In April, Boston-based biotech company Seaport Therapeutics launched a $100 million venture-funded project. The event marked the joining of a growing number of companies working to optimize psychedelic drugs for the treatment of various mental illnesses.
The «next-generation psychedelics» developed aim to overcome some of the limitations associated with the use of classic psychedelics for therapy, such as depression or substance use disorders.
In May, Gilgamesh Pharmaceuticals, another firm working on such psychedelics, announced a collaboration with pharmaceutical giant AbbVie to develop new therapeutics for mental health disorders.
Gilgamesh will receive an initial payment of $65 million from AbbVie, and the total potential of the deal could reach $1.95 billion in royalties and milestone payments, signaling a growing interest in this area.
Classic psychedelics such as psilocybin, found in «magic mushrooms», dimethyltryptamine (DMT), the active ingredient in the South American psychoactive drink ayahuasca, and lysergic acid diethylamide (LSD), known since the 1960s, are already being tested as treatments for mental disorders.
«Five years ago, this was a pretty unusual area of science. Today, billions are being invested in these initiatives and hundreds of companies are developing new psychedelic drugs» — notes Sam Banister, co-founder and chief scientific officer of Psylo, a company working on the next generation of psychedelics.
The growing interest in psychedelics is largely due to the significant demand for effective solutions. The World Health Organization reports that 280 million people worldwide suffer from depression, while commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are often not effective enough.
The recent success of Spravato (esketamine), one of the enantiomers of ketamine, has demonstrated the demand for new therapies. The drug was approved by the FDA for the treatment of depression in 2019, and last year Johnson & Johnson earned $689 million in sales from it.
«Five years ago, this was a pretty unusual area of science. Today, billions are being invested in these initiatives and hundreds of companies are developing new psychedelic drugs» — notes Sam Banister, co-founder and chief scientific officer of Psylo, a company working on the next generation of psychedelics.
The growing interest in psychedelics is largely due to the significant demand for effective solutions. The World Health Organization reports that 280 million people worldwide suffer from depression, while commonly prescribed antidepressants such as selective serotonin reuptake inhibitors (SSRIs) are often not effective enough.
The recent success of Spravato (esketamine), one of the enantiomers of ketamine, has demonstrated the demand for new therapies. The drug was approved by the FDA for the treatment of depression in 2019, and last year Johnson & Johnson earned $689 million in sales from it.
Nevertheless, the psychoactive effects of these substances lead to certain difficulties. For example, creating a reliable placebo for blinded clinical trials can be difficult because patients would have difficulty confusing a sugar pill with a dose of LSD. In addition, patients require serious observation for several hours while under the influence of drugs, making these trials difficult and costly.
To avoid the aforementioned problems, some companies are modifying psychedelics to create shorter or milder «trips» that won't require intensive patient monitoring. Others, such as Seaport, are redesigning molecules to completely eliminate their psychedelic effects while maintaining therapeutic efficacy.
«Many patients experience anxiety going through these trips and don't want to revisit the experience» — says Aaron Koenig, chief medical officer at Boston-based Delix Therapeutics.
To avoid the aforementioned problems, some companies are modifying psychedelics to create shorter or milder «trips» that won't require intensive patient monitoring. Others, such as Seaport, are redesigning molecules to completely eliminate their psychedelic effects while maintaining therapeutic efficacy.
«Many patients experience anxiety going through these trips and don't want to revisit the experience» — says Aaron Koenig, chief medical officer at Boston-based Delix Therapeutics.
Some researchers believe that psychedelic experiences are important for achieving long-term mental health improvements, but it's still unclear whether the therapeutic effects can be maintained without the necessary tripping. «This is a question that has not been answered in the field» — states Andrew Kruegel, scientific director and co-founder of Gilgamesh.
Banister notes that companies developing next-generation psychedelics are taking different approaches to optimizing their molecules.
«My observation is that each company chooses its own unique path» — he says. This may be due not only to a lack of scientific consensus on the role of the psychedelic trip, but also demonstrates the diversity of approaches in a field that has faced limited pharmaceutical progress since the advent of SSRIs in the 1980s and 1990s.
Psychedelics represent a broad and diffuse class of compounds. Their psychoactive effects, including hallucinations and feelings of dissociation, vary greatly depending on the type of compound and dose.
Banister notes that companies developing next-generation psychedelics are taking different approaches to optimizing their molecules.
