Category Archives: Psychedelics

Psychedelics and grief share a surprising kinship. Both are shrouded in societal taboos and folklore mysticism that places them at cultural outskirts and conversations. More importantly, they are both a delicate, natural and ancient human experience that it seems the world may finally be ready to learn not just about but learn from.

What we know well is that grief is an emotional and bodily traumatic event that rewires the brain, much like PTSD. When a bond is formed, there are significant changes to the way those proteins are folded in the nucleus accumbens of the brain. Over time, our neurons are devoted to firing in a certain pattern and with it, devoted to this bond or a partner. The nucleus accumbens plays a motivational role in our reward system responsible for feeding, sexual behavior, stress and drug self-administration, aka addiction. Drugs like heroin and cocaine activate and disrupt this same reward system. The comparison between love and its drug-like addictive effects is a widespread theme, but we are growing privy to the fact that grief chemically functions along that same neural pathway. The lacking bond or missing person causes this loss to be a shock to our reward, nervous, limbic and physiological systems. In other words, it rocks your entire world and in a devastating way at first.

Neurologist, Lisa M. Shulman says that grief is an evolutionary adaptation to promote survival in the face of emotional trauma. Thinking of grief as a tool for transformation is a relatively new idea. Most household conceptions about grief are in fact outdated like the five stages of grief otherwise known as The Kbler-Ross model introduced by Elisabeth Kbler-Ross in 1969. This model was actually shaped off of the series of emotions experienced by a person who is dying, not necessarily grieving. It still became a tangible and accepted explanation of the complex and abstract emotional upheavals one experiences during the varying phases along their grief journey. The last stage was once reaching a point of inevitable acceptance, but it was her protege and partner, David Kessler, todays most popular media expert on Grief and Grieving, that shifted the laymans narrative in 2019 with his book Finding Meaning: The Sixth Stage of Grief. Since then, new-age grief work like experiential retreats or writing workshops such as the Make Meaning Workshop, provide avenues to alchemize their grief into meaning.

This critical sixth step to find meaning offers a bridge between grief and a more fulfilled and emotionally balanced life. But this innate ability to adapt to the shock of grief by making meaning from it was explored in Dr. Robert A. Neimeyers book Meaning Reconstruction and The Experience of Loss published in 2001. Very similar to psychedelic integration models, Neimeyer discusses Meaning-Reconstruction Theory as the capacity to reconstruct, reshape and rethink our experiences or stages of bereavement to initiate recovery and personal growth beyond our previous capacities.

This seemingly simple sixth step of grief can present itself as a perilous and daunting task for the average bereaved person, but if one successfully practices the process and skill of creating or reconstructing meaning, then one successfully integrates a new evolutionary coping mechanism and life tool for the brain, body and spirit.

It is an emotional excavation and reconstruction that asks us to explore the depths and caverns of our most treacherous memories to essentially form new bonds in the brain. This is where psychedelic-assisted therapies come into play for those seeking more holistic and nuanced approaches to overcome prolonged grief. Psychedelics help those grieving in the similar ways that psychedelics have been proven to help heroin addicts, PTSD victims and those who have experienced traumatic events. They help access memories and pivotal events that have negatively altered the reward system in order to confront and offer their brain a path to reconstruct them in a positive way.

New-age grief work looks at symptoms of bereavement or stages of grief as opportunities or entry points for meaning reconstruction to take place. Psychedelic-assisted therapies provide a catalyst to meaning reconstruction, among countless other benefits. Nonetheless, new-age grief work and psychedelic-assisted therapies have similar methodologies. They encourage self-exploration and the notion that we have all we need within ourselves to find true healing and growth if we can only take the pieces of what was to create and admire what now is.

Excerpt from:

The Connection Between Psychedelics and Grief - Psychedelic Spotlight

RESEARCH UPDATE

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelics that are candidates for the treatment of psychiatric disorders.1-4 Both agents stimulate serotonin 5-HT2A receptors; LSD also acts at dopamine D13-3 receptors, and the active metabolic of psilocybin (psilocin) inhibits the serotonin transporter.5 The similarities, acute effects, and dose equivalence of these agents in humans remains unclear.

The Current Study

Holze and colleagues6 directly compared the acute subjective, autonomic, and endocrine effects of LSD and psilocybin at 2 doses and placebo within the same participants. The acute subjective effects of these agents were assessed with validated psychometric instruments, and pharmacokinetic data were obtained over 24 hours. The investigators performed a double-blind, placebo-controlled crossover study with 5 experimental test sessions (placebo, LSD 100 g, LSD 200 g, psilocybin 15 mg, psilocybin 30 mg), with a washout period of at least 10 days between sessions.

The authors recruited 28 healthy participants; their mean age was 35 years and 50% were male. Exclusion criteria were: age less than than 25 years or greater than 65 years, pregnancy, family history of major psychiatric disorders in first-degree relatives, current psychotropic medication use, acute or chronic physical illness, tobacco smoking of more than 10 cigarettes/day, lifetime illicit drug use exceeding 10 times (except use of tetrahydrocannabinol [THC], the principal psychoactive cannabinoid of cannabis), or illicit drug use in the past 2 months or during the study period. In terms of previous drug use, 11 participants had previously used LSD and 6 had previously used psilocybin; 13 had previously used a stimulant; and 10 participants had no history of noncannabis illicit drug use. LSD was administered as an oral solution and psilocybin as an oral capsule. A double-dummy method was used such that participants received 6 capsules and 2 solutions at each test session.

Each test session lasted 25 hours and was conducted in a calm hospital room. Abstinence from illicit drugs was verified with a urine drug screen. Outcomes were repeatedly assessed for 24 hours. Standardized meals were served. An investigator was present in the room during the acute effect phase and remained in a room next to the participant for up to 24 hours. Subjective effects were assessed repeatedly using visual analogue scales (VAS), the Adjective Mood Rating Scale (AMRS), the 5 Dimensions of Altered States of Consciousness scale (5D-ASC), and the Mystical Effects Questionnaire(MEQ). Effect durations were assessed using the classic pharmacokinetic-pharmacodynamic link module. Blood pressure, heart rate, and temperature were repeatedly measured. Adverse effects were assessed 1 hour before and 12 and 24 hours after drug administration. Plasma LSD and psilocybin concentrations, and cortisol, prolactin, oxytocin, and brain-derived neurotrophic factor (BDNF) measurements were also obtained at multiple time points. Pharmacokinetic parameters were estimated using noncompartmental methods. Peak drug effects (minimum, maximum, or change from baseline) were determined for repeated measures, then analyzed using repeated-measures analysis of variance.

Both doses of LSD and the 30-mg psilocybin dose produced comparable subjective effects, based on VAS and 5D-ASC outcomes. There was significantly greater ego dissolution and a trend toward greater anxiety with 200 g versus 100 g LSD. Psilocybin 15 mg had significantly lower effects than psilocybin 30 mg and both LSD doses, based on VAS and 5D-ASC outcomes. Both LSD doses had significantly increased emotional excitation on the AMRS compared with psilocybin. There were no differences in subjective effects of LSD or psilocybin based on sex.

Both LSD and psilocybin significantly increased systolic and diastolic blood pressure, temperature, and pupil diameter compared with placebo. Psilocybin 30 mg produced significantly greater increases in blood pressure and temperature compared with psilocybin 15 mg and both doses of LSD. By contrast, both LSD doses produced a greater increase in pulse compared with both psilocybin doses and placebo. Psilocybin produced greater impairments in pupil contraction compared with LSD. Both LSD and psilocybin increased the total acute (0-12 hours) adverse effect score compared with placebo. Subacute (12-24 hours) adverse effect scores were significantly greater with LSD 200 g LSD and psilocybin 30 mg compared with placebo. The most common adverse effects were headaches. Five participants had 9 flashback episodes within 72 hours. No severe adverse events were observed.

