical and clinical studies to reach the goal of personalized medicine. 

Through the core curriculum, students within the program will gain a fundamental understanding of pharmacology and the important of signaling transduction pathways in human disease and the molecular mechanisms of current successful drugs. Elective courses allow students to tailor their training by obtaining additional exposure to such topics as drug design, the use of animal models, and drug delivery, including biological agents such as viruses. This program aims to train students with the skills to translate knowledge gained from basic research to clinical setting. In addition to the core curriculum, for a student to receive the transcript designation of experimental therapeutics, he/she must complete a total of 10 credit hours.

Upon completion of a PhD with a distinction in experimental therapeutics, students will be well-equipped for the pursuit of careers in multiple fields including, academic research and the pharmaceutical and biotechnology industries.

Matthew Summers , PhD , and Rosa Lapalombella, PhD Faculty Liaisons

Program Curriculum

Course Requirements

• PHR 5010 Fundamentals of Pharmacology (3 credits): This course overviews principles underlying drug action, including an investigation of current treatments for a variety of common diseases. In addition, this course will implement activities that emphasize the ethical aspects and implications of a variety of drug therapies. Prereq: Not open to students with credit for 2010, or 4400, or Pharmcl 5600, or HthRhSc 5510; or enrollment in BSPB or PharmD program.
• PHARMCL 8300 Molecular Pharmacolodesignatigy and Human Disease (2 credits): Molecular mechanisms of actions of blockbuster drugs in the treatment of human disease. Prereq: Not open to students with credit for 2010, or 4400, or Pharmcl 5600, or HthRhSc 5510; or enrollment in BSPB or PharmD program.
• MOLBIOC 7928 Signaling Pathways and Human Disease (2 credits): Current concepts of signal transduction and its role in controlling genes involved in various disease states, including cardiovascular diseases, neurological diseases, and cancer. 

Elective Courses

• PHR 7350 Drug Discovery and Drug Design (2 credits): A study of the discovery and design of new drugs; topics include natural products isolation, molecular modeling, molecular targets, and biosynthesis and metabolism. Prereq: Grad standing and permission of instructor. Not open to students with credit for Pharmacy 735.
• PHR 7580 Principles of Safety Pharmacology (3 credits): Introduction to organ system studies of current experimental models, risk assessment, and regulatory guidelines for evaluating drug candidates in various organ systems. Prereq: Admission to the MS in Applied Clinical and Preclinical Research program, or permission of instructor.
• MOLBIOC 7781 Animal Models of Human Disease (1 credit): Transgenic and knockout mouse technology and examples of models for genetic disease with each pattern of inheritance. Examples are collagen diseases (osteogenesis imperfecta), Huntington diseases, muscular dystrophy, and Friedreich ataxia. Prereq: MolGen 5701 (701) or Biochem 5701 (702). Not open to students with credit for MolBioch 781.
• PHR8040 Drug Transport (2 credits): Drug administration, drug absorption, biological barriers, and technology to overcome these barriers. Prereq: Grad standing, or permission of instructor. Not open to students with credit for Pharmacy 804.
• PHR 8070 Advanced Drug Delivery Systems (2 credits): Topics on drug delivery systems with emphasis on tumor targeted delivery and nanovehicles. Prereq: Grad standing or permission of instructor. Not open to students with credit for Pharmacy 807.
• CBG 7741 Molecular Biology and Pathogenesis of Viruses (5 credits): An integrated study of the molecular mechanisms of virus replication and host-virus relationships that control virus pathogenesis or use as a therapeutic agent. Cross listed as MolGen 7540 and in VetBios.
• BSGP 8800.04 Cancer Biology & Therapeutics (2 credits): Topics on translational research with emphasis on cancer biology, genetic and epigenetic basis of cancer pathogenesis, as well as preclinical and clinical drug development. Prereq: Enrollment in MD or DO degree program, or permission of instructor.

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• BSGP Student Handbook PDF
• Contact Biomedical Sciences Graduate Program 1022 Graves Hall , 333 W. 10th Ave Columbus, OH 43210  614-685-9140 [email protected]  

Experimental and Therapeutic Medicine

ISSN 1792-0981 (Print); ISSN 1792-1015 (Online)

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Leading Change in Cancer Clinical Research, Because Our Patients Can’t Wait

May 31, 2024 , by W. Kimryn Rathmell, M.D., Ph.D., and Shaalan Beg, M.D.

Greater use of technologies that can increase participation in cancer clinical trials is just one of the innovations that can help overcome some of the bottlenecks holding up progress in clinical research. 

Thanks to advances in technology, data science, and infrastructure, the pace of discovery and innovation in cancer research has accelerated, producing an impressive range of potential new treatments and other interventions that are being tested in clinical studies . The extent of the innovative ideas that might help people live longer, improve our ability to detect cancer early, or otherwise transform care is staggering. 

Our understanding of tumor biology is also evolving, and those gains in knowledge are being translated into the continued discovery of targets for potential interventions  and the development of novel types of treatments. Some of these therapies are producing unprecedented clinical responses  in studies, including in traditionally difficult-to-treat cancers. 

These advances have contributed to a record number of Food and Drug Administration (FDA) approvals in recent years with, arguably, the most notable approvals being those for drugs that can be used for any cancer, regardless of where it is in the body . 

In some instances, the activity of new agents has been so profound that clinical investigators are having to rethink their criteria for implementation in patient care and their definitions of treatment response. 

For example, although HER2 has been a known therapeutic target in breast cancer for many decades, the new antibody-drug conjugates  (ADCs) that target HER2 have proven to be vastly more effective than the original HER2-targeted therapies. This has forced researchers to rethink fundamental questions about how these ADCs are used in patient care: Can they be effective in people whose tumors have lower expression of HER2 than we previously thought was needed ? And, if so, do we need to redefine how we classify HER2-positive cancer? 

As more innovative therapies like ADCs hit the clinic at a far more rapid cadence than ever before, the research community is being inundated with such fundamentally important questions.

However, the remarkable progress we're experiencing with novel new therapies is tempered by a critical bottleneck: the clinical research infrastructure can’t be expected to keep pace in this new landscape. 

Currently, many studies struggle to enroll enough participants. At the same time, there are patients who don’t have ready access to studies from which they might benefit. Furthermore, ideas researchers have today for studies of innovative new interventions might not come to fruition for 2 or 3 years, or even longer—years that people with cancer don’t have. 

The key to overcoming this bottleneck is to invite innovation to help reshape our clinical trials infrastructure. And here’s how we plan to accomplish that.

Testing Innovation in Cancer Clinical Trials

A transformation in cancer clinical research is already underway. That transformation has been led in part by the success of novel precision oncology approaches, such as those tested in the NCI-MATCH trial .

This innovative study ushered in novel ways of recruiting participants and involving oncologists at centers big and small. And NCI-MATCH has spawned several successor studies that are incorporating and building on its innovations and achievements.

An innovation that emerged from the COVID pandemic was the increase of remote work, even in the clinical trials domain. Indeed, staffing shortages have caused participation in NCI-funded trials to decline. In response, NCI is piloting a Virtual Clinical Trials Office to offer remote support staff to participating study sites. This support staff includes research nurses, clinical research associates, and data specialists, all of whom will help NCI-Designated Cancer Centers and community practices engaged in clinical research activities.

Such technology-enabled services can allow us to reimagine how clinical trials are designed and run. This includes developing technologies and processes for remotely identifying clinical trial participants, shipping medications to participants at home, having imaging performed in the health care settings where our patients live, and empowering local physicians to participate in clinical trials.

We also need mechanisms to test and implement innovations in designing and conducting clinical studies. 

The Pragmatica-Lung Cancer Treatment Trial , an innovative phase 3 study launched by  NCI’s National Clinical Trials Network (NCTN) , was designed to be easy to launch, enroll participants, and interpret its results. 

NCI recently established Clinical Trials Innovation Unit (CTIU) to pressure test a variety of innovations. The CTIU, which includes leadership from FDA and NCTN, is already working on future innovations, including those that will streamline data collection and apply novel approaches to clinical studies, all with the goal of making them less burdensome to run and easier for patients to participate.

Data-Driven Solutions

The era of data-driven health care is here, providing still more opportunities to transform cancer clinical research. 

The emergence of artificial intelligence (AI) solutions, large language models, and informatics brings real potential for wholesale changes in how we match patients to clinical studies, assess side effects, and monitor events like disease progression. 

Recognizing this potential, NCI is offering funding opportunities and other resources that will fuel the development of AI tools for clinical research, allow us to carefully test their usefulness, and ultimately deploy them across the oncology community. 

Creating Partnerships and Expanding Health Equity

To be sure, none of this will be, or can be, done by NCI alone. All these innovations require partnerships. We will increase our engagement with partners in the public- and private-sectors, including other government agencies and nonprofits. 

That includes high-level engagement with the Office of the National Coordinator for Health Information Technology (ONC), with input from FDA, Centers for Medicare & Medicaid Services, and Centers for Disease Control and Prevention.

