new horizons in natural compound research

New Horizons in Natural Compound Research

• 1st Edition - April 18, 2023
• Editors: Surya Nandan Meena, Vinod Nandre, Kisan Kodam, Ram Swaroop Meena
• Language: English
• Paperback ISBN: 9780443152320 9 7 8 - 0 - 4 4 3 - 1 5 2 3 2 - 0
• eBook ISBN: 9780443152337 9 7 8 - 0 - 4 4 3 - 1 5 2 3 3 - 7

New Horizons in Natural Compound Research provides the latest updates in natural compound research (plant, microbes, algae, fungi) and their novel applications in health, agricultu… Read more

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New Horizons in Natural Compound Research provides the latest updates in natural compound research (plant, microbes, algae, fungi) and their novel applications in health, agriculture and environment. The book gives recent advances in the extraction of natural compounds, cutting-edge approaches for natural compound purifications, and emerging trends in natural compound screening and identification. In addition, it provides a detailed explanation of the databases and libraries of natural compounds, as well as their significance. Sections focus on research and multidisciplinary practical techniques of natural product research, encouraging young scientists to pursue unique research while also generating strong research ideas.

From a future perspective, this book acts as a guide to identify potential areas and new research opportunities in the field of natural products and their service towards human beings, animals and the environment.

• Provides a one–stop solution for concepts, cutting-edge techniques, methods, and novel applications of natural products in health and the environment
• Focuses on current gaps in natural product research, as well as methodologies and techniques to assist researchers in resolving existing challenges and speeding up the pace of drug discovery from natural sources
• Highlights new avenues of natural product research
• Contains contributions from well-experienced researchers from academia, research institutes and top-notch young scientists from industry
• Cover image
• Table of Contents
• List of contributors
• Biographies
• Chapter 1. Natural compounds for health and environment: past, present, and future
• 1. Introduction
• 2. Vital natural compounds
• 3. Future of natural compounds
• 4. Conclusions
• Chapter 2. Recent advances in extraction of natural compounds
• 2. Extraction methodologies and their applications
• 3. Concluding remarks
• Chapter 3. Cutting edge approaches for natural product purification
• 2. Extraction
• 3. Pre-isolation
• 4. Isolation
• 5. Purification
• 6. A typical approach for isolation of anthocyanin monomers from red cabbage
• 7. Conclusion
• Chapter 4. Mass spectrometry-based metabolomics for high-throughput natural products screening and compound discovery: an emerging trend
• 2. MS-based metabolomics
• 3. Applications of MS-based metabolomics in NP research
• Chapter 5. Green synthesis of natural compounds
• 2. Conclusion
• Chapter 6. Diversity of chemical skeletons: a practical strategy to benefit
• 2. Structural diversity in natural products
• 3. Semisynthetic or modified NPs
• 4. Synthetic approaches for building chemical skeletons
• 5. Conclusion
• Chapter 7. Modern approaches for mining of novel compounds from the microbes
• 2. Traditional methods and techniques used for mining of novel compounds along with their limitations
• 3. Modern use of databases in hunting new compounds
• 4. Mining for novel compounds using genomic databases
• 5. Proteomics approach for the mining for NCs
• 6. Metabolomics and mass spectrometry approach in the discovery of NCs
• 7. Conclusion and future prospects
• Chapter 8. Informatics and computational methods in natural product drug discovery
• 2. Evolution of bioinformatics concept: a new vision
• 3. High-throughput virtual screening
• Author contributions
• Conflict of interest statement
• Chapter 9. Compound synergy in natural crude extract: a novel concept in drug formulation
• 2. What is the synergy effect?
• 3. Factors responsible for the synergetic effect
• 4. Synergistic effect on diabetes
• 5. Synergistic effect on antimicrobial activity
• 6. Synergistic effect of natural drugs on breast cancer cell
• Chapter 10. Small molecules vs biologics
• Chapter 11. Introduction to enzymes and organocatalysis
• 1. Definition and classifications of enzymes
• 2. Introduction to organocatalysis
• 3. Conclusion
• Chapter 12. Natural products for the prevention and management of nephrolithiasis
• 2. Prospects for nephrolithiasis management and improvements in natural product approaches
• Chapter 13. Enzymatic preparation, purification, and therapeutic applications of marine oligosaccharides
• 2. Marine polysaccharides and their oligosaccharides
• 3. Enzymatic preparation of bioactive oligosaccharides from complex polysaccharides
• 4. Purification of oligosaccharides
• 5. Application of oligosaccharides in biomedicine
• 6. Conclusion and future prospects
• Chapter 14. Marine microalgae: an emerging source of pharmaceuticals and bioactive compounds
• 2. Bioactive compounds from microalgae
• 3. Applications of bioactive compounds
• 4. Microalgae as a source of pharmaceuticals
• 5. Enhancement of algal metabolites
• 6. Conclusion
• Chapter 15. Natural compounds in chemopreventive foods for prevention and management of non-communicable diseases
• Abbreviations
• 2. Cause of civilization diseases
• 3. How oxidative stress cause NCDs and antioxidants can prevent NCDs
• 4. What are chemopreventive foods?
• 5. Antioxidants in chemopreventive foods to prevent or control civilization diseases
• 6. Challenges or loopholes in chemoprevention strategy
• 7. Conclusion and future perspective
• Chapter 16. Insect metabolome: New paradigm of novel metabolites discovery and its potential applications
• 2. Specialized methods for insect metabolome analysis
• 3. Insect metabolome: diversity and spatio-temporal dynamics
• 4. Uniqueness of insect metabolome
• 5. Insect-associated metabolome
• 6. Potential application of insect metabolites
• Chapter 17. New targets for old drugs: drug repurposing approach for accelerating the drug discovery engine with minimum financial inputs
• 1. Introduction to drug repurposing: beyond the “old wine in new bottle”
• 2. Experimental and computational approaches for drug repurposing
• 3. Repurposing the drugs for effective cancer management
• 4. Repurposing for cardiovascular diseases
• 5. Repurposing for neurodegenerative disorders
• 6. Drug repurposing in diabetes
• 7. Repurposing for viral diseases
• 8. Repurposing for microbial diseases
• 9. Conclusion
• Chapter 18. Modern role of essential oils in drug discovery and medicinal products
• 2. Methods of extraction of essential oils (EOs)
• 3. Medicinal plants as a source of essential oils
• 4. Essential oils as a source of medicine and drug discovery
• 5. Conclusions
• Chapter 19. Cyclodextrins (CDs) derived from natural source as an essential component in biopharmaceutics
• 2. Application of cyclodextrins in biopharmaceuticals
• 3. Regulatory aspects of CDs
• 4. Conclusion
• Chapter 20. Natural compound-based scaffold to design in vitro disease systems
• 2. 2D cell culture system
• 3. 3D system
• 4. Scaffold for 3D cell culturing
• 5. Types of scaffolds
• 7. Future perspective
• Chapter 21. Natural compounds as pesticides, emerging trends, prospects, and challenges
• 2. Different sources for biopesticides
• 3. Mode of action of different biopesticides
• 4. Challenges
• 5. Prospects
• 6. Conclusions
• Chapter 22. Natural compounds as insecticides—a novel understanding
• 2. Natural plant compounds as insecticides
• Chapter 23. Nanoformulations of natural compounds for herbicide and agri-food application
• 2. Nanotechnologies in agriculture
• 3. Nanotechnologies in food science
• 4. Summary and future prospect
• Declaration of competing interest
• Chapter 24. Natural compounds for bioremediation and biodegradation of pesticides
• 2. Pesticides and their impacts on sustainability
• 3. Concerns related to pesticide pollution
• 4. Bioremediation of pesticides
• 5. Types of pesticide bioremediion based on the type of microbes/enzymes
• 6. Conclusions and future perspectives
• Chapter 25. Role of natural compounds in metal removing strategies
• 2. Natural compounds used in heavy metals removal
• 3. Conclusions
• Chapter 26. Policies, regulatory requirements, and risks in natural product research
• 2. Protection of new plant variety
• 3. Natural products and international protection
• 4. Natural resources and associated traditional knowledge
• 5. Bioprospecting and biopiracy
• No. of pages : 560
• Language : English
• Edition : 1
• Published : April 18, 2023
• Imprint : Academic Press
• Paperback ISBN : 9780443152320
• eBook ISBN : 9780443152337

