Lykos

Note: Click here for an essay from Helena Founder/CEO Henry Elkus on Lykos and the future promise of psychedelic therapy.

Post-Traumatic Stress Disorder begins with a stressor. A person, or someone close to them, experiences a catastrophic or potentially catastrophic event: a near-death experience, an assault, combat. Then, perhaps right after, perhaps months or years later, the symptoms begin. Intrusive images – nightmare, flashbacks – as if the incident were happening again; hypervigilance; avoidance and emotional numbing; negative thoughts about themselves, their futures, their capabilities. The range of potential symptoms is broad, but the experience is devastating.

The PTSD diagnosis was only introduced in the DSM-III in 1980, but that’s certainly not when it started. Over the years it’s been called many things – “nostalgia” in the 1800s and “irritable heart” after the Civil War; the famous “shell shock” during World War I, reflecting the new artillery; “combat stress reaction,” “battle fatigue,” and “combat exhaustion” post World War II; “survivor syndrome” in Vietnam. Its effects have been observed and chronicled in histories, medical reports, and correspondences for millennia.

Today in the United States alone, an estimated 13 million adults will suffer PTSD in a given year, and 280 million people in their lifetimes worldwide.

Although exposure to combat is a significant indicator – veterans are more than twice as likely as civilians to suffer from PTSD at some point in their lives – the majority of cases are non-military related. Thirty-four percent of PTSD cases are triggered by sexual abuse before the age of 18; 29% by death and loss; 23% by sexual violence; 21% by serious injury; and 6% by military combat.

Individuals with PTSD are twice as likely to abuse alcohol, four times as likely to suffer anxiety, and three to five times as likely to suffer depression. PTSD has been linked to increased rates of eating disorders, substance abuse, cardiovascular disease, autoimmune disease, and Parkinson’s. Women are especially at risk; they represent 66% of the total PTSD cases and exhibit higher levels of PTSD symptoms when exposed to trauma.

The economic burden on society is substantial. In the US, PTSD costs an estimated $232 billion dollars each year. For civilians – who account for 81% of the total cases – the primary drivers are direct health care and unemployment; for military personnel, disability. PTSD’s economic burden is on par with that of depression and anxiety.

The disorder has also proven incredibly difficult to treat. Talk therapy is the most common approach, but it’s only been shown to alleviate PTSD symptoms in about half of cases. Patients treated with Serotonin Reuptake Inhibitors (SSRI’s) like Zoloft and Paxil are responsive in only around 60% of cases, with full remission in only 20-30%. A new drug application hasn’t been approved in over 20 years.

MDMA-assisted therapy suggests a powerful alternative.

Naturally occurring psychedelics – psilocybin (mushrooms), ayahuasca, mescaline (peyote), DMT – have been used for spiritual and medicinal purposes for thousands of years. Prized for the way they promoted empathy and communal connectedness, indigenous leaders and healers have employed them in rites and ceremonies in civilizations all over the world.

Despite their myriad global and historical uses, psychedelics were largely absent from Western medicine until 1938, when the Swiss chemist Albert Hofman synthesized LSD. Intending to create a respiratory and circulatory stimulant for Sandoz Laboratories, Hofman instead discovered the drug’s mental health applications. He began distributing it to psychiatrists under their brand name Delysid in 1947. By the early 1950s, they were seeing incredibly encouraging results in the treatment of alcoholism, depression, and end-of-life anxiety. Between 1950 and 1965, practitioners had prescribed LSD to 40,000 patients and published more than a thousand scientific papers (of varying degrees of robustness) on the topic. Instances of negative reactions in clinical settings were exceedingly rare, results were overwhelmingly positive, and scientists, as they better understood psychedelics, were increasingly optimistic about their potential. The period has been called the “golden age of psychedelics.”

But this heyday of Western psychedelic medicine came to a screeching halt in 1970. Books like Aldous Huxley’s The Doors of Perception, which detailed his experience with clinically-administered mescaline, brought awareness of psychedelics to wider audiences.