Dr. W. Kimryn Rathmell, M.D., Ph.D.

NCI Director

One example of such a partnership is the USCDI+ Cancer program . Conducted under the auspices of the ONC, this program will further the aims of the White House's reignited Cancer Moonshot SM by encouraging the adoption and utilization of interoperable cancer health IT standards, providing resources to support cancer-specific use cases, and promoting alignment between federal partners. 

And just as importantly, the new partnerships we create must include those with patients, advocates, and communities in ways we have never considered before.

A central feature of this community engagement must involve intentional efforts to expand health equity, to create study designs that are inclusive and culturally appropriate. Far too many marginalized communities and populations today are further harmed by studies that fail to provide findings that apply to their unique situations and needs.

Very importantly, the future will require educating our next generation of clinical investigators and empowering them with the tools that enable new ways of managing clinical studies. By supporting initiatives spearheaded by FDA and professional groups like the American Society of Clinical Oncology, NCI is making it easier for community oncologists to participate in clinical trials and helping clarify previously misunderstood regulatory requirements. 

These efforts must also ensure that we have a clinical research workforce that is representative of the people it is intended to serve. Far too many structural barriers have prevented this from taking place in the past, and it’s time for that to change. 

Expanding our capacity doesn’t mean doing more of the same, it means challenging ourselves to work differently. This will let us move forward to a new state, one in which clinical research is integrated in everyday practice. It is only with more strategic partnerships and increased inclusivity that we can open the doors to seeing clinical investigation in new ways, with new standards for success.

A Collaborative Effort

Shaalan Beg, M.D.

Senior Advisor for Clinical Research

To make the kind of progress we all desire, we have to recognize that our clinical studies system needs to evolve.

There was a time when taking years to design, launch, and complete a clinical trial was acceptable. It isn’t acceptable anymore. We are in an era where we have the tools and the research talent to make far more rapid progress than we have in the past. 

And we can do that by engaging with many different communities and stakeholders in unique and dynamic ways—making them partners in our effort to end cancer as we know it.

Together, our task is to capitalize on this work so we can move faster and enable cutting-edge research that benefits as many people as possible. 

We also know that there are more good ideas in this space, and part of this transformation includes grass roots efforts to drive systemic change. So, we encourage you to share your ideas on how we can transform clinical research. Because achieving this goal can’t be done by any one group alone. We are all in this together. 

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June 1, 2024

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Experimental therapy shows promise in pancreatic cancer clinical trial

by Georgetown University Medical Center

Clinicians at Georgetown University's Lombardi Comprehensive Cancer Center reported promising preliminary findings based on outcomes in the first six patients with metastatic pancreatic cancer enrolled in a Phase II clinical trial of the experimental drug BXCL701 in combination with the immunotherapy drug pembrolizumab (Keytruda). Immunotherapy drugs alone have not shown to be responsive to pancreatic cancer.

The findings are being presented at the American Society of Clinical Oncology 2024 annual meeting in Chicago on June 1, 2024 (LBA4132).

BXCL701, made by BioXcel Therapeutics, is an oral drug called an immune activator. It acts by inflaming the microenvironment surrounding the tumor and thereby augmenting the activity of immunotherapies like pembrolizumab. BXCL701 has received Orphan Drug Designation from the U.S. Food and Drug Administration in pancreatic cancer and three other cancer types: acute myelogenous leukemia , stage IIb to IV melanoma, and soft tissue sarcoma.

Pancreatic cancer is the third leading cause of cancer death. The five-year survival rate for all stages of the disease is 13% but there's no early detection method and therefore patients are often diagnosed with later stage disease. For those with disease that has spread beyond the pancreas, the five-year survival rates are an extremely low 3%.

"Pancreatic cancer is a devastating disease that is difficult to treat with standard methods, including chemotherapy," says Benjamin Adam Weinberg, MD, an associate professor of medicine at Georgetown Lombardi and lead investigator of this trial.

"Using immunotherapy alone to harness the body's own immune system has also generally not worked due to the inability of immune cells to infiltrate pancreatic tumors due to dense fibrous tissue that walls tumors off microscopically from the immune system. Hence the need to find another approach."

In pre-clinical mouse studies , published in 2021, researchers led by Louis Weiner, MD, director of Georgetown University's Lombardi Comprehensive Cancer Center, showed that when combined with an immunotherapy drug, BXCL701 boosted the animals' natural immune systems, slowing or even stopping pancreatic tumor growth.

The mouse studies found evidence that tumors had been flooded by natural killer immune cells, a sign that the drug had accomplished its goal of making cancer cells receptive to the immune system. In short order, these mouse studies led directly to this first-in-human trial of the drug in pancreatic cancer.

For the initial part of the trial looking primarily at the safety aspect of the drug combination, three women and three men with a median age of 57 were enrolled. One patient showed no signs of disease progressing after 18 weeks on the trial and one patient had stable disease at nine weeks but was not yet evaluable for the 18-week landmark. The progression-free survival rate (no change or even signs of regression in the tumor) as determined by imaging was 50%.

Three patients had significant reductions in a marker that indicates the presence of pancreatic cancer, CA19-9, with 100%, 97% and 73% reductions. Weinberg says that CA19-9 is the best marker they have in pancreatic cancer, but it is not as good a screening test as PSA is for prostate cancer. He believes, however, that it can be useful for monitoring disease activity in patients with advanced cancers. Not every patient's tumor makes CA19-9 but so far in this study all patients have had elevated CA19-9 levels.

According to Weinberg, the main side effect so far is low blood pressure , which can be mitigated by giving BXCL701 at a lower dose during the first week of treatment. The clinicians are also seeing anemia, nausea, and immune-related arthritis, which has responded to oral steroids.

"Historically, no one has responded to immunotherapy in pancreatic cancer so even one response and another with stable disease could be early signs of efficacy," says Weinberg. "A third patient had an initial drop in their CA19-9 marker even though they had disease progression on imaging, and this may be more early evidence that this drug combination has anti-cancer effects."

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Ewing sarcoma treatment: a gene therapy approach

Affiliations.

• 1 Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre "Digital Biodesign and Personalized Healthcare", I.M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
• 2 National Cancer Institute, National Institutes of Health, Bethesda, MD, 20814, USA.
• 3 Section of Virology, Faculty of Biology, Lomonosov Moscow State University, Moscow, 119234, Russia.
• 4 World-Class Research Centre "Digital Biodesign and Personalized Healthcare", Sechenov First Moscow State Medical University, Moscow, 119991, Russia.
• 5 Group of Experimental Biotherapy and Diagnostics, Institute for Regenerative Medicine, World-Class Research Centre "Digital Biodesign and Personalized Healthcare", I.M. Sechenov First Moscow State Medical University, Moscow, 119991, Russia. [email protected].
• PMID: 37037906
• PMCID: PMC10088695
• DOI: 10.1038/s41417-023-00615-0

Ewing sarcoma (ES) is an aggressive malignant tumor, characterized by non-random chromosomal translocations that produce fusion genes. Fusion genes and fusion protein products are promising targets for gene therapy. Therapeutic approaches and strategies vary based on target molecules (nucleotides, proteins) of interest. We present an extensive literature review of active molecules for gene therapy and methods of gene therapy delivery, both of which are necessary for successful treatment.

© 2023. The Author(s), under exclusive licence to Springer Nature America, Inc.

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Conflict of interest statement

The authors declare no competing interests.

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Bacteriophages as Therapeutic Preparations: What Restricts Their Application in Medicine

• Published: 26 November 2020
• Volume 85 , pages 1350–1361, ( 2020 )

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• V. V. Vlassov 1 ,
• N. V. Tikunova 1 &
• V. V. Morozova 1  

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The increasing prevalence of bacterial pathogens with multiple antibiotic resistance requires development of new approaches to control infections. Phage therapy is one of the most promising approaches. In recent years, research organizations and a number of pharmaceutical companies have intensified investigations aimed at developing bacteriophage-based therapeutics. In the United States and European countries, special centers have been established that experimentally apply phage therapy to treat patients who do not respond to antibiotic therapy. This review describes the features of bacteriophages as therapeutic tools, critically discusses the results of clinical trials of bacteriophage preparations, and assesses the prospects for using phage therapy to treat certain types of infectious diseases.

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This work was financially supported by the Russian Foundation for Basic Research (project no. 18-29-08015).

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Vlassov, V.V., Tikunova, N.V. & Morozova, V.V. Bacteriophages as Therapeutic Preparations: What Restricts Their Application in Medicine. Biochemistry Moscow 85 , 1350–1361 (2020). https://doi.org/10.1134/S0006297920110061

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Experimental Therapy Shows Promise in Pancreatic Cancer Clinical Trial

Posted in News Release  |  Tagged clinical trials , pancreatic cancer , translational research

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Karen Teber [email protected]

WASHINGTON (June 1, 2024) — Clinicians at Georgetown University’s Lombardi Comprehensive Cancer Center reported promising preliminary findings based on outcomes in the first six patients with metastatic pancreatic cancer enrolled in a phase 2 clinical trial of the experimental drug BXCL701 in combination with the immunotherapy drug pembrolizumab (Keytruda). Immunotherapy drugs alone have not shown to be responsive to pancreatic cancer.