Surya Nandan Meena

Vinod nandre, kisan kodam, ram swaroop meena.

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New Horizons in Natural Compound Research (Progress in Biochemistry and Biotechnology)

Description.

New Horizons in Natural Compound Research provides the latest updates in natural compound research (plant, microbes, algae, fungi) and their novel applications in health, agriculture and environment. The book gives recent advances in the extraction of natural compounds, cutting-edge approaches for natural compound purifications, and emerging trends in natural compound screening and identification. In addition, it provides a detailed explanation of the databases and libraries of natural compounds, as well as their significance. Sections focus on research and multidisciplinary practical techniques of natural product research, encouraging young scientists to pursue unique research while also generating strong research ideas.

From a future perspective, this book acts as a guide to identify potential areas and new research opportunities in the field of natural products and their service towards human beings, animals and the environment.

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New Horizons in Natural Compound Research (Progress in Biochemistry and Biotechnology) Kindle Edition

New Horizons in Natural Compound Research provides the latest updates in natural compound research (plant, microbes, algae, fungi) and their novel applications in health, agriculture and environment. The book gives recent advances in the extraction of natural compounds, cutting-edge approaches for natural compound purifications, and emerging trends in natural compound screening and identification. In addition, it provides a detailed explanation of the databases and libraries of natural compounds, as well as their significance. Sections focus on research and multidisciplinary practical techniques of natural product research, encouraging young scientists to pursue unique research while also generating strong research ideas.

From a future perspective, this book acts as a guide to identify potential areas and new research opportunities in the field of natural products and their service towards human beings, animals and the environment.