Both LSD doses had significantly longer effect durations (10-11 versus 6-7 hours) and earlier onset of effects (0.4-0.6 versus 0.8 hours) compared with both psilocybin doses. The elimination half-life values were about 4 hours for LSD and 2.5 hours for psilocybin. Both LSD and psilocybin significantly increased plasma cortisol, prolactin, and oxytocin levels, but neither affected BDNF levels. Both LSD and psilocybin showed linear pharmacokinetics, which were not influenced by body weight.

In terms of blinding, no clear distinction between LSD and psilocybin could be made after the session or at study end point. Participants correctly identified the psychedelic and dose in about 60% of sessions, compared with 96% for placebo.

Study Conclusions

The authors investigated and directly compared the acute effects of LSD and psilocybin in healthy participants in a well-blinded study. They concluded that psilocybin 15 mg exerted clearly weaker subjective effects, and both agents had dose-dependent effect durations (significantly longer for LSD), stimulant autonomic effects, and increased endocrine parameters. Body weight had no influence on blood concentrations. The investigators noted the data further supported the notion that states of consciousness alteration induced by LSD and psilocybin are more likely dose-dependent rather than substance-dependent. In addition, they concluded the differences in the pharmacological profiles of LSD and psilocybin do not relevantly influence subjectively experienced effects of both psychedelics.

Study strengths included the within-subjects design and the use of well-characterized, fixed dosing. The primary study limitations were the use of a highly controlled setting and the participation of healthy participants only.

The Bottom Line

This study supports dose finding for research and psychedelic-assisted therapy. Psilocybin 20 mg is likely equivalent to LSD 100 g. There was no evidence for qualitative differences in altered states of consciousness, except for a shorter duration of action for psilocybin.

Dr Miller is a professor in the Department of Psychiatry and Health Behavior, Augusta University, Augusta, GA. He is on the Editorial Board and serves as the schizophrenia section chief for Psychiatric Times. The author reports that he receives research support from Augusta University, the National Institute of Mental Health, and the Stanley Medical Research Institute.

References

1. Carhart-Harris R, Giribaldi B, Watts R, et al. Trial of psilocybin versus escitalopram for depression. N Engl J Med. 2021;384(15):1402-1411.

2. Griffiths RR, Johnson MW, Carducci MA, et al. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial. J Psychopharmacol. 2016;30(12):1181-1197.

3. Davis AK, Barrett FS, May DG, et al. Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial. JAMA Psychiatry. 2021;78(5):481-489.

4. Gasser P, Kirchner K, Passie T. LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects. J Psychopharmacol. 2015;29(1):57-68.

5. Rickli A, Moning OD, Hoener MC, Liechti ME. Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens. Eur Neuropsychopharmacol. 2016;26(8):1327-1337.

6. Holze F, Ley L, Muller F, et al. Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects. Neuropsychopharmacology. 2022;47(6):1180-1187.

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Effects of LSD and Psilocybin in Healthy Participants - Psychiatric Times

A 49-year-old woman with advanced metastatic breast cancer has successfully halted the spread of the disease with chemotherapy alongside cannabis oil and magic mushrooms, according to a new case report. After halting her conventional cancer treatment, the patient remained disease-free for 18 months while using only cannabis and psilocybin, but experienced a recurrence when she stopped self-medicating with these psychoactive drugs.

Sensational as this sounds, its important not to get carried away by a single case study or to jump to conclusions about whether or not weed and psychedelics were responsible for the patients remarkable recovery. Being an observational study, the report does not provide any biomedical analysis of the womans disease progression or treatment protocol.

The patient was first diagnosed with stage IV breast cancer in August 2018 and soon learned that the disease had spread to her bones, liver, and lymph nodes. She was immediately prescribed a course of chemotherapy and took the personal decision to begin self-treating with cannabis oil. From November of that year, the patient also underwent her first session of psychedelic therapy, ingesting a large dose of magic mushrooms under the supervision of a trained therapist.

Incredibly, scans conducted in January 2019 revealed that the cancer had completely vanished, with no evidence of residual or recurrent disease.

This highlights in the first phase of treatment the possibility of the therapeutic adjunctive effect of both psychedelics and cannabinoids in treating metastatic breast cancer, say the study authors.

Chemotherapy was subsequently stopped while the patient continued to take daily doses of cannabis oil plus magic mushroom microdoses. She also went a further three sessions of high-dose psychedelic therapy over the next two years.

Follow-up scans in September 2019 indicated that the cancer had not returned, at which point the patient reduced her cannabis intake to 56 percent of the initial dose while also temporarily halting the shrooms. However, further tests conducted in June 2020 revealed a recurrence of the disease.

This brings up the possibility that withdrawal of the cannabinoid and psychedelic therapies may have contributed to the return of the cancer, write the study authors.

Having received this news, the patient reintroduced psychedelics to her treatment regimen and boosted her cannabinoid ingestion. By October 2021, a stabilization of the illness was observed, although no details are provided as to the severity of the cancer at this stage.

Though the researchers are unable to explain how or indeed if this self-medication approach successfully arrested the patients cancer, they do point to pre-clinical studies hinting at the tumor-busting potential of both cannabis and psychedelics. For instance, research has shown that compounds in weed and magic mushrooms may inhibit a protein called Hypoxia-Inducible Factor (HIF)-1, which facilitates the development of blood vessels within tumors.

However, this has yet to be demonstrated in human cancer patients and there is no hard evidence that either cannabis or psychedelics have any direct impact on tumor development.

Nonetheless, the study authors conclude that the overall picture of the case presents the strong possibility that cannabinoids and psychedelics have played an important modulatory or additive role to standardized treatment, which warrants further exploration.

The study was published in the journal Drug Science.

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Cannabis And Psilocybin May Have Helped This Woman's Breast Cancer Treatment - IFLScience

The formal lawns and topiary of the garden in which Amanda Feilding, Countess of Wemyss and March, is sitting embody a perfect English orderliness; beyond its edge lies a wilderness of Anglo-Saxon moats, sun-dappled woodland and magical stepping-stone trails. This promise of untamed hinterlands puts the grounds of Beckley Park in perfect sync with their mistress. Lady Wemyss is the queen of psychedelics.

Psychedelics have a history which is probably longer than that of civilisation. They have powerful effects on the brain and their lore is rich in anecdotes about effects on mental health, some for better and some for worse. As pharmaceutical companies tried to find new approaches to the brain, the potential of psychedelics might have seemed an obvious road to go down. But law and stigma blocked it. Until five years ago corporate investment in psychedelics as medicines was more or less unthinkable.

Work by Lady Wemysss Beckley Foundation, the Multidisciplinary Association for Psychedelic Studies (maps) in San Jose, California, and other such groups have helped to change that. So has the broadening acceptance of marijuana as a medicine and the softening or repeal of laws limiting its use. A change in the attitude of regulators and researchers towards running proper trials of the drugs has also contributed. Applying modern scientific techniques to the question of how psychedelics and other drugs affect the brain and mind is now seen as opening up possibilities for insight, treatment and profit.