«My observation is that each company chooses its own unique path» — he says. This may be due not only to a lack of scientific consensus on the role of the psychedelic trip, but also demonstrates the diversity of approaches in a field that has faced limited pharmaceutical progress since the advent of SSRIs in the 1980s and 1990s.
Psychedelics represent a broad and diffuse class of compounds. Their psychoactive effects, including hallucinations and feelings of dissociation, vary greatly depending on the type of compound and dose.
«It can range from a mild high similar to the effects of coffee to a full LSD experience where you feel connected to something divine», explains Jesper Christensen, a medicinal chemist at the University of Copenhagen who is developing next-generation psychedelics at his company Lophora.
Many psychedelics have similar molecular structures. Most of them activate the serotonin receptor 5-HT 2A, which appears to play an important role in their effects. In contrast, ketamine acts as an antagonist of the N -methyl-D-aspartate (NMDA) receptor, which is often targeted by anesthetics.
The psychedelic drug sector continues to grow. «We have recorded around 150 drug development projects based on various psychedelics» — states Jasparam Kaur, senior business analyst at Roots Analysis, a research firm based in Chandigarh, India.
According to a recent report by Roots, companies in this field have raised over $3.5 billion since 2017, and it is projected that the therapeutic psychedelics market could reach $6.7 billion by 2030.
Many psychedelics have similar molecular structures. Most of them activate the serotonin receptor 5-HT 2A, which appears to play an important role in their effects. In contrast, ketamine acts as an antagonist of the N -methyl-D-aspartate (NMDA) receptor, which is often targeted by anesthetics.
The psychedelic drug sector continues to grow. «We have recorded around 150 drug development projects based on various psychedelics» — states Jasparam Kaur, senior business analyst at Roots Analysis, a research firm based in Chandigarh, India.
According to a recent report by Roots, companies in this field have raised over $3.5 billion since 2017, and it is projected that the therapeutic psychedelics market could reach $6.7 billion by 2030.
One of the pioneers in the field of classical psychedelics is Lykos Therapeutics of San Jose, California. The company has completed two Phase 3 clinical trials with 3,4-methylenedioxymethamphetamine (MDMA) for medication-assisted psychotherapy for post-traumatic stress disorder (PTSD) and has submitted an investigational new drug application to the FDA, which is now under review. Although MDMA is not a traditional psychedelic, it is often considered as such.
In second place is Compass Pathways of London, which is testing psilocybin in two Phase 3 trials for treatment-resistant depression, and Mind Medicine, a New York-based biotech company that in March published positive Phase 2b results for its LSD analogue MM120, indicated for the treatment of generalized anxiety disorder. Both drugs received «breakthrough therapy» status from the FDA.
Robert Malenka of Stanford University notes: «I am excited about the therapeutic potential of these substances, but at the same time I would consider it necessary to treat them with caution». He points to the lack of available scientific data on these techniques and adds that «the actual evidence for therapeutic activity remains limited».
In second place is Compass Pathways of London, which is testing psilocybin in two Phase 3 trials for treatment-resistant depression, and Mind Medicine, a New York-based biotech company that in March published positive Phase 2b results for its LSD analogue MM120, indicated for the treatment of generalized anxiety disorder. Both drugs received «breakthrough therapy» status from the FDA.
Robert Malenka of Stanford University notes: «I am excited about the therapeutic potential of these substances, but at the same time I would consider it necessary to treat them with caution». He points to the lack of available scientific data on these techniques and adds that «the actual evidence for therapeutic activity remains limited».
There are also questions about cost-effectiveness, as patients require close supervision by therapists during treatment.
«In Australia, the cost of therapy using MDMA or psilocybin for a single patient can cost around A$20,000-30,000 for a course of treatment that lasts several months» — Banister comments.
Similar issues apply to psilocybin, as a therapeutic session can take up to eight hours. This is due to the need to metabolize psilocybin in the body to produce psilocin, the active ingredient that affects the 5-HT 2A receptor.
Toronto-based Cybin is developing a psilocybin analog, CYB003, that does not require metabolic activation. They have replaced some of the molecule's hydrogen atoms with the heavier isotope deuterium, which helps slow its decay. The result is a more controlled psychedelic experience: although the drug still requires psychotherapeutic support, the session lasts only 4-6 hours.
Cybin has completed a Phase II trial of CYB003 for the treatment of major depressive disorder, using lower doses than classic psilocybin. In March, the company presented data showing that CYB003 provided significant antidepressant effects that were longer lasting than those of SSRIs.