• Provides a one–stop solution for concepts, cutting-edge techniques, methods, and novel applications of natural products in health and the environment
• Focuses on current gaps in natural product research, as well as methodologies and techniques to assist researchers in resolving existing challenges and speeding up the pace of drug discovery from natural sources
• Highlights new avenues of natural product research
• Contains contributions from well-experienced researchers from academia, research institutes and top-notch young scientists from industry
• ISBN-13 978-0443152320
• Sticky notes On Kindle Scribe
• Publisher Academic Press
• Publication date April 18, 2023
• Language English
• File size 102950 KB
• See all details

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During the first two decades of this century, conventional compounds have been found to have more bacterial resistance. What is additionally worrying is the rediscovery of the so-called "natural compounds", which are in good standing due to their plant or animal origin. However, they do not form a well-classified group of substances

New Horizons in Natural Compound Research provides the latest updates in natural compound research (plant, microbes, algae, fungi) and their novel applications in health, agriculture and environment. It gives the recent advances in extraction of natural compounds, cutting edge approaches for natural compound purifications and emerging trends in natural compound screening and identification.

It also provides a detailed explanation of the databases and libraries of natural compounds, as well as their significance.

New Horizons in Natural Compound Research focuses on research and multidisciplinary practical techniques iof natural product research, encouraging young scientists to pursue unique research while also generating strong research ideas.

From a future perspective, it acts as a guide to identify potential areas and new research opportunities in the field of natural products and their service towards human beings, animals, and the environment.

About the Author

Product details.

• ASIN ‏ : ‎ B0C33JRY6R
• Publisher ‏ : ‎ Academic Press (April 18, 2023)
• Publication date ‏ : ‎ April 18, 2023
• Language ‏ : ‎ English
• File size ‏ : ‎ 102950 KB
• Text-to-Speech ‏ : ‎ Enabled
• Enhanced typesetting ‏ : ‎ Enabled
• X-Ray ‏ : ‎ Not Enabled
• Word Wise ‏ : ‎ Not Enabled
• Sticky notes ‏ : ‎ On Kindle Scribe
• Print length ‏ : ‎ 536 pages

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New Horizons in Natural Compound Research 1st Edition

• Author(s) Surya Nandan Meena; Vinod Nandre; Kisan Kodam; Ram Swaroop Meena
• Publisher Academic Press

Print ISBN 9780443152320, 0443152322

Etext isbn 9780443152337, 0443152330.

• Edition 1st
• Copyright 2023
• Available from $ 175.00 USD SKU: 9780443152337

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New Horizons in Natural Compound Research 1st Edition is written by Surya Nandan Meena; Vinod Nandre; Kisan Kodam; Ram Swaroop Meena and published by Academic Press. The Digital and eTextbook ISBNs for New Horizons in Natural Compound Research are 9780443152337, 0443152330 and the print ISBNs are 9780443152320, 0443152322. Save up to 80% versus print by going digital with VitalSource.

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Progress in Biochemistry and Biotechnology

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New Horizons in Natural Compound Research provides the latest updates in natural compound research (plant, microbes, algae, fungi) and their novel applications in health, agriculture and environment. The book gives recent advances in the extraction of natural compounds, cutting-edge approaches for natural compound purifications, and emerging trends in natural compound screening and identification. In addition, it provides a detailed explanation of the databases and libraries of natural compounds, as well as their significance. Sections focus on research and multidisciplinary practical techniques of natural product research, encouraging young scientists to pursue unique research while also generating strong research ideas.

From a future perspective, this book acts as a guide to identify potential areas and new research opportunities in the field of natural products and their service towards human beings, animals and the environment.

• Provides a one–stop solution for concepts, cutting-edge techniques, methods, and novel applications of natural products in health and the environment
• Focuses on current gaps in natural product research, as well as methodologies and techniques to assist researchers in resolving existing challenges and speeding up the pace of drug discovery from natural sources
• Highlights new avenues of natural product research
• Contains contributions from well-experienced researchers from academia, research institutes and top-notch young scientists from industry

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Modern Trends in Natural Antibiotic Discovery

Affiliations.

• 1 Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Miklukho-Maklaya 16/10, 117997 Moscow, Russia.
• 2 Gause Institute of New Antibiotics, Bolshaya Pirogovskaya 11, 119021 Moscow, Russia.
• PMID: 37240718
• PMCID: PMC10221674
• DOI: 10.3390/life13051073

Natural scaffolds remain an important basis for drug development. Therefore, approaches to natural bioactive compound discovery attract significant attention. In this account, we summarize modern and emerging trends in the screening and identification of natural antibiotics. The methods are divided into three large groups: approaches based on microbiology, chemistry, and molecular biology. The scientific potential of the methods is illustrated with the most prominent and recent results.

Keywords: BGC activation; antibiotics; co-cultivation; dereplication; genome mining; in situ cultivation; natural products.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Traditional phenotypic screening (the “Waksman…

Traditional phenotypic screening (the “Waksman platform”).

Structures of gausemycins, recently discovered…

Structures of gausemycins, recently discovered lipoglycopeptide antibiotics.

Main modern approaches in the…

Main modern approaches in the screening of new antibiotics from natural sources.

Basic microbiological approaches to the…

Basic microbiological approaches to the search for new antibiotics.

Peptide antibiotics darobactin and evybactin,…

Peptide antibiotics darobactin and evybactin, recently found to be produced by the nematode…

Instrumentation of the iChip technology:…

Instrumentation of the iChip technology: diffusion chambers and their multiplication on iChip.

Antibiotics teixobactin, amycobactin, and hypeptin,…

Antibiotics teixobactin, amycobactin, and hypeptin, recently discovered using the iChip technology.

Repurposed antibiotics fidaxomicin and hygromycin…

Repurposed antibiotics fidaxomicin and hygromycin A.