The pioneer in this re-evaluation has been ketamine, an anaesthetic that is also used recreationally. About 20 years ago anecdotal evidence that the drug had an effect on depression led to academic trials; the work piqued the interest of j&j, a big drug company. The ketamine sold generically is a mixture of two compounds with the same chemical formula; j&j won a patent on a nasal spray called Spravato which contained just one of those compounds, s-ketamine. Americas Food and Drug Administration (fda) approved it as a treatment for major depression in 2019.

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Barefoot in the cross-head

Spravato demonstrated the potential of innovation based on recreational drugs: it was the first drug for depression based on a novel biological mechanism to have been approved in 30 years. But it has not been a big commercial success. It is expensive and has to be taken under medical supervision, which adds to costs and faff.

Despite that, all manner of drugs that were mooted as being psychiatrically beneficial in the 1960s are finally being put through their paces in rigorous clinical trials under the eyes of strict regulators like the fda. Dimethyltryptamine, ibogaine, lsd, mdma and psilocybin are being tried. These drugs are targeting the treatment of addiction, anxiety, depression, eating disorders and post-traumatic stress disorder (ptsd).

Within 24 hours of a single dose of psilocybin there was a 10% increase in the number of neuronal connections and some connections were stronger

The non-profit group maps is looking at mdma-assisted therapy for ptsd. mdma, widely known as ecstasy, is a small, amphetamine-like molecule prized for creating feelings of empathy. The maps trial put participants through three preparatory sessions, three sessions in which either mdma or a placebo was administered and nine post-treatment therapy sessions. At the end, 67% of participants in the mdma group no longer met the diagnostic criteria for ptsd, compared with 32% in the placebo group.

Psilocybin is a focus for compass Pathways, a London-based startup. Last year it published the results of a trial comparing different doses of psilocybin, all paired with therapy, in cases of treatment-resistant depression (trd). Three weeks after treatment 29% of those who got the highest dose were in remission.

Given what the tr in trd stands for, a response rate of almost 30% was exciting to scientists. But it was a disappointment to many who had been listening only to the media hype about the potential of psychedelics. The remission seen by fewer than one in three did not always last; only one in four were still in remission three months on. And three of the patients in the high-dose group displayed suicidal behaviour, compared with none in the other cohorts. Suicidality is common in trd and in trials of anti-depressants, but it is nonetheless a cause for concern.

One of the two underlying capabilities of psychedelics that interests researchers is that they seem to be able rapidly to induce neural plasticityphysical changes in the growth of neurons and of the connections between them. A recent study by scientists at the Yale University School of Medicine showed that, within 24 hours of a single dose of psilocybin, neurons in the prefrontal cortex of a mouse brain changed; their dendritesthe bits which receive inputs from their neighboursgrew longer and denser. There was a 10% increase in the number of neuronal connections and evidence that some of those connections were stronger.

Think of the neurons as close-packed trees flourishing in the lush gardens of the prefrontal cortex, which organises thoughts and actions. Dendrites are their tangled branches. A healthy brain has a rich canopy. Withered branches can lead to losses in connectivity and less communication between the context and areas associated with motivation and reward.

In the study, the connections between neurons in the mices brains became both more numerous and stronger, suggesting connectivity was improved. Not all the changes lasted; but a month later some were still visible. And they were correlated with changes in the animals stress-related behaviour.

The drugs trigger this sort of change in the neurons by activating various combinations of a specific set of receptor proteins which includes three types of serotonin receptor (5-ht1b, 5-ht2a and 5-ht2b) and nmda, a glutamate receptor. Different drugs favour different receptors (see diagram) which is why they have different effects. mdma, which produces psychedelic-like effects but without hallucinations, works on the 5-ht2 receptors, inducing a rapid release of serotonin and dopamine. Ketamine and ibogaine, which is extracted from an African shrub, both work on nmda as well as other receptorsincluding, in the case of ketamine, opioid receptors. The biochemistry of this is also linked to anatomy. Activation of 5-ht2ain which the visual cortex is comparatively richseems to be necessary (although not sufficient on its own) to generate hallucinations.

If plasticity is one interesting aspect of psychedelics, the other is that by firing up receptors they also disrupt activity within the brains neural networks. Srinivas Rao, the chief scientific officer of atai Life Sciences, a German company that specialises in psychiatric drugs, says the psychedelics and their kin are loosening connections in the brain and then altering network functions. Atai is pursuing ketamine for trd and ibogaine for opioid addiction.

Dr Rao warns that psychedelics are not going to be cures for most people with chronic conditions like depression. The loosening of connections in a network-disrupting trip might shift some of them out of a rut; it will not stop them returning to it. But many think the drugs open the door for talking therapies to work better and for patients themselves to initiate new approaches to life. A few patients will be lucky enough to have durable responses. Guy Goodwin of compass Pathways sees psychedelic treatment as a way for some patients to achieve a step change. It may be for a minority, he admits. How we increase that minority is a question we are going to have to work on in the future.

There are other factors which could limit the uptake of these medicines. Like Spravato they will probably be approved for use only in certified health-care settings and with strict protocols; a patient given a dose of psilocybin, or mdma, requires many hours of supervision. That makes these drugs very unlikely to be the first line of therapy offered to people who roll up at their doctors office with depression or anxiety. They are also likely to be approved for use only in the context of psychotherapy.

Such requirements may mean that more people seek the benefits more cheaply. The approval of Spravato coincided with an uptick in the use of generic ketamine, given by intravenous infusion, in clinics across America and Europe. And the drugs in question are all, more or less by definition, available informally.

Whos for a short, unstrange trip?

One alternative would be to develop second-generation drugs based on the same principles but more easily administered. Delix Therapeutics, based in Boston, Massachusetts, is heading full tilt to the creation of psychedelic substances with the hallucinatory effects eliminated, which would mean they could be used by patients without supervision. Dave Olsen, chief innovation officer at Delix, says the drugs work because they encourage neuroplasticity; if that is the case, then the trippiness may not be necessary. He points to studies showing that dental patients anaesthetised with ketamine wake up with an enhanced mood; having some kind of conscious experience is not integral to the drugs effects.

There will be potential patients who hope he is right. Some proponents of psychedelics think the mystical experience is integral to the clinical outcome, revealing insights into the psyche that are impossible to obtain any other way. This means they find it hard to bend their minds around the idea that some of the mentally unwell do not want to change their consciousness. They just want to get better. Rory, a hairdresser from Lancashire, had suffered from depression all his life; he had tried everything and was keen to find something that worked. Yet his first experience with a ketamine infusion was so horrendous he did not want to come back.

Delix, for its part, is not saying that the world does not need hallucinogens to treat mental-health disorders, nor that the network effects they offer are not useful. It is just saying that drugs that do only part of what psychedelics do could be useful in and of themselves. Dr Rao says, being empiric I view the hallucinations as a manifestation of network disruption.

Psychedelics are obviously not the be all and end all of new approaches to clinical neuroscience, let alone the one true path to raised consciousness and, as some would have it, humankinds continued evolution. They may well be particularly prone to placebo effects, something it is hard for trials to rule out since people tend to know if they have been given a placebo or sent on a trip. But if high hopes (sorry) seem likely to court disappointment, their study in clinical settings should yield some helpful therapeutic advances and new insights into the way minds sit in brains.

2022 The Economist Newspaper Limited. All rights reserved.

From The Economist, published under licence. The original content can be found on https://www.economist.com/technology-quarterly/2022/09/21/ketamine-psilocybin-and-ecstasy-are-coming-to-the-medicine-cabinet

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Ketamine, psilocybin and ecstasy are coming to the medicine cabinet - Yahoo Finance

Santa Monica, California--(Newsfile Corp. - September 26, 2022) - American Legion Post 123 has officially partnered with Reality Mgmt Technologies (RMT) and its flagship facility Reality Center, located at the heart of Silicon Beach. This partnership will allow the Reality Center team to continue providing patented, drug-free psychedelic experiences to veterans in order to help treat post traumatic stress.