The findings were presented at the American Society of Clinical Oncology 2024 annual meeting in Chicago on June 1, 2024.

BXCL701, made by BioXcel Therapeutics, is an oral drug called an immune activator. It acts by inflaming the microenvironment surrounding the tumor and thereby augmenting the activity of immunotherapies like pembrolizumab. BXCL701 has received Orphan Drug Designation from the U.S. Food and Drug Administration in pancreatic cancer and three other cancer types: acute myelogenous leukemia, stage IIb to IV melanoma, and soft tissue sarcoma.

Pancreatic cancer is the third leading cause of cancer death. The five-year survival rate for all stages of the disease is 13%, but there’s no early detection method and therefore patients are often diagnosed with later stage disease. For those with disease that has spread beyond the pancreas, the five-year survival rates are an extremely low 3%.

“Pancreatic cancer is a devastating disease that is difficult to treat with standard methods, including chemotherapy,” says Benjamin Adam Weinberg, MD, an associate professor of medicine at Georgetown Lombardi and lead investigator of this trial. “Using immunotherapy alone to harness the body’s own immune system has also generally not worked due to the inability of immune cells to infiltrate pancreatic tumors due to dense fibrous tissue that walls tumors off microscopically from the immune system. Hence the need to find another approach.”

In preclinical mouse studies published in 2021 , researchers led by Louis Weiner, MD, director of Georgetown University’s Lombardi Comprehensive Cancer Center, showed that when combined with an immunotherapy drug, BXCL701 boosted the animals’ natural immune systems, slowing or even stopping pancreatic tumor growth. The mouse studies found evidence that tumors had been flooded by natural killer immune cells, a sign that the drug had accomplished its goal of making cancer cells receptive to the immune system. In short order, these mouse studies led directly to this first-in-human trial of the drug in pancreatic cancer.

For the initial part of the trial looking primarily at the safety aspect of the drug combination, three women and three men with a median age of 57 were enrolled. One patient showed no signs of disease progressing after 18 weeks on the trial and one patient had stable disease at nine weeks but was not yet evaluable for the 18-week landmark. The progression-free survival rate (no change or even signs of regression in the tumor) as determined by imaging was 50%.

Three patients had significant reductions in a marker that indicates the presence of pancreatic cancer, CA19-9, with 100%, 97% and 73% reductions. Weinberg says that CA19-9 is the best marker they have in pancreatic cancer, but it is not as good a screening test as PSA is for prostate cancer. He believes, however, that it can be useful for monitoring disease activity in patients with advanced cancers. Not every patient’s tumor makes CA19-9, but so far in this study all patients have had elevated CA19-9 levels.

According to Weinberg, the main side effect so far is low blood pressure, which can be mitigated by giving BXCL701 at a lower dose during the first week of treatment. The clinicians are also seeing anemia, nausea and immune-related arthritis, which has responded to oral steroids.

“Historically, no one has responded to immunotherapy in pancreatic cancer, so even one response and another with stable disease could be early signs of efficacy,” says Weinberg. “A third patient had an initial drop in their CA19-9 marker even though they had disease progression on imaging, and this may be more early evidence that this drug combination has anti-cancer effects.”

In addition to Weinberg, authors include Alexander Lekan, Allison Fitzgerald, Zoe Malchiodi, Martin Gutierrez, Anteneh A. Tesfaye, Ming Tony Tan, Marcus Smith Noel, Aiwu Ruth He, Reetu Mukherji, John Marshall, Princess Jones, Pascal Borderies, Vincent O’Neill and Louis M. Weiner at Georgetown and the Georgetown-affiliated John Theurer Cancer Center, Hackensack University Medical Center, Hackensack, New Jersey.

This research was supported by BioXcel Therapeutics, New Haven, Connecticut.

Weinberg reports having no personal financial interests related to the study. Weiner’s research is supported in part by BioXcel Therapeutics, Inc., the company developing BXCL701. Support for his work is also provided by the Edwin and Linda Siegel Family Foundation. Weiner reports no other conflicts related to the study. The clinical trial is supported by BioXcel Therapeutics, Inc. and Merck.

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Psychedelic therapies reconsidered: compounds, clinical indications, and cautious optimism

• Jennifer M. Mitchell   ORCID: orcid.org/0000-0002-7567-8129 1 , 2 , 3 , 4 &
• Brian T. Anderson 2 , 4  

Neuropsychopharmacology volume  49 ,  pages 96–103 ( 2024 ) Cite this article

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The clinical investigation of psychedelic medicines has blossomed over the last 5 years. Data from a Phase 3 industry trial and a multicenter Phase 2 industry trial, in addition to multiple early phase investigator-initiated and industry trials, have now been published in peer-reviewed journals. This narrative review summarizes both the recent data and the current clinical trials that are being conducted with various classes of “psyche-manifesting” substances, which may prove beneficial in the treatment of a broad range of conditions. Methodological considerations, unique challenges, and next steps for research are discussed in keeping with the uniquely “experiential” nature of these therapies.

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Introduction.

The past few years have ushered in a renewed wave of psychedelic interest and research that has led to the clinical testing of multiple psychedelic agents for various health conditions. Australia and Canada have even recently approved the clinical use of certain psychedelic medicines under restricted circumstances [ 1 , 2 ]. However, along with this renewed wave of interest has come a series of challenges with respect to the taxonomy of psychedelics, the implementation of best practices for the evaluation of psychedelic therapies, and the capacity to stay abreast of developments in this rapidly expanding scientific field. Here we review the contemporary clinical research to provide an overview of the different classes of psychedelics currently under investigation for clinical use, their proposed indications, and—because they are “experiential medicines”—considerations for their judicious use.

Psychedelics have long been implicated in the treatment of mood and anxiety disorders, as well as disorders related to impulsivity, repetitive behaviors, and impaired decision-making, such as alcohol and other substance use disorders [ 3 , 4 , 5 ]. Yet the clinical promise of mid-20th Century psychedelic research was ultimately overshadowed by methodological limitations [ 6 ], regulatory restrictions, and a political landscape that made psychedelic research all but untenable for several decades [ 7 ]. Current biomedical theories speculate that psychedelic therapies improve clinical functioning by regulating affective states (such as anhedonia) and self-referential cognitive processes and may therefore ultimately involve interrelated neural circuits across a broad range of conditions [ 8 , 9 ]. Along these lines, the current clinical research landscape has expanded significantly compared to even a few years ago [ 10 ], and now includes evaluations of the effects of psychedelic therapies in a wide array of diagnostic categories, including mood disorders, substance use disorders, obsessive compulsive and related disorders, trauma-related disorders, and disorders of dysfunctional coping such as pathological grief and end of life distress. Typically, when investigated as therapies for psychiatric conditions, psychedelics are administered as adjuncts to a brief course of behavioral therapy to mitigate the risk of adverse events and to augment efficacy [ 11 , 12 ].

In addition to psychiatric indications, psychedelics are also being studied more generally as neuroplastic agents, potentially capable of inducing change in intractably crystalized neurological pathways. As such, they are being pursued as therapeutics for age-related degenerative conditions—including Alzheimer’s and Parkinson’s—as well as for pain, headache and migraine, autism, and visual impairments. Only time will tell if these compounds can reverse ingrained neurological processes, perhaps by enabling neuroplasticity, to the point where previously inflexible systems can be adjusted and reset.

Defining psychedelic

The original definition of the term psychedelic , as coined by the psychiatrist Humphry Osmond, is “mind-” or “soul-manifesting”, and as such is independent of biological mechanism. With this definition in mind, drugs that activate the serotonin 5-HT2A receptor directly (typically termed classic psychedelics) [ 13 ] as well as those that activate serotonin receptors indirectly or not at all, or that work through binding to a combination of receptors (including glutamatergic, dopaminergic, and opioidergic receptors) would all be considered psychedelic if they demonstrate the capacity for allowing greater access to the psyche in a manner similar to the classic psychedelics. Therefore, this review will include a series of drugs that meet the original definition of psychedelic for which there exists preliminary evidence from modern trials of the potential to affect psychotherapeutic change in humans. Some atypical, or non-classic, psychedelics are also included here; these are drugs with psychoactive effects that are not primarily or uniquely mediated through the activation of the 5-HT2A receptor. The decades-long history of the use of substances like ketamine [ 14 , 15 ] and psychedelic amphetamines like 3,4-methelenedioxyamphetamine (MDA) [ 16 ] in psychedelic therapy suggests that a comprehensive review of psychedelic therapies should include drugs beyond the classic psychedelics.