Narrow-spectrum antibiotics threoglucin A and…

Narrow-spectrum antibiotics threoglucin A and tryglusins A and B.

Basic molecular biology approaches to…

Basic molecular biology approaches to the search for new antibiotics.

Clinically approved antibiotic daptomycin and…

Clinically approved antibiotic daptomycin and its congeners taromycins discovered using a metagenomics approach;…

Lipopeptide antibiotics malacidins and cadasides…

Lipopeptide antibiotics malacidins and cadasides discovered using metagenomics search for the Ca-binding motif.…

Glycopeptide antibiotics A50926 and A40926.

New antimicrobial (lipo)peptide antibiotics macolacin,…

New antimicrobial (lipo)peptide antibiotics macolacin, cilagicin and dynobactin, discovered by genome mining.

Structures of corbomycin, rimomycins A–C,…

Structures of corbomycin, rimomycins A–C, and misaugamycins A,B.

Structures of marinolactam A and…

Structures of marinolactam A and bipentaromycins A–F.

Peptide antibiotic cebulantin and its…

Peptide antibiotic cebulantin and its inductors furosemide and fenofibrate; peptide antibiotic cinnapeptin and…

Cyclopeptide momomycin and its elicitors.

Structures of auroramycin, oxazolepoxidomycin A,…

Structures of auroramycin, oxazolepoxidomycin A, piloquinone and homopiloquinone.

Structures of gaudimycins D, E…

Structures of gaudimycins D, E discovered by means of RGMS.

Reporter strain-assisted screening strategy.

Basic chemical approaches to the…

Basic chemical approaches to the search for new antibiotics.

Molecular networking used for dereplication.

Structures of arromycin and echinoserine…

Structures of arromycin and echinoserine sulfoxide.

Structures of amychelin C and…

Structures of amychelin C and dracolactam C.

Chemical derivatization of labile isonitrile…

Chemical derivatization of labile isonitrile natural products.

Structures of unstable bacillaenes.

Schematic representation of modern trends…

Schematic representation of modern trends in antibiotic discovery.

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• World Health Organization Prioritization of Pathogenes to Guide Discovery, Research and Development of New Antibiotics for Drug-Resistant Bacterial Infections, including Tuberculosis. 2017. [(accessed on 20 April 2023)]. Available online: https://www.who.int/publications/i/item/WHO-EMP-IAU-2017.12 .
• Waksman S.A. What is an antibiotic or an antibiotic substance? Mycologia. 1947;39:565–569. doi: 10.1080/00275514.1947.12017635. - DOI - PubMed
• Bentley R., Bennett J.W. Advances in Applied Microbiology. Volume 52. Elsevier; Amsterdam, The Netherlands: 2003. What is an antibiotic? Revisited; pp. 303–331. - PubMed
• Davies J. Are antibiotics naturally antibiotics? J. Ind. Microbiol. Biotechnol. 2006;33:496–499. doi: 10.1007/s10295-006-0112-5. - DOI - PubMed
• Cook M.A., Wright G.D. The past, present, and future of antibiotics. Sci. Transl. Med. 2022;14:eabo7793. doi: 10.1126/scitranslmed.abo7793. - DOI - PubMed

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New Horizons in Natural Compound Research: Progress in Biochemistry and Biotechnology - Chapter 14: Marine microalgae: an emerging source of pharmaceuticals and bioactive compounds

Marine microalgae are microscopic and ubiquitous in nature that can grow as single cells, colonies, or extended filaments. Some microalgae like Arthrospira platensis are edible with a rich natural source of valuable secondary metabolites with medicinal properties. Microalgae serve as a prominent source of nutrient supplements and several microalgal metabolites are commercialized for their application in pharmaceutical and nutraceutical industries. Some of the metabolites exhibit anti-proliferative and anti-oxidative properties while some others possess apoptotic and anti-aging properties. Their cell-free extracts have been examined as additives for food and feed formulation in experiments to elude the use of antimicrobial compounds of synthetic origin and hence reduce antimicrobial resistance. Microalgae may soon become a top-tier challenger from the bottom of the marine food chain to withstand global warming as well as energy and food insecurity. They are a potent source of pharmaceuticals and bioactive compounds in addition to being the largest primary biomass. This chapter focus on pharmaceuticals and bioactive compounds from marine microalgae, their applications, and future prospects.

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• v.4(2); Apr-Jun 2012

Physicochemical Biology: Conquered Boundaries and New Horizons


D.g. knorre.

Institute of Chemical Biology and Fundamental Medicine, Siberian Branch, Russian Academy of Sciences, prosp. Akademika Lavrent’eva, 8, 630090, Novosibirsk, Russia

In this paper, we shall consider the main evolutionary stages that occurred within the field of physicochemical biology during the 20th century, following the determination of the tertiary structure of DNA by Watson and Crick and the subsequent successes in the X-ray structural analysis of biopolymers. The authors’ ideas on the pre-emptive problems and the methods used in physicochemical biology in the 21st century are also presented, including an investigation of the dynamics of biochemical processes, studies of the functions of unstructured proteins, as well as single-molecule investigations of enzymatic processes and of biopolymer tertiary structure formation.