Since January of this year, the RMT team has successfully treated more than 200 veterans suffering from PTS at their new, state-of-the-art sensory wellness center and digital therapeutics lab only steps away from the Santa Monica Pier. These treatments have earned the interest of their local VSO, American Legion Post 123 in Santa Monica,as they became aware of the treatments Reality Center was already offering some of their members.

"Post 123 is committed to integrating our community of veterans with the rapidly growing wellness ecosystem here in Santa Monica," stated Post Commander Bailey Steele. Since partnering, the local American Legion post has been offering free monthly treatments to their members as a way to increase their post 9/11 veteran membership and promote their focus on a new mental health ecosystem.

Reality Center's patented tech and modalities work by combining ancient and modern science. They are able to address a wide array of mental, physical and emotional issues in a one-of-a-kind healing environment. Providing a safe and effective alternative to psychedelics and pharmaceuticals, Reality Center provides a controlled, drug-free experience using frequency technologies to stimulate the nervous system's natural healing mechanisms.

The main treatment veterans experience include Reality Center's most popular offering which involves having each veteran lay on a vibrational platform or liquid mineral bed for 30 minutes while experiencing pulsing lights and synchronized sounds that allow individuals to immediately exit fight or flight and journey deep into their consciousness.

PR Contact: Sharon FoxEmail:sfox@realitymgmt.com

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To view the source version of this press release, please visit https://www.newsfilecorp.com/release/138445

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American Legion and Reality Center Partner to Provide Patented, Drug-Free Psychedelic Experience to Veter - Benzinga

Tahlia Harrison has been bombarded with questions about psychedelics. A practicing therapist, Harrison recently graduated from the bioethics and science policy program at Duke University, where I teach and served as her masters thesis supervisor. Her patients are increasingly interested in experimental regimens that use drugs like LSD, psilocybin, and MDMA to treat post-traumatic stress disorder and other forms of trauma.

Harrisons patients are hardly alone. Since 1970, psychedelics have been considered Schedule I drugs in the U.S., with the feds maintaining that they have no accepted medical use. But in recent years, the government has softened its stance and, accompanied by no small amount of hype, psychedelic-assisted therapies are now being tested in dozens of clinical trials. These studies can present substantial health and safety risks to the patient, and a number of trials have been attached to allegations of sexual abuse. To better understand how these risks are communicated to prospective study participants, earlier this year Harrison set out to collect consent forms used in more than three dozen psychedelic-assisted therapy trials listed on the federally run website clinicaltrials.gov.

To her disappointment, she was able to download consent forms from just five of the trials that met her criteria. And despite directly contacting the organizations running the studies, only one responded to her queries.

Since the long parade of ethics scandals that plagued biomedical research during the 20th century from Nazi doctors experiments, to the Tuskegee Syphilis Study, to a Brooklyn hospital study that injected patients with live cancer cells informed consent has been a hallmark of research on human beings. It enshrines the idea that we cant experiment on people without first informing them of the risks and benefits and, obviously, getting their permission. The consent forms used in clinical trials, as dense and lawyerly as they might be, are meant to answer questions like: What is involved in the study? How long will it take? Will I get paid? What happens if it goes sideways?

But in many cases, few people outside of the researchers, participants, and the institutional review boards charged with approving a study ever see the language used in a trials consent form. Recently, there has been a push toward greater transparency, under the rationale that broadly publicizing the forms researchers use to communicate the risks and benefits of clinical trials will improve accountability, boost public trust in research, and inform the development of future consent forms. But what Harrisons experience, and what my own look at clinicaltrials.gov seem to show, is that the science community isnt pushing nearly hard enough.

A major win for informed consent transparency came in 2018, when federal officials updated the so-called Common Rule a regulation that covers human subjects research funded by 20 U.S. agencies, including the Department of Health and Human Services, under which the National Institutes of Health falls. Effective January 21, 2019, the rule change requires federally funded clinical trials to publish an approved consent form on a public federal website; the form is to be posted after the close of patient recruitment but no later than 60 days after participants last required study visit. Researchers are given an option to upload the form either to clinicaltrials.gov or to a designated folder at the federal website regulations.gov.

Late last year researchers at Brigham and Womens Hospital and the National Library of Medicine found that while the number of posted consent forms is indeed rising, it is hardly keeping pace with the Common Rules requirements. The authors found, for example, that fewer than 18 percent of NIH-funded studies had posted forms.

Late last year researchers at Brigham and Womens Hospital and the National Library of Medicine found that while the number of posted consent forms is indeed rising, it is hardly keeping pace with the Common Rules requirements.

In September, I conducted my own search of clinicaltrials.gov and found that only 283 of the 1,112 federally funded interventional studies listed on the site as having started after January 21, 2019 and finished before January 21, 2022 had uploaded consent forms. Some of the studies had yet to upload any results at all, but even when I limited my search to those that had an idea suggested to me by Geisinger research ethicist Michelle Meyer little more than half had posted consent forms. (I also searched all of the more than 427,000 studies listed at clinicaltrials.gov including past, ongoing, and upcoming studies in the U.S. and elsewhere that arent subject to the Common Rule and found that consent forms had been shared by only 1.3 percent of them.) Meanwhile, the designated folder at regulations.gov,the alternative site where studies may deposit consent forms to satisfy the Common Rule, contained just 44 consent forms posted during the three-year window.

To be fair, some people have sounded alarms about publicly sharing consent forms. In practice, they note, researchers often use the forms less as a way to inform participants and more as a means to mitigate institutional liability. (You cant sue us here at Big Academic Medical Center it was all in the consent form!) At least one group of health care attorneys argued that posting requirements could prompt researchers to write even more stilted, legalistic forms aimed at shielding themselves from lawsuits. The same group also fretted that a rule requiring the public posting of a consent form might confuse participants and the public, because a clinical trial will sometimes use different versions of the form for different participants at different sites, and the consent form might get updated throughout the recruitment process. Who would decide which version to post, and how? Elsewhere, there were concerns that a public posting requirement would stifle innovation, for example, by keeping clinical investigators from exploring novel approaches to consent such as interactive video Q&As.

Public posting of consent form language is a low-risk, low-burden act that could give motivated prospective participants a chance to see what they might be signing up for well ahead of time and gives all stakeholders an opportunity to flag problems.

I was and remain unmoved by these complaints. Publicizing consent forms will make them worse? Wait, what? And sharing them with everyone rather than with just the people you want to participate will necessarily increase liability risks? If so, thats a problem with American jurisprudence and not a justification for opacity. As for the potential confusion over multiple versions of a consent form, in an appropriate consent process prospective participants should always be given the most updated version of the consent form, and an opportunity to ask questions. And one provision of the revised Common Rule mandates that multisite trials use a single institutional review board, which should help standardize consent forms across the different sites. We now have some evidence that this is indeed happening, although some local institutions have been reluctant to cede control.

With respect to video consent and other innovative approaches, the updated Common Rule says nothing about them other than references to electronic format, and its not clear why novel consent processes shouldnt be done transparently: Why not post a link to your consent video on clinicaltrials.gov for all the world to see?