While the term hallucinogen is often colloquially substituted for the term psychedelic, hallucinogens are a category of drugs that induce perceptions in the absence of external stimuli (as opposed to inducing perceptual distortions of extant stimuli). Therefore, although there is some overlap in the categories of hallucinogen and psychedelic, here we will only use the term psychedelic, as we are summarizing effects that are more broadly relevant to processes of psychotherapeutic change, and not limited to perceptual alterations per se. With these definitions in mind, and considering the available data and currently registered trials, the modern clinical investigation of the following classic and atypical psychedelics (henceforth, collectively referred to as “psychedelics”) will be discussed in this review: ayahuasca, N,N-dimethyltrypatmine (DMT) and 5-methoxy-DMT (5-MeO-DMT), ibogaine, ketamine, lysergic acid diethylamide (LSD), 3,4-methylenedioxymethamphetamine (MDMA), mescaline, salvinorin A, and psilocybin. In addition, as psychedelics are thought to be “experiential medicines” affected by both set and setting [ 17 , 18 , 19 ], attention will also be focused on the environmental and psychological conditions that modulate the therapeutic efficacy of psychedelics.

Many psychedelic molecules have structural similarities that may enable specific signaling mechanisms. However, molecular differences allow them to be divided into indolamines (including the ergolines and simple tryptamines), phenethylamines, diterpines, and cyclohexanones. Each of these will be discussed in turn in an attempt to provide the reader an up-to-date view of the rapidly evolving field of clinical research into psyche -manifesting drugs.

Indolamines

Ibogaine is an indolamine that is derived from the West African Tabernanthe iboga bush that has long been used as part of the Bwiti religious tradition in the jungles of Gabon [ 20 ]. Ibogaine binds dopamine and serotonin (5-HT) receptors, acts as both an NMDA and a3b4-nicotinic receptor antagonist, and acts as a kappa opioid receptor agonist [ 21 ]. Although ibogaine was originally touted as an anti-addiction medication as far back as the 1960s https://www.nytimes.com/2010/02/17/us/17lotsof.html , it took over 30 years for it to make its way into phase 1 clinical studies, which indicated that, although ibogaine has the potential to be an effective an anti-addiction therapeutic for a number of different substance use disorders [ 22 , 23 , 24 ], it also carries cardiac and neurological risks that complicate its use as a therapeutic [ 25 , 26 , 27 ]. A series of sudden and unexpected deaths halted phase 1 testing for drug abuse and dependence [ 25 , 28 ] and clinical trials have yet to resume in the United States, although there is growing political support for these studies [ 29 ].

Although ibogaine is a Schedule 1 substance and is not FDA approved, over the last few decades it has been administered at drug and alcohol treatment centers in Latin America and the Caribbean, and it is currently under investigation outside of the United States as a potential therapeutic for alcohol misuse (NCT03380728), and for drug use, dependence, and withdrawal (NCT04003948; NCT05029401). Recent data suggest that the potential negative impact of ibogaine on cardiac function can be controlled through careful screening and monitoring during drug administration [ 30 ] and that, as both ibogaine and methadone may induce QT prolongation (an alteration in cardiac ventricular repolarization that is associated with the Torsade de Pointes arrhythmia and increased risk of sudden cardiac death), care should be taken to ensure that those seeking ibogaine treatment for opioid use disorder are screened for the use of methadone and other QT prolonging drugs prior to ibogaine administration.

Elucidation of the mechanism(s) by which ibogaine exerts its clinical effects might lend insight into the contribution of various neurotransmitter systems to the clinical effectiveness of psychedelics, as ibogaine is perhaps one of the least pharmacologically specific, and yet most impactful, psychedelics currently under investigation.

Indolamines: Ergolines

Lysergic acid diethylamide (lsd).

LSD was first synthesized by the chemist Albert Hoffman during his employment with Sandoz Pharmaceuticals in the 1930s while he was searching for novel compounds to treat respiratory depression. LSD has since been shown to bind with high affinity to several 5-HT receptors [ 31 ] and also acts as a dopamine (D1, D2, D4) receptor agonist [ 32 , 33 ]. Potential clinical indications include alcohol and other substance use disorders [ 34 , 35 , 36 ], obsessive compulsive disorder [ 37 ], depression (now in phase 2), end of life anxiety [ 38 ], cluster headache [ 39 ], and attention-deficit hyperactivity disorder (ADHD) [ 40 ]. LSD has long been available through Compassionate Use laws in Switzerland as an adjunct to psychotherapy for the treatment of a number of different mental health conditions [ 41 ].

Although a substantial volume of data from the 1960s to 1970s suggest that LSD could be effective in decreasing alcohol consumption in self-ascribed, and self-selected, “alcoholics,” [ 42 ] and although a more recent meta-analysis that incorporated clinical data from 6 smaller studies demonstrated that a single dose of LSD resulted in a long-term decrease in alcohol “misuse,” [ 35 ] previous outcome measures were not collected using current methodological standards and should therefore be replicated to confirm and extend previous findings in a thoroughly characterized subject population with alcohol use disorder (AUD). Fortunately, a double-blind, placebo-controlled, randomized, multisite study is currently being planned (NCT05474989) to evaluate the effects of two doses of LSD (150 µg for first dose followed by either 150 µg or 250 µg for second dose) on prevention of relapse to alcohol in a population with AUD. These data will hopefully provide insight into whether LSD does indeed hold promise as a potential therapeutic for AUD.

LSD has also recently completed early phase clinical testing for anxiety disorders (NCT03153579; NCT00920387) and the results have shown that LSD decreases anxiety while increasing quality of life [ 43 ] and also, importantly, that these effects are long-lasting [ 38 ]. In addition, a randomized, double-blind, placebo-controlled phase 2 trial of LSD for major depression (comparing two moderate to high doses of LSD = 100 µg/100 µg or 100 µg/200 µg, and two low doses of LSD = 25 µg/25 µg) has now been completed (NCT03866252), although these data were not yet available for review at the time of this publication. Lastly, a multisite, randomized, double-blind, placebo-controlled phase 2 trial is also currently being planned to further study the use of LSD for adults with ADHD (NCT05200936).

In addition to the mental health disorders listed above, both case (40. Sewell et al., 2006) and self-reports [ 44 ] indicate that LSD could be effective in combating cluster headache, and a double-blind, randomized, placebo-controlled phase 2 trial of LSD (3 doses of 100 mcg over 3 weeks) has recently been initiated to evaluate the efficacy of LSD for treatment of cluster headache (NCT03781128). Finally, as part of a drug development program for treating Alzheimer’s Disease, a recent double-blind randomized pilot trial of repeated (every 4 days) low doses of LSD (5 mcg vs 10 mcg vs 20 mcg vs placebo) in healthy older adults (age 55–75) found the drug to be well-tolerated in this population [ 45 ].

Indolamines: Simple tryptamines

Psilocybin is an active agent in Psilocybe mushrooms, which have been used ritualistically for thousands of years by Indigenous communities in Central and North America. Psilocybin exerts its psychedelic effects primarily through activation of 5HT2A receptors [ 46 ] and through activation of a 5-HT2AR-mGluR2 receptor complex [ 47 ]. Likely due to its well-established safety profile, minimal abuse potential, and short duration of subjective perceptual effects, psilocybin is currently the most broadly studied psychedelic for mental health conditions. Clinical indications under investigation currently include major depression [ 48 ], treatment-resistant depression [ 49 ], alcohol and other substance use disorders [ 50 ], smoking cessation [ 51 ], and OCD [ 52 ]. Psilocybin has also been studied in conjunction with individual and group psychotherapy for treating distress in patients with serious illness including cancer-related mood and anxiety disorders, and demoralization in long term AIDS survivors [ 53 ].

Not only has psilocybin been successfully administered for smoking cessation [ 51 , 54 ], but, intriguingly, it has also been shown that change in tobacco consumption following psilocybin administration is correlated with the degree of “mystical-type experience” reported by study participants, such that those reporting greater intensity of mystical-type experiences also report a greater decrease in smoking [ 54 ]. While there remains great debate over the nature and assessment of a “mystical-type experience”, high-dose psilocybin has repeatedly been reported by participants to be a spiritual or transcendent event, which seems to be an important contributor to treatment effectiveness [ 55 ] and, as such, merits further attention.

A modest-sized proof of principle phase 2 trial recently demonstrated the significant and long-lasting efficacy of psilocybin when combined with psychotherapy for the treatment of AUD ( 50 . Bogenschutz et al., 2022). Mechanistic (NCT04141501), head-to-head (NCT05421065), larger, multisite (NCT05646303), and other trials (NCT04620759) of psilocybin therapy for AUD are currently recruiting.

The most detailed exploration of psilocybin for a therapeutic indication thus far has been for treatment-resistant depression (TRD), and a recent, double-blind phase 2 study found a dose-dependent reduction in depression scores in the weeks following administration of a single dose of psilocybin (1 mg, 10 mg, or 25 mg) [ 56 ]. Similarly, a trial investigating the use of two psilocybin administration sessions in conjunction with therapy for major depressive disorder (MDD) not only found a significant attenuation in depression scores at both the primary endpoint and at the 4-week follow up [ 57 ] but also noted that these effects were still durable 1 year after psilocybin administration [ 58 ]. This trial also noted a correlation between mystical-type experience at the time of psilocybin administration and increased well-being at the 12-month follow-up. As multiple studies have noted a positive correlation between the lasting impact of psilocybin on mental health measures and mystical-type experiences, it will be interesting to note whether future studies will be able to elucidate the nature of the relationship between psilocybin-induced mystical-type experiences and durable alleviation of mental health conditions.