The second half of the 20th century represented a period of tremendous achievement for mankind, witnessing an increase in the understanding of the essence of natural phenomena and heralding significant breakthroughs with regard to mankind’s technical abilities. Progress achieved in the use of nuclear energy has enabled us to cover the earth with a network of nuclear power stations, while the appearance of powerful jet engines has opened the doors to space voyage; a process which began with Gagarin’s flight, continued with the landing on the moon, and is now moving towards a flight to Mars. Advancements in electronics and materials science have enabled us to build computers that can perform trillions of computations per second and have facilitated the creation of devices smaller than a matchbox that are capable of storing gigabytes of information, as well as systems for ultrahigh-speed information transfer. These factors have resulted in the emergence of one of mankind’s most impressive technical marvels: the Internet. 


A less obvious, but no less significant, achievement was accomplished in our understanding of the chemical and physical foundation of the functioning of living organisms. It is fair to say that the introduction of physical and chemical approaches into the field of life sciences was a gradual process; this progress made a significant leap forward after the publication of the famous paper by James Watson and Francis Crick in 1953, which presented a three-dimensional structure of deoxyribonucleic acid (DNA) [ 1 ].


A plethora of mysteries exist within nature. Amongst these is the question of how an unthinkably huge amount of information is transferred accurately from one cell produced by the fertilization of an egg cell to an adult organism. Until 1944, the nature of the carrier of hereditary information remained unknown. Although Miescher had discovered nucleic acids in 1869, the prevailing view was that a protein played the role of such a carrier; indeed, it was not until 1944 that Avery demonstrated that DNA was the actual carrier of hereditary information [ 2 ].


It was evident that such a carrier had to have three main functions. First of all, it was necessary for the carrier to possess a huge storagecapacity with which to store information relating to the manifold properties of a living organism, including its structure and the functions inherent to specific species and even individuals. Secondly, such a carrier should possess a mechanism for the realization of the information in to the definite structures of a living organism and its numerous functions (in order to express this information). Thirdly, the most important requirement was the existence of a mechanism for transferring the information to subsequent generations.


The main claim of DNA to be such a carrier is rooted in its chemical structure. DNA is a linear polymer that is comprised of four different monomers, i.e.nucleotides. Each monomer consists of three fragments: a carbohydrate residue (deoxyribose) bound to an orthophosphoric residue and one of the four heterocyclic residues: adenine, guanine, thymine, and cytosine.


The nucleotides are bound by phosphodiester bonds between deoxyribose and phosphoric acid residues ( Fig. 1 ). 


Fragment of the structure of a DNA molecule. 


Such a structural principle enables the existence of an innumerable quantity of various polymeric structures differing in the set and sequences of nucleotides. For a polymer built from n monomeric units, the number of combinations amounts to 4 n = 10 0.6n . Even for a very short polymer of 200 monomeric units, this amount (10 120 ) exceeds the number of atoms in the observable part of the universe, which is estimated at (10 80 ). In fact, the DNA for even the simplest organisms is comprised of thousands, even millions, of nucleotides.


These calculations imply that most imaginable nucleotide sequences could not, in principle, appear in the universe and are subjected to natural selection. This means that the appearance or generation of organisms more fascinating than those that exist at the present time can not be excluded.


However, neither the light shed upon the role of the DNA as an information carrier, nor the huge information capacity of the DNA molecule, has enabled us to solve one of the most intriguing puzzles of this area of science: i.e., how this vast amount of information is transferred from one generation to the other. It has been established that the answer to this puzzle is rooted in the spatial structure of the DNA. According to the model proposed by Watson and Crick,which has been fully confirmed by numerous subsequent experimental studies, DNA is a construct of two polynucleotide chains which are bound together by hydrogen bonds. Within the structure proposed, adenine may interact only with thymine; and guanine with cytosine. Such sequences are considered complementary. The presence of such a correspondence means that any nucleotide sequence in one chain unambiguously corresponds to one nucleotide sequence in another chain, hereby following the mechanism of information transfer from maternal to two daughter cells at cell division. According to this mechanism, two polynucleotide chains separate prior to cell division, each of them governing the formation (synthesis) of a new complementary chain, thus double-stranded structures are formed that are identical to the DNA of the maternal cell. The existence of such a process was confirmed by Meselson and Stahl [ 3 ] soon after the appearance of Watson-Crick’s work. These authors prepared Escherichia coli cells grown on a medium containing 15 NH 4 Cl as a single source of nitrogen. Thereafter, the cells were permitted to grow for several generations in a medium with the usual nitrogen isotope. In all subsequent cell generations, the presence of heavy DNA with the same amount of the heavy nitrogen isotope was observed; indicating that the 15 N-DNA formed in the first step of the experiment remained intact and was simply transferred to one of the daughter cells during each subsequent division of the daughter cells.


The defining feature of Watson-Crick’s work was the fact that the structure of a biologically significant macromolecule was derived using the established geometrical parameters of definite chemical bonds; therefore, the elucidation of the biological phenomenon that begins with the physicochemical parameters of the molecule responsible for the phenomenon was achieved. Consequently, this work can be considered as having heralded the birth of physicochemical biology.