As someone who has served on an institutional review board, read thousands of pages of mind-numbing consent forms, and participated in research as a human subject over the past 15 years, I think that the Common Rule more or less gets it right. Public posting of consent form language is a low-risk, low-burden act that could give motivated prospective participants a chance to see what they might be signing up for well ahead of time and gives all stakeholders an opportunity to flag problems. It could lead to more equitable, safer, better research. Or maybe not. But the only way we can know is by doing the experiment.

For patients like Harrisons, who seek risky but potentially life-saving experimental therapies, the stakes couldnt be higher. Some contend and, for what its worth, I agree that the fervor of the current psychedelic hype cycle is driven more by a messianic push for legitimacy than by an unbiased search for truth. But what if MDMA really works? What if psychedelic-assisted therapy, delivered in a safe environment, can bring relief and healing to people suffering from PTSD and other traumas? Dont we want as many folks as possible considering all of the risks and benefits, the promises and disclaimers? Couldnt controversial psychedelic-assisted therapy studies have benefited from a few more eyes on their consent forms?

We can read millions of scientific papers, court documents, real estate listings, restaurant menus, drug prices, and movie reviews all with just a few keystrokes.

So why not consent forms?

Misha Angrist is associate professor at Duke Universitys Social Science Research Institute and a senior fellow in its Initiative for Science & Society.

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Let's Bring the Informed Consent Process Out of the Shadows - Undark Magazine

Your story Shelter recounts the adventures of an American man on a business trip to Israel who gets caught up in an unexpected drama. What drew you to Cohen as a character?

In the story, Cohen, middle-aged, believes himself to be in stasis, but stumbles unwittingly into a moment of great dynamism. As a younger person, I used to think of middle age the way many coastal people driving across the country think of the Midwest: as a huge, vaguely menacing, but mostly boring expanse where one contemplates how far one has come and how far one still has left to go. I didnt understand what was meant by amidlife crisis,beyond the disappointment of no longer being what I still happily was: fabulously young. For that reason, I mostly avoided middle-aged characters in my writing, preferring the young or the old, whose crises I somehow imagined myself more equipped to fathom. But, now that Ive arrived at middle age myself, I realize that I couldnt have been more mistaken. I guess its always the case that we believe whatever age we are at to be the most interesting. But what a radical, rich, utterly riveting time of life it is! I look around at my friendsadmittedly a lively, searching bunchand Im just amazed by the variety of dramatic positions and problems and possibilities everyone is facing. Theres something very moving to me about all the late revelations that are not yet so late that they can be ignored, about the deep settling into oneself that makes settling for what doesnt fit no longer acceptable. To be honest, Ive come to feel a great warmth for middle age, and more and more I find myself wanting to be there in my writing.

The climactic scene of the story takes place in amamak, a reinforced safe room, in Tel Aviv. Why did you choose that space for Cohens moment of action and the birth of a baby?

Being in Tel Aviv while rockets are exploded overhead by anti-missiles is a surreal experience. I mean, war itself must always seem surreal. But, in Tel Aviv, what often fascinates me is the way that, a moment after the missiles have been destroyed and the sirens have fallen silent, the whole city snaps back to whatever it was doing right before the emergency began. The conversation that had stopped midsentence resumes, the waiters and waitresses once more sail smoothly between tables, and everything continues as if nothing had happened. This deft restoration of normalcy is itself surreal, the result of a collective refusal to allow a certain aspect of realitythe one where fear and horror liveto take root and unfurl. The shelter, then, where one goes to wait for the danger to pass is, in a sense, the only place where that realitythe reality of death, of the fact that people want to kill and are killedis acknowledged. So it interested me, by contrast, to set a birth there. And not just any birth but one attended to by a man who is returning from his own private excursion into surrealism, courtesy of psychedelics, and descending back into a reality he would rather not face.

Why did you choose to have Cohen be on psilocybin in this scene?

For the reason above. And Id add that in this scene hes actually coming down from his trip. Like sex, psychedelics are easier done than written about. Its nearly impossible to convincingly describe the specific experiences one has had on psilocybin because an aspect of sobriety is skepticism, and skepticism is completely annulled by psychedelics. Everything one feels and experiencespositive or negative, beautiful or scaryis wholly felt and believed. Doubt requires distance, and there is no distance in a psychedelic experience, no stepping back or away. But then one has to come down, and that return, I suppose, is what I was interested in writing aboutthat middle zone where one has not yet lost access to that state of being and belief, even as one is recalled to a reality that cant fully host it. When Cohen is confronted with, as they say, the miracle of life, he hasnt yet lost his sense of wonder, his belief in his own goodness; he hasnt yet been reminded of his own failures, so he can half believe himself to be a part of the miracle.

Cohen feels that he has played a momentous role in the delivery of Navas babyand, of course, physically, he has. But, since we see everything in the story through his eyes, its difficult to know how Nava feels about what happened. Do you have an idea?

Of what Nava feels for Cohen and his part? In the grand scheme of her own experience, probably not all that much. Giving birthtalk about a totalizing experience. Talk about be here now! I dont know of another sober experience more self-absorbing than labor. Everyone elsethe nurses, the doctor, even the fathersort of fades away offstage, as far as I recall, and you are alone inside this enormous event. Which is ironic, because the moment you give birth you cease to be the main protagonist of your own life. Your child takes up that role, and you fall back to play all the other parts. So the labor of delivery is your last chance to be the star of your own life, at least for a very long while.

The story is written in the third person, but, as discussed, its more or less Cohens internal monologue. What appeals to you about writing from that perspective?

Theres a line in the story: between Cohen and Cohen something else had slipped in, courtesy of the perspective of middle age: a hand span of ironic distance. I think its that hand span of distancenot too much and not too littlethat also attracts me to a close third person. The photographer Diane Arbus once described how everyone has a need to look one way but is always seen in another. This space between what we want people to know about us and what we cant help people knowing about us she called the gap between intention and effect. And its that gap that a close third-person perspective bridges, allowing for irony and a touch of humor.

Shelter reminds me a little of your story Zusya on the Roofanother narrative in which a man at a turning point in his life is confronted with the so-called miracle of birth and deeply affected by it. Why do you think this is such a rich subject for you? What do Brodman, the protagonist of Zusya, and Cohen have in common?

A writer friend of mine described the character of Cohen as one of my less ruined men. Its true that theres a certain kind of stymied character that interests me, though not so much for his failure or his ruination as for the moment when he suddenly sees, shining up ahead, a way out. It allows for a story that both looks back at a life and looks forward into the future, a view that can be heady, even breathtaking. Whether the escape or the solution is real or notwhether he actually transcends what he feels bound or oppressed byinterests me less than the encounter with possibility. The chance for redemption: isnt that finally the great subject of all literature?

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Nicole Krauss on Death, Birth, and Middle Age - The New Yorker

The Story

A psychedelic could treat depression.

Yesterday, a newly-published study found that ketamine was effective at reducing symptoms of suicidal thoughts, depression, and anxiety. During a year-long period involving over 400 patients, about three-quarters saw their moods improve. And nearly 40% say they were symptom-free after 10 infusions of ketamine.

Thats because ketamine (aka Special K) is used by some to get a psychedelic high. But its also used medically and legally as an FDA-approved anesthetic. And it's increasingly used as an off-label mental health treatment. ketamine is also proven effective in treating psychiatric conditions like eating disorders. Now, the real-world data from the study is giving experts a better understanding of the drug. And it couldnt come at a better time

Last month, the new 988 Suicide and Crisis Lifeline saw a 45% uptick in calls, chats, and text messages compared to the year before. And it comes as Americans have seen reported increases in rates of anxiety and depression since the pandemic began. If youre struggling with symptoms of depression, youre not alone.