As the drugs seeped into the mainstream, they exited the scientific community’s oversight and care. Instances of recreational abuse increased, stories of the potential dangers of psychedelics mounted, and the drugs became associated less with scientific breakthroughs and more with a burgeoning counterculture and the decay of classic American values, especially against the backdrop of the Vietnam War. In 1970, President Nixon signed the Controlled Substances Act into effect, classifying LSD and other known psychedelics (DMT, psilocybin, mescaline) as Schedule I drugs – illegal to possess, with no accepted medical use.

Less than a decade later, in a UC-Berkeley lab in 1975, a chemist named Alexander Shulgin, together with student Carl Resnikoff, synthesized 3,4-Methyl​enedioxy​methamphetamine, better known as MDMA.

This was not the first time MDMA had been synthesized; it was originally formulated in 1912 by German Merck scientists trying to make a blood coagulant. It was (probably) not even the first time Shulgin himself had synthesized it –  his lab notes suggest he had formulated it in 1965 and had shared the process with a chemist in Los Angeles in 1970.

It wasn’t until 1976 however, that Shulgin ingested it himself for the first time. He wrote, “this substance stimulated but was not a stimulant; it disinhibited without being an intoxicant; it helped to express feelings and emotions more freely, but without impairing self-control.” He said it “enabled me to see outside without distortion or reluctance, and to look inside myself.”

Recognizing MDMA’s potential in psychotherapy. Shulgin gave the compound to a psychologist named Leo Zeff, who had overseen thousands of psychedelic-assisted therapy sessions in the 60s. Zeff called the drug Adam because it seemed to put users in a primordial, neuroses-free state, and he introduced it to hundreds of his fellow therapists. “I kept him supplied with the drug and he went out and supplied the Western world with the experience itself,” Shulgin said. “That was the blossoming of its use in psychotherapy.”

However, just like the psychedelics did before it, MDMA leaked out of psychiatry offices and science labs and into the pockets of recreational users. Ecstasy, as it became known, became incredibly popular, and its demand – and visibility – grew.

This visibility was, of course, a potential death knell for the legality of MDMA. But the therapeutic community had learned its lesson. Anticipating a DEA response to recreational use, therapists and researchers began preparing a petition to classify MDMA as Schedule III instead of Schedule I – a designation that would outlaw recreational use but preserve medical and research applications.

In early 1984, a group called the Association for the Responsible Use of Psychedelic Agents (ARUPA) met at the Big Sur retreat-center and educational institute Esalen to carve out a pathway for the continued, sanctioned use of MDMA in psychiatric settings. Among those invited was a 30-year-old psychotherapist named Rick Doblin.

Galvanized by the meeting, Doblin co-founded the Earth Metabolic Design Laboratories to support ongoing psychedelic research. He installed Shulgin, Zeff, and others as the board of advisors. They funded toxicity studies, set up meetings with FDA officials, and secured legal counsel. When the DEA announced that it intended to classify MDMA as a Schedule I drug, Doblin filed the necessary legal documents to request a hearing.

But shortly thereafter, Charles Schuster, founder and director of the University of Chicago’s Drug Abuse Research Center, appeared on The Phil Donahue Show to discuss MDMA. Though he, too, supported the medical and therapeutic use of MDMA, his appearance instigated an uproar based on his citation of a neurotoxicity study he had conducted that tied large doses of MDA (not MDMA) to brain damage in rats.

The fact that the drug administered in the study was MDA and not MDMA, the massive doses used, and the fact that it was injected instead of ingested – key differences between the applications of MDMA Doblin and allies were promoting –  did little to quell the alarms Shuster’s media moment sounded. In response, the DEA asserted emergency powers and placed MDMA on its list of Schedule I drugs. (Notably, MDMA has not been shown to be neurotoxic in the years since, despite extensive testing.)

For Doblin and other proponents of the medical use of MDMA, things looked bleak, but there was a way back in: the long, arduous FDA approval process.

Doblin was steadfast, and in 1986, he founded the Multidisciplinary Association for Psychedelic Studies to shepherd MDMA through regulatory channels.

MAPS undertook the study of MDMA-assisted therapy (MDMA-AT) and commenced the FDA’s four-phase approval process.