Currently, physicochemical biology includes several scientific disciplines: biological chemistry, biophysics, bioorganic chemistry, and molecular biology. It can reasonably be argued that the traditional separation of these disciplines is not entirely appropriate. For example, molecular biology, according to Wikipedia, is defined as a science that deals with the molecular backgrounds of biological activity; however, biological chemistry has focussed for a considerable period of time upon molecular concepts which describe the most essential biochemical processes as being conversions of molecules with a commonly known chemical structure and has considered the catalysts of these processes to be individual compounds, i.e. as molecules. Therefore, the entire concept of modern biological chemistry refers to molecular science and could therefore reasonably lay claim to the appellation “molecular biology”. For the remainder of this paper the term physicochemical biology will be used to refer to the science that studies biological phenomena on the basis of the physicochemical properties of separate atoms and chemical bonds.


The work of Watson and Crick inspired vigorous efforts which eventually resulted in the identification of the primary biochemical mechanisms that ensure the transfer and expression of genetic information. The concept of the matrix synthesis of biopolymers was the central element of these mechanisms; according to this, each step of elongation of a new biopolymer molecule is not only catalyzed by a specific enzyme, but is also checked by a special nucleic acid, indicating which monomer should be bound to the growing polymer chain at a given stage. These mechanisms are described in all contemporary international and Russian biological chemistry textbooks and manuals, such as [ 4 , 5 ].


The discovery of the enzymes that catalyze the synthesis of complementary DNA molecules has led to the elaboration of the polymerase chain reaction (PCR) [ 6 ], which has found application in medical diagnosis, forensic science, and archaeology.


The elucidation of the mechanisms of DNA expression and the achievement of chemists in the synthesis of oligonucleotides of a desired sequence has led to the appearance of genetic engineering [ 7 ]. It has become possible to carve out definite genes, to modify them and then to subsequently insert them into the proper region of the genome, thus performing site-directed mutagenesis [ 8 ].


The greatest scientific effort in the field of physicochemical biology was launched in 1990 under the name “Human Genome,”a program aimed at the mapping of the complete nucleotide sequence (sequencing) of human DNA [ 9 ]. As early as in 2001, Venter and 272 co-authors had published a complete nucleotide sequence of the human genome [ 10 ]. The methods elaborated within the framework of the program and those that are still being improved have opened the doors to the obtaining of genetic maps for any individual; as well as for the obtaining of genome structures for all the animals, plants and microorganisms on Earth. Consequently, irrespective of the striking success that has been achieved in the elaboration of high-speed efficient sequencing methods, scientists dealing with molecular biology have had enough work on their plate to last for several decades.


The entire breadth of ground that physicochemical biology has covered, from Watson and Crick’s effort to the determination of the structure of the human genome, can be viewed as an incremental effort with clearly formulated tasks and with the purpose of investigating and designing new, innovative methods. During that journey, new and unexpected advances were made along the way; among such advances is the discovery of ribozymes by Thomas Cech [ 11 ] and Sidney Altmann[ 12 ],as well as the discovery of small interfering RNAs [ 13 ].


The appearance of new physicochemical peculiarities for living matter in the future is an eventuality which cannot be excluded a priori . The role of a significant portion of the human genome remains unclear, since only 1.5% of it is responsible for the 23,000 genes coding human proteins. A significant portion of the genome determines the synthesis of various non-coding RNAs: transfer and ribosomal RNAs, introns. However, this does not account for the remaining 98.5% of the genome,and thus a significant portion is considered junk DNA. Establishing the role of this DNA is one of the most challenging problems in the field of physicochemical biology. The functional importance of the extracellular nucleic acids present in appreciable amounts in the blood plasma still remains unclear [ 14 ].


Among the main achievements in physicochemical biology in the past century, it would be short-sighted not to mention the great progress achieved through X-ray crystallography and the NMR study of proteins in the understanding of the mechanisms of biological catalysis. A large body of material has been accumulated relating to the atomic structure of an enzyme’s active sites and their complexes with specific ligands, which has enabled the formulation of reasonable hypotheses pertaining to the mechanisms of recognition and catalytic conversions. For a perspective on the degree of information obtained on the nature of an enzyme’s active sites, a scheme of the arrangement of the reaction intermediate phenylalanine adenylate in the active site of the phenylalanine-tRNA-synthetase is presented in Fig. 2 , with the bonds formed by enzyme active site groups, including the water molecules participating in the interaction [ 15 ].


Structure of the active site of phenylalanine-tRNA-synthetase in complex with the intermediate (phenylalanine adenylate). Dots indicate hydrogen bonds between the intermediate atoms and the enzyme with binding water molecules.


However, this author believes that the focus of physiochemical biology in the 21 st century should shift to other matters. Several aspects which require primordial development both at the theoretical and experimental levels should receive more attention. First and foremost, the role of molecular dynamics requires significantly more attention.


Certainly, the dynamic character of the functioning of the biopolymer did not come as an unexpected revelation. However, organic chemistry, including bioorganic chemistry, has dealt predominantly with structures that are, in essence, static. Dynamic events have been considered as a transfer from the static structure of the reagents to the static structure of the reaction products. In the best cases intermediates were taken into account; however, these were also presented as static structures. It is absolutely common knowledge amongst chemists that molecules, including biopolymer molecules, are subjected to internal motions: the atomic vibrations proceeding at a subpicosecond time scale, fluctuations of a side radical at a pico-nanosecond time scale, conformational rearrangements in the millisecond range, and even slower intramolecular movements. The problem with the molecular dynamics of biopolymers is not limited to simply stating and describing these motions but expands into establishing the role of these dynamic events in the recognition process, catalytic conversions, as well as intra- and extracellular signalling. At the time of writing, the most discussed topic is the role of dynamic factors in enzymatic catalysis [ 16 ].