While ketamine could prove to be a game changer for mental health, researchers say more trials are needed to assess the drug's full effects. But reminder: psychedelics are still illegal in most of the US.

PS: If you or someone you know is struggling with suicidal thoughts, call the National Suicide Prevention Lifeline at 988.

The Justice Dept. Since last week, the DOJ has reportedly subpoenaed around 40 of former President Trump's associates. Its considered a significant escalation in the DOJs investigation into the Jan 6 Capitol riot and other attempts to overturn the 2020 election. The subpoenas were sent to everyone from low-level aides to senior advisers. The DOJ also seized two cell phones that were apparently in connection with the fake elector plan. Aka the alleged plot to overturn the 2020 election by submitting fake electors in seven swing states like Georgia, Pennsylvania, and Arizona...the ones President Biden won by thiiiis much. It comes as the Jan 6 House committee is nearing the end of its investigation. They could decide whether to request testimony from Trump and former VP Mike Pence as early as today.

...Oh and in other Trump news, the DOJ's signaling it's open to one of Trump's picks for a special master. Judge Raymond Dearie could serve as the third party person to review the docs taken from Mar-a-Lago last month. But a federal judge overseeing the case needs to sign off.

Nurses. Yesterday, about 15,000 nurses in Minnesota walked out on their jobs across several hospitals to protest understaffing and work conditions. Its reportedly the largest protest in US history involving private sector nurses. They claim some units operate without a lead nurse on duty. And that inexperienced nurses are saddled with tasks more senior figures usually handle. Now, the protest is expected to last three days. The nurses are asking to have a say in staffing plans and pay bumps over 30%. And the president of the Minnesota Nurses Association says meeting their wage demands will help resolve retention problems. But hospitals say they cant afford the wage demands and say the nurses have refused to meet at the mediating table.

Johnson & Johnson. Over the weekend, the company reached a settlement in Australia over allegedly selling defective pelvic mesh. The material is often used in women who are suffering from urinary incontinence (which can be common after childbirth and menopause) or to help hold pelvic organs in place. J&Js been in trouble for this mesh before. Earlier this year, a California court ordered them to pay $302 million for not being upfront about the risks. But thousands of women filed complaints against J&J, alleging the companys pelvic mesh led to chronic pain, urinary problems, and painful sex. Now, Johnson & Johnson will be paying $300 million in two class action suits.

The Emmy Awards.

iMessage is letting people hit the edit button.

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Daily Skimm: Psychedelics, The DOJ, and iMessages - theSkimm

Ali has suffered from depression since she was 12 years old. Now a trained paediatric nurse living in Bristol, she has taken antidepressants and other medication for most of her adult life. In her late twenties, following the death of a close friend, Alis depression spiralled and she was unable to continue working. Trapped at home, the drugs she was being prescribed were causing her to gain weight, have recurring nightmares and sleep paralysis.

I was in a desperate place, Ali recalls. I had tried all sorts of therapies and medications. I was on really high doses. I think my mental health team didnt know what else to do with me. In 2019, Ali joined a trial being run by David Nutt, professor of neuropsychopharmacology at Imperial College, and Robin Carhart-Harris, head of Imperials Centre for Psychedelic Research, testing the impact of psilocybin the main active ingredient in magic mushrooms alongside psychotherapy, in 59 people with moderate to severe depression.

During her first psilocybin trip Ali experienced euphoria and a kind of spaciousness that was very different from the insular, crushing feelings of depression. She recalls wandering outside her own body through a cathedral-like building. In her second dosing session she travelled through different landscapes and memories. During one stage she was reunited with her deceased friend. I floated as a river with her for what felt like hours. It was a way of saying goodbye because I didnt get to do that, she recalls.

Not only were these psychedelic experiences life-affirming for Ali, but they also liberated her from myopic ways of thinking: I felt like myself for the first time in a long time. I wasnt completely free from my depression, but I was able to start seeing the good in life again and enjoy things, she explains. I promised myself that I was going to try to live, and to enjoy life.

During the trial, Prof Nutt and his colleagues found the psilocybin, when used in conjunction with therapy, produced rapid antidepressant effects. It was as effective as escitalopram (used to treat depression) and scored better in two key areas: participants reported a better sense of wellbeing and 58 per cent were considered in remission six weeks after treatment, compared with 28 per cent in the escitalopram group.

Prof Nutt has been researching psilocybin for around 20 years, but interest in psychedelic treatments is growing. Research from Kings College, London, published in January 2022, evaluated the safety of psilocybin as part of therapy in the largest randomised controlled trial of psilocybin in the UK to date; documentaries like Michael Pollans How to Change Your Mind are reaching new audiences on Netflix; and this month Europes first commercial facility for psychedelic drug trials is opening in central London.

Situated in an Edwardian townhouse off Harley Street, the clinic is a bland place with revolutionary aims. Apart from its calming dcor and opaque curtains there are few indications that it is a site where participants will experience mind-bending drug trips. But while the new era of psychedelic research might have its roots in the hippie communes of the 60s, and the turn on, tune in, drop out mantras of US psychologist Timothy Leary and his LSD acolytes, todays practitioners are rigorous, data-driven scientists.

Later this month, a team of around a dozen scientists, psychotherapists and clinicians will step into this newly renovated facility to launch Clerkenwell Health, a commercial contract research organisation (CRO) founded to facilitate clinical trials to test psychedelics for drug developers.

If you listen to the psychedelic purists of the 60s, the only setting is a hut in the middle of the Amazonian jungle, but thats been a challenge to reproduce in Central London, Emilio Arbe, Clerkenwells chief medical officer, tells i.

Since the ultimate aim is to bring these treatments to mainstream psychiatry, weve moved away from anything too exotic.

The first trials here, scheduled to begin in October, will test the effects of psilocybin, along with psychotherapy, on around 60 cancer patients struggling with terminal diagnoses. After three sessions of psychotherapy, half will receive the drug and half a placebo. The trial is being conducted for the Toronto-based biotech company, Psyence.

Using these drugs for psychiatric therapy isnt new. English psychiatrist Humphrey Osmond famous for trying to cure alcoholism with LSD coined the term psychedelic in 1956 in a letter to writer and mescaline user Aldous Huxley. The same year British psychiatrist Ronald Sandison was working in the worlds first purpose-built LSD unit at Powick psychiatric hospital near Malvern in Worcestershire, using the substance to help treat depression and schizophrenia.

In the late 60s and early 70s countries including the US and UK moved to make the use of LSD and psilocybin illegal. In the UK, the Misuse of Drugs Act (1973) also restricted medicinal use. Both remain Class A, schedule 1 listed drugs, meaning they are illegal and officially classified as having no medical use. The ruling has severely restricted, but not prohibited, clinical research into the ways psychedelics can influence the mind.

Clerkenwell is not the first organisation in the UK to experiment with mind-altering substances, but it is the first commercially funded venture to conduct clinical trials on its premises.

Having a specialist facility for psychedelic drug trials is essential to help bring new treatments to market, says co-founder and chief scientific officer Henry Fisher. A drug development company wants to run a clinical trial as quickly, efficiently, and safely as possible, he says. Its not just about giving someone a drug. The therapy is a vital and fundamental component to the intervention, as is the setting in which its delivered.

Like Ali, Ian Roullier, 45, has also taken psilocybin as part of a previous clinical pilot run by Imperial College London in 2015. After suffering for years from anxiety and depression, Roullier hit rock bottom in 2014. As a journalist he had worked himself to the point of exhaustion and was feeling burnt out. He took various types of antidepressants to try to find some respite from his low moods but they only made him feel numb and lifeless. After hearing about the trial at Imperial he enlisted, desperate to see if psilocybin-assisted therapy could help.