«After four and a half months, we saw that the majority of patients continue to respond and remain in remission» — states Cybin's chief medical officer Amir Inamdar. CYB003 has been granted breakthrough therapy status and will soon begin Phase 3 trials, with $150 million dollars raised in March.
Cybin is also working on a DMT analog, CYB004. When administered intravenously, DMT metabolizes quickly and causes an intense trip lasting less than 20 minutes, which may not be enough for a full treatment. In contrast, a single injection of CYB004 induces a 90-minute trip, and Cybin is about to begin enrolling participants for a Phase II trial of a product aimed at treating generalized anxiety disorder.
Another concern is that some traditional psychedelics also activate the 5-HT 2B receptor, which is present in heart tissue and can cause long-term heart problems. Lophora, a company led by Christensen, is trying to address this with its compound LPH-5, a phenylethylamine derivative that shows high selectivity for 5-HT 2A over 5-HT 2B.
«After four and a half months, we saw that the majority of patients continue to respond and remain in remission» — states Cybin's chief medical officer Amir Inamdar. CYB003 has been granted breakthrough therapy status and will soon begin Phase 3 trials, with $150 million dollars raised in March.
Cybin is also working on a DMT analog, CYB004. When administered intravenously, DMT metabolizes quickly and causes an intense trip lasting less than 20 minutes, which may not be enough for a full treatment. In contrast, a single injection of CYB004 induces a 90-minute trip, and Cybin is about to begin enrolling participants for a Phase II trial of a product aimed at treating generalized anxiety disorder.
Another concern is that some traditional psychedelics also activate the 5-HT 2B receptor, which is present in heart tissue and can cause long-term heart problems. Lophora, a company led by Christensen, is trying to address this with its compound LPH-5, a phenylethylamine derivative that shows high selectivity for 5-HT 2A over 5-HT 2B.
The company has multiple analogs that have been tested at different receptors, and results from experiments in rats show that LPH-5 can have a sustained and potent antidepressant effect. Lophora plans to initiate a phase I trial of LPH-5 for treatment-resistant depression, using electroencephalography to evaluate the drug's effects. Christensen believes therapeutic doses should not induce tripping in patients, based on experiments conducted with mice.
Some companies believe they can minimize or eliminate psychoactive effects without losing therapeutic properties. For example, Gilgamesh applies this approach to ketamine, DMT and psilocybin. In the case of ketamine, dissociative effects require patient monitoring. Gilgamesh has therefore developed a ketamine analog, GM-1020, which does not cause dissociative effects and has better oral bioavailability than ketamine itself.
After a successful Phase 1 trial last year, GM-1020 began Phase 2 use in March for the treatment of major depressive disorder. «We’re hoping the side effects will be limited enough that the patient can use it at home» — Kruegel says.
Some companies believe they can minimize or eliminate psychoactive effects without losing therapeutic properties. For example, Gilgamesh applies this approach to ketamine, DMT and psilocybin. In the case of ketamine, dissociative effects require patient monitoring. Gilgamesh has therefore developed a ketamine analog, GM-1020, which does not cause dissociative effects and has better oral bioavailability than ketamine itself.
After a successful Phase 1 trial last year, GM-1020 began Phase 2 use in March for the treatment of major depressive disorder. «We’re hoping the side effects will be limited enough that the patient can use it at home» — Kruegel says.
Gilgamesh is also using machine learning to analyze video of mice in experiments to accurately assess their movements. They use Neuropixels probes to monitor the response of hundreds of neurons to drugs, which provides higher resolution than traditional electroencephalograms.
The company is also developing GM-2505, a 5-HT 2A agonist that is structurally similar to psilocybin and DMT. GM-2505 completed Phase 1 trials late last year and plans to begin Phase 2 trials for the treatment of major depressive disorder this year.
The drug's psychedelic effects last 60 to 90 minutes, giving patients enough time to «explore the altered state of consciousness necessary for long-term efficacy», according to Kruegel. However, this achieves control limits acceptable to the health care system.
Nevertheless, Gilgamesh is also investigating non-hallucinogenic compounds for their ability to affect neuroplasticity. This process refers to the brain's ability to adapt and reorganize its neural networks. The company hopes that their «neuroplastogenic» compounds can maintain the efficacy of traditional psychedelics, eliminate hallucinogenic effects, and be safe for unsupervised patients.