A myriad of additional phase 2 trials with psilocybin are now underway for a variety of other indications including PTSD (NCT05554094; NCT05243329; NCT05312151), OCD (NCT05370911; NCT04882839; NCT03300947; NCT05546658; NCT03356483), depression in bipolar 2 disorder (NCT0506529; NCT04433845), anorexia nervosa (NCT04656301; NCT04052568; NCT04661514; NCT05481736; NCT04505189), binge eating (NCT05035927), fibromyalgia (NCT05548075; NCT05128162; NCT05068791), phantom limb pain (NCT05224336), migraine (NCT03341689; NCT04218539), cluster headache (NCT02981173), concussion headache (NCT03806985). Multiple trials are assessing psilocybin therapy for distress associated with serious medical illness (NCT04950608; NCT05398484; NCT05506982; NCT04522804; NCT05220046; NCT04593563; NCT05403086). In addition, a series of studies have been evaluating the potential of psilocybin to attenuate methamphetamine use disorder (NCT04982796; NCT05322954) and cocaine use disorder (NCT02037126). With any luck, the next couple of years should further quantify the myriad of potential therapeutic uses of psilocybin.

Ayahuasca is typically an admixture of the Banisteriopsis caapi vine, containing MAO-inhibiting beta-carboline alkaloids, and the DMT-containing leaves of the Psychotria viridis shrub, although other plants, such as Diplopterys cabrerana , are at times used to make decoctions that are also referred to as ayahuasca. The drink has been used ceremonially in the Amazon Basin for at least hundreds of years and is used widely today in shamanic and other religious contexts within and outside of South America [ 59 ]. Potential indications for ayahuasca include alcohol and other substance use disorders, anxiety and depression disorders [ 60 ] and possibly prolonged grief disorder [ 61 ] and eating disorders [ 62 ]. Naturalistic studies have indicated that regular users of ayahuasca consume less alcohol and other drugs compared to other populations [ 63 , 64 , 65 ], and that ritual participants self-report improved affective symptoms after drinking ayahuasca [ 66 ], however individuals with anxiety and mood disorders may also be at higher risk of experiencing adverse effects in rituals settings [ 67 ]. One recent placebo-controlled proof of principle trial has also shown that a single administration of ayahuasca can attenuate symptoms of treatment-resistant depression [ 68 ].

DMT & 5-MeO-DMT

N,N-Dimethyltryptamine (DMT) is a substituted tryptamine that constitutes one of the primary active ingredients in ayahuasca and is structurally similar to the psychedelic compounds 5-MeO-DMT and bufotenin (5-HO-DMT). In addition to high binding affinity at a number of 5-HT receptors, DMT acts as a TAAR agonist [ 69 ], and a sigma receptor agonist [ 70 ] and may mediate effects at metabotropic glutamate receptors [ 71 ]. Although the clinical data are currently limited, DMT is now being studied in a fixed order, open-label, dose-escalation study in participants with major depression (NCT04711915), and a double-blind, randomized, placebo-controlled study of intravenous DMT in subjects with major depressive disorder (MDD) has now been completed (NCT04673383). Because the subjective effects of DMT are short-lasting compared to other psychedelic compounds [ 72 ], DMT might lend itself more readily to use in clinical settings.

Phenethylamines

3,4-Methylenedioxymethamphetamine (MDMA) was originally synthesized by the pharmaceutical company Merck in 1912 as part of a research program on anticoagulating agents. Early case reports suggested that MDMA could be a remarkably effective catalyst in both individual and couples psychotherapy [ 73 , 74 ] for a variety of psychological issues. The psychedelic-like effects of MDMA were eventually immortalized by Alexander and Ann Shulgin in their book, PiHKAL [ 75 ].

MDMA acts on human monoamine transporters [ 76 ], though most of the subjective effects of MDMA are dependent on serotonin release, which MDMA potentiates through a series of different mechanisms. MDMA inhibits the 5-HT vesicular transporter (VMAT2) and activates the intracellular presynaptic terminal receptor (TAAR1), which impacts both the release and reuptake of serotonin [ 69 , 77 , 78 ]. Downstream of serotonin efflux, MDMA promotes the release of oxytocin [ 79 ], a neuromodulator shown to play a critical role in bonding and social interactions [ 80 ], which may therefore facilitate the therapeutic process by enabling participants to remain emotionally open while they explore difficult memories and subject matter.

MDMA most likely exerts its influence through effects within the amygdala, and previous human research indicates that MDMA attenuates left amygdalar responses to angry facial expressions and enhances ventral striatal responses to happy expressions [ 81 ]. More recent research has found that, when administered to subjects with severe PTSD, MDMA induces changes in functional connectivity between the left amygdala and both the left insula and bilateral posterior cingulate cortex during autobiographical memory recall [ 82 ]. Further experiments are needed to address individual differences in responsivity to MDMA and to determine if and how to maximize the effects of MDMA administration on retrieval and reconsolidation of negative memories.

MDMA is typically administered in conjunction with therapy and the combination of MDMA plus therapy is has recently been investigated for use in indications including PTSD [ 83 , 84 ], social anxiety in adults with [ 85 ] and without autism (NCT05138068), AUDs (NCT05709353), illness-related anxiety (NCT02427568), adjustment disorder (NCT05584826), fear extinction (NCT03527316), and eating disorders (NCT04454684). The most thoroughly investigated of these indications is currently PTSD. Indeed, MDMA for PTSD might well be the first psychedelic to be submitted to the FDA as part of a new drug application (NDA) for regulatory approval and is the only psychedelic to date to have completed phase 3 clinical trials. Phase 3 findings demonstrated that MDMA-therapy was both safe and effective in treating PTSD, functional disability, and symptoms of depression in a population with severe PTSD [ 83 ].

In addition to the current manualized inner-directed therapy that has been used in conjunction with MDMA administration in phase 3, several other studies are now underway to investigate the pairing of MDMA with other gold standard, manualized therapies for PTSD. Studies are being conducted to investigate the combination of MDMA plus exposure therapy for PTSD (NCT05746572), MDMA plus group therapy for Veterans with PTSD (NCT05173831), MDMA plus cognitive processing therapy for PTSD (NCT05067244), and MDMA plus cognitive behavioral conjoint therapy for couples with PTSD (NCT02876172). Also, because of its ability to potentiate self-compassion [ 86 ], MDMA could be particularly powerful in those suffering from moral injury in relation to PTSD.

Mescaline is currently found in four species of cacti: Bolivian Flame, Peruvian Flame, San Pedro, and Peyote, the last of which has been used in ritual by Native American communities for thousands of years [ 87 ]. It has long been used as a treatment for alcoholism within Native American communities [ 88 , 89 ].

Recent self-reported data (via an online questionnaire) indicate that mescaline may attenuate symptoms of anxiety, PTSD, depression, and both alcohol and substance use [ 90 , 91 ]. In keeping with studies into the mechanistic actions of psilocybin, many participants rated their experience with mescaline as one of the most spiritually significant and meaningful experiences of their lives [ 91 ]. In addition, improvements in symptoms of anxiety, PTSD, depression, and both alcohol and other substance use were associated with greater “intensity of insight”, again demonstrating that some aspect of the subjective effect of the psychedelic experience is linked to clinical outcome. While clinical research with mescaline is still in its infancy, the data thus far suggest that mescaline may hold similar promise to other phenethylamines for the treatment of multiple mental health disorders.

Salvinorin A

Salvia divinorum is a sage species that is used ritualistically among the Mazatec tribe of Mexico. The active constituent, salvinorin A, is a kappa opioid agonist that has no discernable action at the 5HT 2A receptor, giving pause to the assertion that all psychedelics act primarily through 5HT 2A receptor activation. As a kappa agonist, salvinorin A may also hold clinical potential as a treatment for pain, ischemia, cardiac damage, and addiction [ 92 ], perhaps especially in biological females who do not find kappa agonists particularly aversive [ 93 ]. While there is still a paucity of human research on salvinorin A, recent findings indicate that when smoked, salvinorin A produces intense but short acting hallucinations and out of body experiences but, notably, no significant changes in heart rate or blood pressure [ 94 ]. In keeping with the classic psychedelics, administration of salvinorin A has also been shown to reduced brain wide dynamic functional connectivity (most notably in the default mode network), while increasing between-network static functional connectivity [ 95 ]. Unlike ibogaine, which also activates kappa opioid receptors and demonstrates anti-addictive properties, salvinorin A has not, to date, been shown to induce the notable adverse effects that have curtailed ibogaine’s development as a clinical therapeutic, and emergent events are rare ( https://calpoison.org/news/salvia-divinorum ). Because of its potential safety and novel pharmacological mechanism of action, further effort should be made to evaluate the pharmacological potential of salvinorin A.