Roullier describes the ordeal as a visceral and challenging exercise. During his hallucinatory trip he engaged with feelings and emotions he had been avoiding for years. It was a Wizard of Oz moment, Roullier recalls. That doesnt mean that everything was rosy and beautiful, but my anxiety and depression had lifted. I approached situations openly, the self doubt, and self recrimination in my head had faded away.

Psilocybins potential to be a therapeutic enabler seems to stem from its ability to break down the rigidity of depressive thinking. Brain scans show that it increases connectedness between different parts of the brain. In particular, the compound stimulates a serotonin receptor in the cortex linked to neuroplasticity. Nutt hopes that it can induce fresh states of consciousness and not only unearth repressed memories, but when aligned with therapy help people re-evaluate them, and thus think differently about their future.

The first major insight we found was that psilocybin dampens down a part of the brain that is one of the driver hubs for depression, Nutt explains. We knew that antidepressants and psychotherapy did that, but usually it takes weeks or months to happen. With psilocybin, it happened within minutes.

The other conclusion Nutt and his colleagues drew was that psilocybin disrupted a part of the brain that contains our sense of self, a faculty that commandeers more brain activity in depressed people.

Sarah Bateup, therapy lead at the Clerkenwell clinic, believes that psychedelics like psilocybin could yield significant breakthroughs in mental healthcare. If youve had depression for 20 years, youve had therapy 10 times, youve tried every drug, youve had electroconvulsive therapy, and you dont get better, youre already thinking: Im not curable.

A psychedelic like psilocybin creates this window of opportunity, where the person is very open and more receptive to therapy, she adds. But she stresses that psychedelic-assisted therapy is a novel and highly challenging form of psychiatric care, and one that carries significant risks. After all, these substances are powerful and unpredictable.

Were being very robust, scientific and evidence based, Bateup says. We also think that its very important to strip out the symbolism that comes with psychedelics. If this is a medicine of the future, then it needs to be fit for world health systems its our responsibility to do high quality research, and show people that were boring scientists and clinicians, not people that have done too many drugs.

There is a growing interest in using other drugs, such as MDMA and ketamine in mental health treatments. Awakn, a life sciences firm with clinics in Bristol and London, is researching the potential for ketamine and MDMA to treat alcoholism, gambling addiction, binge eating, and sex addiction. In the US, treatments that include MDMA are likely to be approved soon for patients with post-traumatic stress disorder (PTSD), though regulator approval in the UK is likely to take longer.

Meanwhile, Compass Pathways, a mental health care company and developer of a synthesised psilocybin, has this year announced a collaboration with Kings College Hospital and South London and Maudsley NHS trust to accelerate research into emerging psychedelic therapies.

To ensure that Clerkenwell delivers safe and beneficial treatments, Bateup has devised a training programme to help therapists work across multiple conditions with a range of psychedelic compounds. The screening process has been extremely rigorous.

We dont just take people that have the right qualifications, Bateup says. Were looking for scientists and practitioners who can reflect on their work, take feedback, and always want to be learning.

It is this thorough approach that Roullier has also sought to champion. In 2021 he set up The Psychedelic Participant Advocacy Network (PsyPAN) with Leonie Schneider, another participant in the second Imperial trial. The non-profit aims to connect a global network of participants in psychedelic trials. By pooling together these lived experiences, they hope to help clinicians create more effective treatment models, and improve participant safety and wellbeing.

Although trials do indicate some successes, they are still limited and operating on a small-scale number of patients. These treatments may be very effective tools but its very important to push back a bit, Roullier advises. Weve gone from these drugs drive you mad to these drugs could cure this condition for ever. Even when psychedelics do work, Roullier stresses that they are not a quick fix. Roullier still suffers with depression, but he has not taken antidepressants since taking part in a second psilocybin trial in 2019, and regularly attends counselling sessions.

Im living proof that one trial doesnt fix you for ever. Psychedelics have huge potential, but it would be simplistic to say that they are the answer to the mental health crisis, Roullier cautions. We need to deliver these treatments as ethically and safely as possible, so they have the best chance of making it to market.

For Bateup, while psychedelic-assisted therapy is a challenging and nascent field, the biggest gamble would be to keep things as they are. Our mental health care system is pitiful and its getting worse. Treatment outcomes have stagnated. Nobodys invented anything new, she says. Theres a big group of people who are really suffering, and this could be something that makes a huge difference to them. Thats what I want. Thats what its all about.

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Inside the UK's new psychedelic drug trial clinic trying to treat depression and anxiety - iNews

Mark Rus, MSc., Chief Executive Officer and Director of Delix Therapeutics.

Clinical interest in psychedelic chemicalsclassic hallucinogens like LSD (D-lysergic acid diethylamide) and dissociative drugs like ketamineis becoming increasingly mainstream. In 2019, the U.S. Food and Drug Administration (FDA) approved a nasal spray called esketamine (Spravato) containing a ketamine-like compound for treatment-resistant depression.

Although ketamine and now esketamine are available in clinics, most psychedelic compounds remain illegal. Psilocybin, the magic ingredient in psychedelic mushrooms, is farthest down the path to FDA approval. Just a few weeks ago, researchers at NYU Grossman School of Medicine showed that two doses of psilocybin, a compound found in psychedelic mushrooms, reduce heavy drinking by 83 percent on average among heavy drinkers when combined with psychotherapy.

Besides the issue of legality, taking psychedelic compounds has risks. In addition to poisoning, there are long-term side effects that include memory loss, seizures, and anxiety. Also, the eponymous side effects of psychedelic compoundshallucinations (seeing the world turn into fractals, hearing voices, or tasting colors) and dissolution (feeling out of control or disconnected from their body and environment)pose a risk to serious harm because of the profound alteration of perception and mood. While not inherently dangerous, consumption of psychedelics has led people to harm themselves and others while having a mind-altering experience, with tales of people becoming suicidal and violent.

To harness the clinical power of psychedelics, the mechanism of action underlying the antidepressant and anxiolytic effects need to be separated from hallucinatory and dissolutive. Research has shown that result from their ability to promote structural and functional plasticity in prefrontal cortical neurons. Isolating the chemical structures driving the rapid and long-lasting antidepressant and anxiolytic effects of psychedelics may be used as lead structures to identify next-generation neurotherapeutics with improved efficacy and safety profiles.

Delix Therapeutics is a neuroscience company focused on harnessing the power of isolating psychoplastogensnovel neuroplasticity-promoting therapeuticsto better treat mental health disorders at scale. Based in Boston, Massachusetts, the companys compounds, which do cause not cause hallucinatory or dissociative side effects, are easily manufactured small molecules capable of rapidly inducing structural and functional neural changes in targeted brain areas. Many of these molecules are inspired by psychedelic compounds and preserve their efficacy-promoting mechanisms while avoiding their hallucinogenic properties and other safety liabilities.

GEN Edge has taken a look into the motivation and structure of Delixs R&D pipeline with CEO Mark Rus, a veteran industry executive. He joined Atlas Venture after previously leading Shire Pharmaceuticals Global Neuroscience Business.

GEN Edge: What motivated the founding of Delix Therapeutics?

Rus: Neuropsychiatry and neurodegeneration have had a shortage of innovation for the past few decades. Were still using a similar selective serotonin reuptake inhibitor (SSRI). You cant even find meaningful advances on the neurodegenerative side. Pick your access moral, strategic, or financial. All roads lead to the need for better mental health treatments. The treatments do not match the unmet need in the space.