«If this works, the absorption of such therapies will be much easier» — Kruegel notes, adding that such drugs can be used just like any other medication.
Non-hallucinogenic analogs of psychedelics are also safe for people with schizophrenia or dementia, says Kurt Rasmussen, CSO of Delix. In phase 1 trials of their drug DLX-001, which is a neuroplastogen, results showed no hallucinogenic effects. In laboratory animals, DLX-001 and other Delix neuroplastogens stimulate the renewed growth of damaged dendrites, which are necessary for neurons to communicate.
Animal experiments have also confirmed that DLX-001 activates 5-HT 2A receptors, but not 5-HT 2B, which is associated with cardiac risks. The drug is in preparation for phase 2 trials to treat depression by 2025.
Boston-based Seaport is also developing neuroplastogens to treat depression and anxiety disorders. «Our concept is based on the fact that you don't have to experience a psychedelic trip to get the beneficial effects of these agents» — says founder and chairman Steve Paul.
One of the company's drug candidates is the non-hallucinogenic LSD analog SPT-348. Although LSD itself is a 5-HT 2A agonist, its rate of metabolism in the liver varies from patient to patient, making it difficult to determine the optimal dose. Therefore, Seaport have linked their LSD analog to a new delivery system known as Glyph to avoid metabolism in the liver. Through a special linker, the drug binds to triglyceride, which is absorbed through the intestinal lymphatic system, entering the bloodstream before releasing the active ingredient.
Clinical trials with classic psychedelics often face a placebo problem, but SPT-348 can avoid this difficulty. «Since we have no psychedelic experience, this opportunity to do a placebo-controlled trial I think would be useful» — Paul emphasizes.
In Australia, Psylo uses computational models extensively to study the interaction of hundreds of millions of molecules with the 5-HT 2A receptor and has developed thousands of potential candidates based on the data. Their non-hallucinogenic lead compound PSYLO-100X is not derived from classical psychedelics, and Banister prefers to call it «adjunctive to psychedelics». The company is currently conducting toxicology studies, but expects to begin Phase I trials in the future.
Boston-based Seaport is also developing neuroplastogens to treat depression and anxiety disorders. «Our concept is based on the fact that you don't have to experience a psychedelic trip to get the beneficial effects of these agents» — says founder and chairman Steve Paul.
One of the company's drug candidates is the non-hallucinogenic LSD analog SPT-348. Although LSD itself is a 5-HT 2A agonist, its rate of metabolism in the liver varies from patient to patient, making it difficult to determine the optimal dose. Therefore, Seaport have linked their LSD analog to a new delivery system known as Glyph to avoid metabolism in the liver. Through a special linker, the drug binds to triglyceride, which is absorbed through the intestinal lymphatic system, entering the bloodstream before releasing the active ingredient.
Clinical trials with classic psychedelics often face a placebo problem, but SPT-348 can avoid this difficulty. «Since we have no psychedelic experience, this opportunity to do a placebo-controlled trial I think would be useful» — Paul emphasizes.
In Australia, Psylo uses computational models extensively to study the interaction of hundreds of millions of molecules with the 5-HT 2A receptor and has developed thousands of potential candidates based on the data. Their non-hallucinogenic lead compound PSYLO-100X is not derived from classical psychedelics, and Banister prefers to call it «adjunctive to psychedelics». The company is currently conducting toxicology studies, but expects to begin Phase I trials in the future.
Banister notes that regulators have recently become more open to clinical trials with psychedelic drugs, as there is growing evidence that these therapies can help patients.
«We are seeing an increase in mental health disorders exacerbated by the COVID-19 pandemic. I believe that psychedelics deserve a second chance» — Steffen Thirstrup, chief medical officer at the European Medicines Agency, said in an online session summarizing the findings.
In the coming years, the results of these companies clinical trials may bring clarity to the question of whether psychedelic drugs can have therapeutic effects without tripping. A positive outcome could mark an important step forward in neuropharmacology. If successful, the results could be truly significant.
«We are seeing an increase in mental health disorders exacerbated by the COVID-19 pandemic. I believe that psychedelics deserve a second chance» — Steffen Thirstrup, chief medical officer at the European Medicines Agency, said in an online session summarizing the findings.
In the coming years, the results of these companies clinical trials may bring clarity to the question of whether psychedelic drugs can have therapeutic effects without tripping. A positive outcome could mark an important step forward in neuropharmacology. If successful, the results could be truly significant.