Dissociative agents (Cyclohexanones)

Ketamine is a selective NMDA antagonist that has long been used as an anesthetic and animal tranquilizer, and which has recently found new use as a fast-acting—albeit temporary—treatment for depression [ 96 ]. While ketamine is best considered an atypical psychedelic, or perhaps a drug with psychedelic-like effects, the mechanism of action of ketamine (NMDA antagonism) is a contributor to the effects of several classic psychedelics (such as ibogaine and DMT) and may prove relevant to the further development of psychedelics as therapeutics. It is therefore worth briefly mentioning the state of current research with ketamine.

In addition to its use as an antidepressant, ketamine might hold promise for the treatment of anxiety and PTSD. A recent review indicates that, under certain circumstances (e.g., specified dose and route of administration), ketamine is effective in temporarily attenuating some anxiety disorders [ 97 ] and may therefore merit further investigation. With respect to PTSD symptomology, although a randomized, double-blind active-placebo-controlled trial demonstrated that 2 weeks of 3× weekly ketamine infusions are efficacious for up to a month in those with severe PTSD [ 98 ], a larger trial found no significant effect of 4 weeks of 2× weekly ketamine infusions in a population of military Veterans and service members with comorbid depression and PTSD [ 99 ]. Furthermore, recent years have seen the publishing of promising data on the use of ketamine as a rapid-acting therapy for substance use disorders and other neuropsychiatric conditions like obsessive-compulsive disorder [ 100 ]. As with previous depression trials, even if initially efficacious under certain dosing regimens, the limited durability of positive clinical outcomes of ketamine complicates drug administration and adoption as a frontline therapeutic [ 101 ] for a number of conditions. It is possible that, as with MDMA and psilocybin, durability of ketamine’s effects on mental health indications could be potentiated with the addition of psychotherapy and, to this end, a recent study has found that an automated, computerized training protocol might extend the effects of ketamine on depression [ 102 ]. Additional data are needed to determine whether and how the coupling of ketamine administration with psychotherapy [ 103 ] renders the drug more efficacious and durable for different indications.

Set and setting are key variables

Set and setting have long been recognized as fundamental elements driving the clinical outcomes of psychedelic administration [ 104 ], but more research is needed to operationalize and investigate how best to incorporate these factors into treatment protocols. Set is typically defined as the mindset, psychosocial education, and experience that a participant brings with them as they enter treatment, and setting is defined as the environment in which the psychedelic compound is administered. The dependence of the clinical and psychological effects of psychedelics on the mindset and environment of the user suggests that they truly are “experiential medicines”. Increasingly, human studies with psychedelics are attempting to systematically modify set and setting, either to study set and setting as independent variables affecting the outcomes of the study (NCT04410913), or by making them a fixed key part of the study design, such as electing to use group psychotherapy and/or drug administration instead of individual sessions [ 105 , 106 ]. Group treatment processes likely result in qualitatively different therapeutic environments that differ from individual treatments in ways beyond economics and scalability. The long history of the group use of psychedelic substances in Indigenous and other traditional settings across North and South America suggests that, with the proper context and training, it is possible for group psychedelic experiences to be safely managed and to result in positive outcomes for the participants [ 107 , 108 ]. Nevertheless, most of the clinical data to date have been generated using a fairly homogenous clinical approach, and so specific experiments should be conducted with more variation in set and setting to determine how best to potentiate the therapeutic value of these variables, while mitigating possible harm when administering psychedelics as medical therapies.

Optimizing set while maintaining blinding

One concern that is repeatedly raised in the discussion of psychedelic trials is the conundrum around experimental blinding [ 109 ]. The prevailing belief is that psychedelic trials are difficult to blind and therefore one must always worry that expectation is coloring outcome. This is especially true when participants enroll in a trial that not only takes up weeks of their life, but also assesses whether the investigational compound occasions a particularly meaningful, and often spiritual, life experience. While maintaining a double-blind is indeed a common challenge in psychedelic trials, several methods can be utilized to minimize the impact of expectation and ensure that clinical outcome measures reflect the long-term and durable effects of psychedelic therapies. For example, the use of an active control drug and/or a psychedelic naïve subject population may make it more difficult for even a well-informed participant to be confident of their treatment assignment. In addition, the use of a centralized assessment core to evaluate outcome measures ensures that data collection is blinded and homogeneously collected across study sites while also mitigating the risk of participants inflating their improvements to please study staff with whom they have developed a therapeutic alliance. Perhaps most importantly, the collection of long-term follow-up data from study participants can partially address concerns regarding expectation effects and can speak to the potential durability of psychedelic-induced change. While it is reasonable to suggest that a participant in the throes of a clinical trial might inadvertently exaggerate their improvements when surrounded with engaged and supportive staff, it is less reasonable to assume that this effect would last months after the trial has ended and the participant is again immersed in their regular environment.

Limitations and future directions for psychedelic therapies

The recent explosion in interest in psychedelic therapies has been based on multiple preliminary reports suggesting the potential of safety and efficacy in various psychiatric and general medical conditions, especially mood disorders, alcohol use disorder, and PTSD. These data, however, are not without their limitations. As clinically effective as psychedelics can be when administered under the right conditions, it would be negligent to forego mention of the study participants who do not respond discernably to psychedelic agents. For example, while the recent phase 3 trial of MDMA therapy for PTSD showed that 67% of participants gain complete remission from PTSD, and another 21% exhibited a clinically meaningful response, this still left 12% of study participants with no clinically meaningful response. Similarly, a recent phase 2 trial of psilocybin therapy for an episode of treatment-resistant depression showed that, while 37% of participants displayed a clinically meaningful response to psilocybin at the primary endpoint (week 3), most did not [ 56 ]. While some of this can perhaps be chalked up to the impact of set and setting, some of it is undoubtedly due to differences in sensitivity to psychedelic compounds, and perhaps also to differences in the response to the uncertainty and change brought about by these therapies. In addition, genetics play a role not only in pharmacokinetics but also in suggestibility and the development and maintenance of emotional memories [ 110 ] and may therefore also impact the effects of psychedelic therapies. One would hope that, as precision medicine advances, and as adaptive trials and genetic testing enable us to better tailor treatments to individual patients, biological and behavioral factors will be used to ensure that the potential therapeutic impact of psychedelic therapies is maximized.

Psychedelics are powerful compounds that are capable of enabling great change. As such, they should be approached with care and caution. Under the best of circumstances, and when properly facilitated, psychedelic therapy can kindle the release of some of the most deeply entrenched negative affective states and thought processes, resulting in clinical recovery and positive growth. However, the experiential flipside is equally relevant: occasionally, and especially when taken under suboptimal conditions, without adequate support, or at too high a dose, psychedelics can trigger dysphoria, disorganize thought, and spark delusional perceptions [ 111 , 112 , 113 , 114 ]. In addition, given the largely explanatory trials dataset available to date, it remains to be seen how clinical outcomes will be shaped by different real-world factors such as personality disorders, significant psychiatric and medical comorbidities, and the combination of psychedelics with different behavioral therapies or even with other psychedelics (e.g., psilocybin plus MDMA). We must therefore move forward with care and forethought. These compounds may potently manifest aspects of the human psyche in a manner that can both help and harm. As such, scientific investigations into the judicious use of psychedelics test our capacity for, and professional commitment to, the proper uses of clinical power in the service of healing. It is time that psychedelic therapies be carefully reconsidered [ 115 ].

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Mitchell, J.M., Anderson, B.T. Psychedelic therapies reconsidered: compounds, clinical indications, and cautious optimism. Neuropsychopharmacol. 49 , 96–103 (2024). https://doi.org/10.1038/s41386-023-01656-7

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New era of medicine breaks through against the most aggressive lung cancer

A pharmaceutical that links lymphocytes with malignant cells to destroy them reinforces the role of immunotherapy in small cell tumors.

The small cell (or microcytic) tumor is a lung cancer that grows furiously, quickly and very aggressively. It is a disease that spreads vertiginously and, by the time it shows its face, is usually quite advanced, with metastasis in other organs and accompanied by a very unfavorable prognosis. For decades, doctors have puzzled over how to treat this kind of cancer, with few tools apart from chemotherapy, which is useful for dealing the first blow but less so if the cancer reappeared. However, this journey through the treatment desert appears to be at an end. Step by step, and with steady if modest results, a new generation of drugs has begun to point towards ways to combat the nefarious tumor.

Oncologists aren’t claiming victory just yet, but many say that a new constellation of treatments for small cell lung cancer invites optimism. Particularly given the severity of the condition. In 70% of times the tumors are detected, they are already in very advanced stages. Five-year survival rates are below 5%. Given this context, and after decades of convincing positive results from new experimental drugs, the first immunotherapy of this new wave, which debuted five years ago to a modest success rate, generated a high level of interest. Since then, trials of new pharmaceutical combinations, studies of promising molecules and, in particular, the arrival of a new medication that links lymphocytes to tumor cells to destroy them, has raised new hope for improving survival rates when it comes to these complex tumors.