The role of dynamics in enzymatic catalysis was first brought under discussion in the induced fit hypothesis formulated by Koshland [ 17 ]. According to this hypothesis, no ideal compliance exists initially in the structure of the enzyme active site and the substrate which would enable procession to the execution of chemical conversion immediately after the formation of the enzyme–substrate complex. The process is supposed to be preceded by a conformational adjustment of the complex; i.e., a certain relocation of the atoms, which provides the necessary concordance of the chemical bonds subjected to conversion and a portion of the enzyme active site participating in the catalytic process.


The concept was confirmed by pre-stationary kinetic data. Such changes may be observed using rapid kinetic methods, such as stopped-flow in the millisecond range and relaxation methods (T-jump) in the microsecond range [ 18 ]. As an example, Fig. 3 shows the curves obtained by the stopped-flow method for the splitting of the base reaction (8-oxoguanine), which is catalyzed by 8-oxoguanine-DNA-glycosidase. The conversion was followed by fluorescence of tryptophan residues. At the first stage, the changes in conformation are clearly visible, whereas when several stages are recorded, the release of the reaction product (8-oxoguanine) is distinctly observed only at the final stage [ 19 ].


Kinetic curve of the changes in fluorescence intensity (arbitrary units) during the initial phase of the reaction of 8-oxoguanine excision from the oligonucleotide containing an oxidized guanine residue.


The time range in the use of relaxation methods is significantly expanded by the application of modern lasers capable of irradiating systems via femtosecond impulses, thus generating a T-jump within such a short time period [ 20 , 21 ]. Moreover, if the solution contains a reagent with p K a of the excited state significantly different from that of the ground state present in the solution, a pH jump may be performed via a laser impulse [ 22 , 23 ]. 


The essential dynamics problem is the mechanism by which the system switches from one regime of functioning to another, significantly different, regime. The question already arises with regards to enzymes and enzymatic complexes that possess several catalytic functions manifesting themselves in a certain order. This relates to all the multifunctional enzymes which realize the sequential switching of different functions through a “swinging arm” that is capable of reaching various active sites. A number of such enzymes are known. For example, there is a fatty acid synthase which represents a complex of proteins that catalyze the sequential lengthening of the fatty acid carbon backbone by two-carbon fragments [ 24 ]. During the whole process, the growing chain of carbon residue is bound by a thioether bond to the SH-group of phosphopantothein


-ОРО 2 - -O-СН 2 -С(СН 3 ) 2 -СНОН- -СО-NH-(CH 2 ) 2 -CO-NH-(CH 2 ) 2 -SH,


which is covalently bound by a phosphodiester bond to the serine residue of the acyl carrier protein (ACP). The arm contains a large number of σ-bonds and is therefore highly flexible. This allows the acyl residue to move alternately between the active sites catalyzing sequential stages of the biosynthesis of fatty acid from acetyl residues. The primary source of acetyl residues is the acetylated coenzyme A, CoAS-COCH 3 , the main product of the catabolism of carbohydrates, fats, and a number of amino acids. The acetyl residue is carboxylated, and the malonyl residue formed is transferred from coenzyme A to ACP via the reaction 


СоАS-СОСН 2 СОО - + АСРSH → → АСРS-СОСН 2 СОО - + СоАSН.


Fig. 4 represents a scheme of the processes that occur in all the two-carbon fragments introduced during the process. Malonyl-ACP is the direct donor of these fragments; it binds to the growing chain resulting in the detachment of CO 2 and the cleavage of the bond of the fragment with the protein, reduction of the fragment to –CHOHCH 3 , its dehydration to –CH=CHCH 3 , and reduction to –CH 2 CH 3 .


Scheme representing the lengthening of two-carbon fragments catalyzed by fat acid synthase.


Clearly, each reaction proceeds with the participation of its own active site. The active sites may reside in different polypeptide chains (in eubacteria) or in one polyfunctional protein (in eukaryotes, including humans). The swinging arm must transport fragments of COCH 2 R in a definite order to the four active sites for the procession of all sequential conversions.


The notion of intrinsically unordered proteins is a problem which has recently come to light and requires further study from the perspective of molecular dynamics [25– 27 ]. Currently, there are a large number of such proteins which, in contrast to the commonly held view, function in the absence of a definite tertiary structure. Such proteins are unlikely to exist in the form of a statistically coiled polypeptide chain. In all likelihood, they represent an ensemble of rapidly, mutually transferring conformations in the solution. The predominance of proteins with an unordered conformation is typical of many neurodegenerative diseases, such as the Huntington disease and spinocerebellar ataxia (disorders of the gait and other types of movement coordination). However, many proteins with an unordered structure or at least containing rather expanded (more than 50 amino acid residues) unordered fragments are encountered within the established norm and more often in eukaryotes than in unicellular organisms. Among such proteins, the transcription factors and proteins responsible for chromatin remodeling and intracellular signalling occur more often. This certainly does not mean complete disorder. This can be supported by the fact that many of these proteins become structured after binding to their targets. The absence of order creates a serious problem for the elucidation of their spatial structure, since these proteins do not give rise to reflexes during the X-ray analysis. Meanwhile, more data has been accumulated pertaining to the fact that these unordered parts are most typical of polyfunctional proteins. In all likelihood, the conformations with an affinity to different partners are also present among the conformations of these pseudo-unordered proteins.These proteins are typically characterized by a small content of bulky hydrophobic amino acid residues and an increased content of polar and charged residues.