Through that motivation, Delix co-founder David Olson was working on ketamine at the Broad Institute on why these rapid structural and functional changes, called neuroplasticity, occur in the PFC. We know the intangible benefits associated with like ketamine or true psychedelics like psilocybin. Perceived dissolution of ego and the unique intrinsic experiences that one can have are very powerful. Who am I to say that those cant be the most transformative experiences for someone in their lives?

But Im a neuro drug developer, and Im more interested to know whats happening at the synapse or circuit-based level. It was inconceivable to me that structural and functional neuroplasticity did not play a role. That ultimately led to the foundation of Delix.

GEN Edge: How do psychoplastogens work?

Rus: If you think of a neuron as a trees trunk, the dendrite is the branch coming off that tree and the synapses or the leaves on the edge of the branches. A well-functioning circuit connective circuit of pre-frontal cortex (PFC) to other brain parts is like a rich forest, where the neurons are all connected. But then, in a scenario where theres trauma, whether genetic or external, in both cases, those leaves start falling off, the dendrite branches retract, and the synaptic connectivity in the circuit is essentially lost or suboptimal.

To me, thats a fascinating nexus that sits at the heart of a range of neuropsychiatric and neurodegenerative conditions. So, why do psychedelics seem to help so quickly and so robustly? Its an indisputable fact that there is a massive and significant growth in the dendritic spine density process called synaptogenesis. David and I felt it was worth pursuing and drawing that lineup further. There are great companies, people, and funding behind hallucinatory-based approaches. But what if you could do it without the hallucinatory-based approach and some other aspects that may be suboptimal for some of these compoundsside effects, like HERG inhibition, other than removing the hallucinations?

For any brand, product, or therapeutic, I ask: What does it mean to a patient? Is it going to help? Will it make a difference in motivating them to want to take it? What does it mean for a payer and the prescriber? Is it sufficiently simple or motivating enough to change an ingrained habit that physicians may have in treating a particular condition? What does it mean for pharmacists, psychologists, and others in terms of ease of use? What does it mean for policymakers?

What motivated the Delix story was whether we could pursue the neuroplasticity-focused element, tease that out, and subtly tweak known hallucinatory compounds to generate our own novel IP. These eventually become very different compounds that, inspired by the hallucinatory ones, become more tolerable and orally bioavailable. You can take them home and thus be scalable to fit the current care frameworks and speak to the scalability of manufacturing, commercial, and patient access.

GEN Edge: What advantages do psychoplastogens have over hallucinogenic psychedelics?

Rus: I saw an inherent scalability issue regarding first- or second-generation hallucinatory psychedelics. Its not a reason not to do it. People can and will be helped by those experiences, but spending eight hours in an inpatient treatment clinic with multiple therapists surrounding you to support you and to walk you through that mission is one of the reasons why Spravatowhich a lot of people were excited by, the first ketamine derivative that was approved launched by Janssen and justifiably created a lot of motivation for our space and approved by the FDAhasnt been a huge success. Its tough to get high throughput payers to pay for it, and people that want to come back to take it with that high degree of complexity. Now, many people have been and will be helped with it.

There is a wide proportion of patients with comorbidities who will never even be candidates for hallucinatory psychedelic therapy. For someone with bipolar, schizophrenia, or a history of psychosis, its not the first, second, or third thing youd want to take to risk exacerbating that condition. When you start moving in that neurodegenerative direction and particularly individuals who are perhaps older or later in life, the ability to build rapport with therapists is plausible for some, and for others, it isnt. Im not sure how one discerns that early on.

So, the need for more options is there. Theres a mix of scalability, comorbidity, and other related reasons. That makes a lot of sense for more treatments in our approach. And thats what the Delix approach was all about. We wanted to take this non-hallucinatory approach to validate it preclinically. Ive been searching for the right scalable approach in this space because I see the promise that rapid structural and functional neuroplasticity changes may bring.

Delix is a psychoplastogen platform company. We now have thousands of compounds at this stage at various stages of characterization. We have two candidates that we nominated last year and moved into IND-enabling studies. We are in the process of completing those now. Well be in phase one early next year to show the translatability of this non-hallucinatory reality in man, efficacy, and safety with our approach while continuing to characterize, develop, and nominate subsequent candidates. We have a pipeline that we can produce from our platform as we drive forward the Structure-Activity Relationships (SAR) and the related screening discovery full of the scheme.

GEN Edge: What is the Delix R&D pipeline scheme?

Rus: Were certainly inspired by the fact that this work has been going on for a long time. Were standing on the shoulders of a lot of great work that has been going on for decades in the hallucinatory psychedelic space. But all our novel chemical and composition matter-supported compounds are synthesized and built in-house and are inspired by predicate compounds.

We have a phenotypic-driven drug discovery engine. Each one of these lens tests produces compounds that fit the Delix narrative for what an eventual clinical candidate would be. The first thing we do is assess for psychoplastogenic propertiesif something is a compound generating robust neurite outgrowth. We look at targeted binding and functional assays that one would typically use and the classic battery of safety profiles you do in neuro-drug discovery, such as ADME and PK. Then, we quickly test for the likelihood of hallucinogenic properties and an efficacy profile. So, weve got a range of multiple assays we assess so that as early as possible in the process, we can take some compounds off the assembly line that we feel are likely to display hallucinogenic properties and separate them from the non-hallucinogenic ones.

We dont allocate resources, time, or effort to the early-stage compounds weve developed and synthesized that have robust IP but are likely to be hallucinogenic. Over time, I feel those could be good candidates for other companies who are better natural owners and stewards of the hallucinatory approach. Thats not our lane, but we have identified and can build compounds that perhaps have an optimized hallucinatory profile.

The preclinical to clinical translatability is not great for hallucinatory properties. Some pretty good models like head twitch and related rodent models also have a pretty good R-square value for not being hallucinatory in man. We test efficacy through assays such as the non-forced four swim test, where we do the highest possible bar and most possible assays to demonstrate effectiveness in early-stage rodent models.

We also directly compare the compounds that we find most attractive against positive and negative controls. How are they doing against ketamine for being rapid-acting and long-lasting? We also dont want to develop another SSRI or something you must take daily. We want to be a once a month, twice a month, once every two months therapy, not once a day. Finally, we look at safety, toxicology, and dosing models that inform eventual clinical candidate selection and then patient subtypes.

GEN Edge: What is Delixs approach to funding?

Rus: The syndicate you build is essential, not just from the capital perspective. Its important to build with investors who truly understand neuro-drug development and are interested in building a leading neuroscience company, not short-term investors. And were fortunate to have that syndicate, having raised about a hundred million last year through our Series A and convertible note round. We have great teammates from ARTIS Ventures, RA Capital Management, founding investor OMX Ventures, and others.

GEN Edge: Whats on the horizon for Delix?

Rus: We want to get into the clinic to demonstrate human translatability for a Delix compound ASAP next year and continue to advance our pipeline candidates out of our platform, ready to move into IND-enabling studies adjacent to those clinical studies from phase one. We feel that being the leading non-hallucinatory, psychoplastogen company globally is a step towards being a leading neuroscience company by 2030.

Were building out our headquarters, and well be moving in next year here in Massachusetts in Q1. We couldnt be more thrilled to have a shot at making a big meaningful difference in something that all of us face one way or the othereither with ourselves, loved ones, or friendswith the suboptimal standard of care in mental health.

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What A Trip: Delix Therapeutics is Treating Mental Health at Scale with Psychoplastogens - Genetic Engineering & Biotechnology News