Throughout 2024, 33,000 lung cancer cases will be diagnosed in Spain, according to figures released by the Spanish Society of Clinical Oncology. Of these, around 15% will be microcytic, a tumor closely linked to tobacco and common among heavy smokers. “It is the most aggressive tumor, with a very high capacity for proliferation. It is usually diagnosed in advanced stages and can metastasize in the liver or brain. In addition, when it appears, the patient can be very symptomatic. It is a tumor that can push patients to their limits,” says Ernest Nadal, director of the thoracic tumor program at the Catalan Institute of Oncology.

In this context, treatment options are limited. As it is often detected late, the chances of operating to remove the tumor is “anecdotal,” says Luis Paz-Ares, head of clinical oncology at the Hospital 12 de Octubre in Madrid. Chemo and radiotherapy are the most common approaches, but they are far from infallible: “The prognosis is poor because, despite being sensitive to chemotherapy and radiotherapy, sensitivity is short-lived and the tumor become resistant,” says Paz-Ares.

There have been attempts to incorporate innovative strategies to cure other types of lung cancer, searches for apt molecular targets and formulas geared towards reactivating the immune system, but these have not borne fruit. The behavior and surrounding environment of the tumor cells present certain difficulties, explains Paz-Ares: “There are no targets for treatment. There are no aberrations or alterations in the oncogenes where the disease starts. Also, it has a very immunosuppressive immunological context and immunotherapy tends to be less effective.”

An orphan disease

As a product of tobacco, the tumor may feature many mutations, but scientists have been unable to use these to locate the genes that are key to the proliferation of this type of cancer. If that weren’t enough, its tumor cells have the capacity to evade the immune system: they camouflage to avoid lymphocytes, which form part of the body’s defenses, being able to recognize and kill them. “The primary strategy is chemotherapy. If nothing is done, you can lose the patient in a matter of weeks. There are few chances of long-term survival. Because of this, it’s like an orphan disease, and any advancement is a source of hope,” says Nadal.

The glimmer of a solution arrived five years ago with the appearance of the first immunotherapies in combination with traditional chemotherapy. This constituted, in the words of Margarita Majem, oncologist at Barcelona’s Sant Pau Hospital, “a small improvement,” but nothing comparable to the impact immunotherapy has had on non-small cell lung cancer and other types of tumors. Paz-Ares agrees: “It benefits a little. Survival at three or five years has gone from 2% to 5% up to 12% to 15%.” The increase in survival rates may have been modest, but it represented a break with the slow progress that had taken place over the preceding 30 years, when 60 molecules tested in 40 trials all produced negligible results.

After this turning point, other therapeutic approaches have appeared that are proving to be increasingly effective in combating the complicated tumors. Last year, a phase II study was presented with a new drug, Tarlatamab, an antibody that works as an intermediary, bringing lymphocytes into contact with tumor cells so that these bodily defenses can recognize and annihilate them. “We are beginning to understand how we can intervene in the immunological context, and that is what has happened with Tarlatamab,” says Paz-Ares, lead author of the research. The molecule is a bispecific antibody with two arms: one binds to the lymphocyte and the other sticks to a protein present on the membrane of tumor cells, and presents them to the immune system in order to identify and kill the malignant cells.

According to the study’s results, tumors were shrunk in 40% of patients. The median survival rate rose above 14 months. “With more follow-up, we are seeing that the median survival rate rises above 18 months. We speculate that there will be an impact on survival,” says Paz-Ares. The FDA has already approved the treatment.

Cautious optimism

At the moment, Tarlatamab is the most promising treatment, but it is not free of risks. There can be side effects, like neurotoxicity (confusion, changes in behavior) or cytokine release syndrome, which is the most worrying, and refers to when the immune system is stimulated and lymphocytes begin to release substances, such as cytokines, and generate a kind of systemic inflammation which, if not treated in time, can lead to multi-organ failure and death. Paz-Ares explains that the cytokine storm occurred in 50% of cases, but less than 5% were severe.

Enriqueta Felip, head of thoracic tumors and cancers of the head and neck at Barcelona’s Vall d’Hebron Hospital Institute of Oncology (VHIO) says that, given what we know of it, Tarlatamab is “a relevant drug.” “Its toxicity, which worried us at first, is manageable. We see lasting results and that is very relevant in this situation,” she says. Majem agrees, but calls for prudence: “It’s been seen to work well and that opens a door for us in terms of hope for new treatments, but we are still learning which patients, exactly, will benefit most.”

At the last meeting of the American Society of Clinical Oncology (ASCO), which took place last week in Chicago, a phase I/II study was also presented that features a new combination of chemotherapies: Lurbinectedin with Irinotecan, which showed “promising antitumor activity.” “It is a combination that, in preclinical studies, has been shown to be very effective and we have confirmed very significant remission rates in pretreated patients. In this study, which features a large number of patients, survival rates are in an appreciable range for its clinical context,” says Paz-Ares, who oversaw the research that was presented at the meeting.

Majem says that these response rates are “very interesting.” Above all, among patients who are especially sensitive to chemotherapy . “This combo presents promising results, and the toxicity profile comes from the chemotherapy, known risks that we know how to manage,” she says. Patients are already being recruited to confirm these findings in a phase III study.

Changing expectations

Although the majority of patients are diagnosed in an advanced stage, around 25% of patients are diagnosed with a localized tumor. Among these cases, prognosis is initially more favorable, but new therapeutic approaches are being investigated to improve survival rates. “Each year, we diagnose 60 cases of small-cell lung cancer and of these, 10 to 12 are localized. There is some hope there: the combination of chemotherapy with radiotherapy can cure a small fraction (around 20% to 25%), although the majority very often end up relapsing later with metastases. There is now a study that is trying immunotherapy after chemo and radiotherapy,” says Nadal.

He is referring to the Adriatic study, which tests the benefit of adding to standard treatment Durvalumab, a type of immunotherapy that reactivates immune cells so that they attack the tumor. “If results are positive, there will be a change in clinical practice,” says Felip. Preliminary data presented at ASCO pointed to a median survival rate after Durvalumab as consolidation therapy for localized tumors was 56 months, compared with a median of 33 months among patients who had received a placebo. “The data is encouraging,” says Nadal.

With all this new therapeutic arsenal in the making, the long journey through the desert does appear to be nearing its end. Neither the new immunotherapies nor the new drug combinations “will be a cure,” warns Majem, but they are steps forward that “improve survival.” Nadal agrees: “We are beginning to see, taking into account the seriousness of the disease and modest results, that there is a change in the level of expectations we can have. But we must not be satisfied, we must continue.”

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Nutritional and prognostic value of bioelectrical phase angle as a potentially modifiable marker in acute myeloid leukemia, tiantian jiang, yue weng, nan zhang, xiaoqiong tang, article number: 142 published online on: 13 february 2023.