At the time of writing, the theoretical investigation of biopolymer molecular dynamics is limited by the capabilities of computer techniques. The calculation of molecular dynamics assumes that a stepwise procedure is used, and it requires femtosecond time increments. Even for the modern supercomputers and software, the advance for several tens of nanosecond incrementscan only be attained for the biopolymers consisting of thousands atoms. Meanwhile, the most interesting conformational events occur in the micro- and even millisecond ranges. 


Most studies focused on the physicochemical ground of the vital activity, in particular in the case of quantitative characteristics, were carried out in vitro . Most of the values obtained may be to a significant extent related to intracellular processes, especially to those in eukaryotic cells. A common eukaryotic cell may carrya large number of biopolymer molecules. The conditions in its cytosol do not significantly differ from those in a test tube.This may be demonstrated via a simple calculation for a spherical cell with a linear dimension of 20µm, which is typical of a eukaryotic cell. A spherical cell of a 20-µm diameter was used to simplify the evaluation. For illustrative purposes, it is more convenient to perform calculations in Daltons (Da) as mass units and angstroms as length units (they can be qualified as the “cell” ones). Since 1g = 6 × 10 23 Da and 1cm = 10 8 Å, the density is measured in 1g/cm 3 = 0.6Da/Å 3 . The cell volume amounts approximately to 4 × 10 15 ; the volume of a relatively large protein molecule (approximately 100kDa) is ~ 10 5 Å 3 . Assuming that the proteins occupy 10% of the cytosolic volume, 4 billions of such molecules can be accommodated in one cell. Therefore,it can be reckoned that cytosol conditions (with allowance made for the increased viscosity of the 10% protein solution) do not differ significantly from those in a tube. The arrangement of proteins on the cell surface can be estimated in a similar manner. Assuming that 10% of the plasma membrane surface is occupied by embedded proteins (functioning as receptors, transport and channel-forming proteins, etc.), it is simple to calculate that ~4·10 5 proteins of 100 kDa can be accommodated therein.


Both in vitro and whole-cell studies provide data on the physicochemical characteristics of biochemical processes averaged on the entire set of the molecules involved in it. Therefore, the new possibilities that open up with the development of techniques for dealing with single molecules represent a new and important direction of research. On one hand, these investigations are aimed at elaborating methods for the sequencing of single DNA molecules; a considerable degree of progress has been made in such work in recent times [ 28 ]. The second direction is the investigation of reactions catalyzed by a single enzyme molecule. In this case, the reaction should be accompanied by a fluorescence change. Cholesterol oxidase (EC 1.1.3.6) [ 29 ], which catalyses cholesterol oxidation through molecular oxygen, can be used as an example.The reaction involves two stages:


Cholesterol + FAD ↔ ↔ cholesterol oxidized + FADH 2


FADH 2 + O 2 ↔ FAD.


Cholesterol is oxidized by fluorescent cofactor flavin adenine dinucleotide (FAD) bound to the protein moiety of the enzyme. During the process of cholesterol oxidation, FAD is transformed into the non-fluorescent reduced form FADH 2 . At the second stage of the reaction, FADH 2 is oxidized by molecular oxygen to the initial FAD. Each separate catalytic process is characterized by the attenuation and intensification of fluorescence, allowing one to follow each process of enzyme functioning. Fig. 5 shows the results of the registration of fluorescence upon the catalytic oxidation of cholesterol.


Registration of cofactor fluorescence during catalytic oxidation of cholesterol.


The investigation of macromolecule folding is another important aspect of the application of single molecule spectroscopy. Thus, single molecule fluorescence can be used to observe the dynamics of the formation of the spatial structure of RNA, which can also be recorded via the FRET (Forster resonance energy transfer) technique [ 30 ]. The intensity of the fluorescence energy transfer between the fluorophores bound to certain points of a fluorescence donor being irradiated and its acceptor is in inverse proportion to the sixth power of the distance between them. Any changes in the distance between the fluorophores during the formation of the spatial structure affect the fluorescence of an acceptor between them. The acceptor fluorescence will change with changes in the spatial structure.


The problems considered above, which arise in physicochemical biology, are related to proteins and nucleic acids, the investigation of which was a priority in research in the 20th century. When discussing new horizons in physicochemical biology, one should mention the demand for increasing the level of attention paid to other groups of compounds, with reference primarily directed at carbohydrates of an irregular structure, which play a significant role in the provision of a number of highly selective processes (i.e., the distribution of biochemical processes between cellular organelles). In addition to their cognitive significance, these directions will contribute significantly to the design of new drugs, the investigation of their interactions with living organisms, as well as their transformations and side effects. Therefore, these directions have the potential of becoming important elements of medicine in the 21st century. 


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• Published: 21 July 2023

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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DOI : https://doi.org/10.1038/s41386-023-01656-7

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