Odontogenic keratocyst in the mandibular condyle base region: A case report

Sho miyamoto, takahiro goto, jumpei shirakawa, toshihiro kawano, makoto murahashi, kentaro ide, nobuyuki maruyama, akira matayoshi, kazuhide nishihara, hiroyuki nakamura, article number: 141 published online on: 13 february 2023, lncrna‑mirna‑mrna network in female offspring born from obese dams, yong song, hong-lin guo, min-zhe zhang, ze-lin zhang, ke jin, qi-qiang he, hui li, article number: 140 published online on: 13 february 2023, salviae miltiorrhiza against human lung cancer: a review of its mechanism (review), qingwen an, mengting wu, chuqi yang, yewen feng, xuefei xu, hang su, guangji zhang, article number: 139 published online on: 13 february 2023, conditioned medium of pc‑3 prostate cancer cells affects microrna and mrna profiles in mechanically strained osteoblasts, zhen cao, zhixiong yan, jiahui wang, huan yang, biao han, jintao gao, yong guo, article number: 138 published online on: 13 february 2023, pure endoscopic minimally invasive surgery with a non‑expandable tubular retractor for intradural extramedullary spinal tumors, gang zhang, bin jia, pan wang, chaoling xu, jie liu, chao tang, haotian jiang, xiaorong tan, nan wu, article number: 137 published online on: 13 february 2023, fndc5 and akr1b10 inhibit the proliferation and metastasis of adrenocortical carcinoma cells by regulating ampk/mtor pathway, danyan chen, rongxi huang, fang ren, hongman wang, chengjian wang, yu zhang, article number: 136 published online on: 13 february 2023, wiltse transforaminal thoracic interbody fusion approach for the treatment of single‑segment thoracic spinal tuberculosis in elderly patients with osteoporosis: a retrospective study of 20 cases, hao zeng, simi liao, yingfang liang, abu moro, guanghui chen, hongyu qin, article number: 135 published online on: 13 february 2023, dock8 interference alleviates aβ‑induced damage of bv2 cells by inhibiting stat3/nlrp3/nf‑κb signaling, xueying zhou, ji hu, deyi xu, sheng zhang, qianyan wang, article number: 134 published online on: 10 february 2023, platelet‑related parameters as potential biomarkers for the prognosis of sepsis, chao zhang, xueyi shang, yuan yuan, yan li, article number: 133 published online on: 10 february 2023, sclerosing extramedullary hematopoietic tumor of the colon: a case report and literature review, zhibo zuo, qi zhang, wanxin wu, xin li, lin zhang, jingyu wang, zhiqin guo, shaoqing hu, hongyan liu, article number: 132 published online on: 10 february 2023, tobacco nicotine promotes trail resistance in lung cancer through snhg5, xin xiao, juan xu, xiaoan sheng, chao wang, juanjuan dong, xianfeng shi, article number: 131 published online on: 10 february 2023, ocular trauma, visual acuity related to time of referral and psychosocial determinants, during covid‑19 pandemic: a prospective study, elli d.o. kyriakaki, efstathios t. detorakis, antonios k. bertsias, georgios markakis, nikolaos g. tsakalis, panagiotis volkos, demetrios a. spandidos, emmanouil k. symvoulakis, article number: 130 published online on: 08 february 2023, repeated bleeding caused by acquired hemophilia a after endoscopic submucosal dissection: a case report and literature review, song liu, nian wang, zhimou mei, xiaoyang gao, zhaohong shi, article number: 129 published online on: 08 february 2023, ethanol extract of chrysanthemum zawadskii inhibits the nlrp3 inflammasome by suppressing asc oligomerization in macrophages, ah-ra jang, ha-nul lee, jung joo hong, young-min kim, jong-hwan park, article number: 128 published online on: 07 february 2023, mir‑221 and mir‑222 regulate cell cycle progression and affect chemosensitivity in breast cancer by targeting anxa3, ju-yeon kim, eun jung jung, jae-myung kim, youngsim son, han shine lee, seung-jin kwag, ji-ho park, jin-kyu cho, han-gil kim, taejin park, sang-ho jeong, chi-young jeong, young-tae ju, article number: 127 published online on: 07 february 2023, tumour‑derived exosomes and their emerging roles in leukaemia (review), lei chen, ting xie, bing wei, da-lin di, article number: 126 published online on: 06 february 2023, impact of sglt2 inhibitors on metabolic status in patients with psychiatric disorders undergoing treatment with second‑generation antipsychotics (review), octavian vasiliu, article number: 125 published online on: 06 february 2023, drug resistance of hepatoma cells induced by atp‑binding cassette transporter g2 by reducing intracellular drug concentration, yuekao li, boyue ding, jianghui liu, xing li, caiyi he, jing wang, liang liu, article number: 124 published online on: 06 february 2023, cyclooxygenase‑2 contributes to the hypoxia‑induced aggravation of the neuroinflammation response stimulated by lipopolysaccharide in microglia, yifan yang, yanan geng, xiang cheng, jiayue gao, zibi shi, ming zhao, article number: 123 published online on: 03 february 2023, serum galectin‑3 and α‑1‑acid glycoprotein levels in diagnosis and prognosis of idiopathic sudden sensorineural hearing loss, mustafa mert basaran, hande arslan, tuba candar, article number: 122 published online on: 02 february 2023, long‑term prognosis and comprehensive endoscopic treatment strategy for esophageal cancer, including salvage endoscopic treatment after chemoradiation therapy, junya shiota, naoyuki yamaguchi, hajime isomoto, yasuhiro taniguchi, kayoko matsushima, yuko akazawa, kazuhiko nakao, article number: 121 published online on: 01 february 2023, impact of obstructive sleep apnea on outcomes of pulmonary embolism: a systematic review and meta‑analysis, wen zhang, yongmin ding, article number: 120 published online on: 01 february 2023, knockdown of ncapg promotes the apoptosis and inhibits the invasion and migration of triple‑negative breast cancer mda‑mb‑231 cells via regulation of egfr/jak/stat3 signaling, juanyun li, jialu zheng, baohang lin, hao sun, shan lu, dandan wang, hongjun huo, article number: 119 published online on: 01 february 2023, roles of padi4 in the expression of cytokines involved in inflammation and adhesion in differentiated nb4 cells treated with atra, xiaobai sun, xiao mu, fu li, yaping wang, xiaomei yang, qingwei guo, article number: 118 published online on: 31 january 2023, mir503hg silencing promotes endometrial stromal cell progression and metastasis and suppresses apoptosis in adenomyosis by activating the wnt/β‑catenin pathway via targeting mir‑191, xiaoping xu, bin cai, yang liu, ruiqian liu, jia li, article number: 117 published online on: 30 january 2023, efficacy and mechanism of lipoic acid in the treatment of reproductive injury caused by perfluorooctanoic acid, zhiyan zhang, rong wen, wenlong zhang, na ge, jinwei bo, article number: 116 published online on: 30 january 2023, multiple nocardial abscesses secondary to anti‑neutrophil cytoplasmic antibody‑associated vasculitis in an elderly patient: a case report and literature review, xu chen, yaping fan, yide zhang, article number: 115 published online on: 30 january 2023, endoscopic endonasal transsphenoidal approach for craniopharyngioma: case series, jie liu, pan wang, chao tang, hao-tian jiang, gang zhang, nan wu, article number: 114 published online on: 27 january 2023, regulation of the p53‑mediated ferroptosis signaling pathway in cerebral ischemia stroke (review), shuangli xu, xuewei li, yanqiang wang, article number: 113 published online on: 26 january 2023, polygonum tinctorium leaf extract ameliorates high-fat diet-induced intestinal epithelial damage in mice, shogo kawaguchi, hirotake sakuraba, hidezumi kikuchi, kota matsuki, yudai hayashi, jiangli ding, yusuke tanaka, kazuhiko seya, tomoh matsumiya, hiroto hiraga, shinsaku fukuda, kenroh sasaki, tadaatsu imaizumi, article number: 112 published online on: 26 january 2023, esketamine for treatment‑resistant depression: a review of clinical evidence (review), article number: 111 published online on: 25 january 2023, can we identify the risk factors for sirs/sepsis after percutaneous nephrolithotomy a meta‑analysis and literature review, dragoş puia, ştefan gheorghincă, george daniel radavoi, viorel jinga, cătălin pricop, article number: 110 published online on: 25 january 2023, quantitative evaluation of the reduction of distortion and metallic artifacts in magnetic resonance images using the multiacquisition variable‑resonance image combination selective sequence, masaki hirano, yuki muto, masahiro kuroda, yuta fujiwara, tomoaki sasaki, kazuhiro kuroda, ryo kamizaki, satoshi imajoh, yoshinori tanabe, wlla e. al-hammad, yuki nakamitsu, yudai shimizu, kohei sugimoto, masataka oita, irfan sugianto, babatunde o. bamgbose, article number: 109 published online on: 24 january 2023, laser nasal surgery (review), mihai ionuț tănase, mara bulmaci, constantin stan, rădeanu gheorghe doinel, marcel cosgarea, septimiu sever pop, alma aurelia maniu, article number: 108 published online on: 24 january 2023, evaluation of the detection rate of high‑grade gastric intraepithelial neoplasia using linked color imaging and white light imaging, jun-hui lu, hai-hua chen, xing chen, hezhao zhang, jing fan, wenbin zhang, article number: 107 published online on: 24 january 2023, knockdown of lncrna snhg16 attenuates myocardial ischemia‑reoxygenation injury via targeting mir‑183/foxo1 axis, tao geng, zesheng xu, jingxian xing, yonggang yuan, juan liu, article number: 106 published online on: 23 january 2023, uterovesical fistulas as obstetric complications: diagnosis, management and prognosis (review), anca jilaveanu, bogdan socea, roxana bohiltea, ovidiu stiru, adnan al aloul, bogdan ursut, cornel savu, alexandru filipescu, irina balescu, nicolae bacalbasa, article number: 105 published online on: 23 january 2023, g‑csf delays tooth extraction socket bone healing via the inhibition of bone turnover in mice, masayuki oshitani, kazuki takaoka, miho ueta, kohei tomimoto, hirokazu hattori, naomichi yoneda, koji yamanegi, kazuma noguchi, hiromitsu kishimoto, article number: 104 published online on: 20 january 2023, foxf1 attenuates tgf‑β1‑induced bronchial epithelial cell injury by inhibiting cdh11‑mediated wnt/β‑catenin signaling, qin chen, xing liao, ling lin, ling wu, qiuyu tang, article number: 103 published online on: 20 january 2023, [retracted] mir‑365 induces hepatocellular carcinoma cell apoptosis through targeting bcl‑2, mingfei li, yuan yang, yu kuang, xianfeng gan, wei zeng, yuping liu, hua guan, article number: 102 published online on: 18 january 2023, new diagnostic and therapeutic procedures applied in pediatric esophageal achalasia in a pediatric tertiary center: a case series, daniela pop, radu samuel pop, teodora surdea blaga, liliana david, carmen asavoaie, marcel tantau, dan lucian dumitrascu, dorin farcau, article number: 101 published online on: 17 january 2023.

March-2023 Volume 25 Issue 3

Print ISSN: 1792-0981 Online ISSN: 1792-1015

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