The process is laborious and expensive, even for non-Schedule I drugs. The first two initial studies must prove safety and effectiveness. Based on the results of these Phase 1 and 2 trials, the FDA must then approve an indication for a large-scale Phase 3 study. This is no easy feat –  While 70% of indications move from Phase 1 to Phase 2, just 33% make it to Phase 3. To make matters even more challenging, not only was MAPS attempting to have the FDA approve an indication using a Schedule I drug, but the indication itself – MDMA-AT – would be the first time in FDA history that it approved a drug in conjunction with a therapy.

Almost 30 years later, having completed Phase 1,2, and 3 trials, MAPS established Lykos to finance the resource-intensive final steps in the FDA approval process and develop the strategy to bring the treatment to market.

The neurological effects of PTSD are myriad and highly variable, but there are some general commonalities. Rachel Nuwer explains it excellently in her book I Feel Love. Even in normal, calm situations, people with PTSD have higher levels of stress hormones like adrenaline. They have been shown to have increased activity in the amygdala, which is involved in threat detection, as well as heightened connectivity between the amygdala and the insula, which is how we perceive bodily sensations. So not only are they more prone to perceive threats, but, when they do, they are more prone to “feel” the threat sensorily.

Recalling their trauma–voluntarily or involuntarily– is associated with decreased activity in Broca’s area, which is responsible for speech, and increased activity in the visual cortex. So not only are they less able to verbalize their suffering, but the suffering itself feels more real and more present. This often results in alexithymia, or emotional blindness, which is, essentially, difficulty experiencing, identifying, and expressing emotions. This emotional cut-off is likely a defense mechanism the person uses to isolate from the dangerous, terrifying feelings associated with the trauma, but it means the person is also isolated from beneficial, soothing, connected emotions as well, making it that much harder to reach them in those moments of suffering.

MDMA, meanwhile, induces feelings of well-being, connectedness, and social acceptance by increasing levels of dopamine (which contributes to mood elevation and motivation) and serotonin (which creates feelings of warmth and social connection) in the brain. The effect for a person is elevated energy and motivation, coupled with and guided by feelings of emotional openness and empathy, both for others and for themselves. (This is why MDMA is called an empathogen). A more detailed explanation for the science behind MDMA can be found here.

Importantly, MDMA does not treat PTSD on its own; Lykos is seeking approval for MDMA-AT because the effectiveness of MDMA in PTSD treatment is predicated on it being paired with good talk therapy. It is thought that MDMA opens what is called a “critical period,” in which a person is particularly impressionable and sensitive to stimuli. Critical periods can be both positive–they can catalyze lasting growth–and negative–they can catalyze lasting trauma. Talk therapy is necessary to make the best use of that openness and vulnerability, to guide the patient through reprocessing the trauma. As Nuwer writes, “Severe PTSD tends to be triggered by social interactions gone awry, and the maladaptive habits that result from these traumas which become symptoms of PTSD largely pertain to the social environment including distrust, guilt, paranoia, fear, and disconnection from the self and others.” With MDMA-AT, “people are literally given the ability to rewire the neural memory circuits they’ve built around the personal narrative of their trauma; the memories are not erased but they can be recontextualized.”

MDMA-AT is a 14-week process. An initial patient intake and screening is followed by three 90-minute sessions with a pair of talk therapists, spaced one week apart. The patient then undergoes three eight-hour MDMA sessions with the same two therapists. In those sessions, the patient ingests a controlled dose of MDMA, and may take an optional booster two hours in that is half the strength of the initial dose. After those sessions, the patient will again undergo three 90-minute, MDMA-free talk therapy sessions, one week apart.

By 2016, Lykos had compiled data from 107 pilot studies of MDMA-AT and presented its findings to the FDA. The results were remarkable. While the control group (therapy with no MDMA) saw 23% full remission, the number more than doubled for the MDMA-AT group: 56% no longer met the diagnostic criteria of PTSD. And the number grew even after the treatment, suggesting that patients continued to improve on their own; at the 12-month check-in, two thirds of the MDMA-assisted group no longer retained the diagnosis.

Not only did the FDA greenlight MDMA Assisted Therapy for Phase 3 trials, it designated it a “breakthrough therapy,” fast-tracking its development and review. The company launched its larger-scale studies almost immediately: eleven study sites were established in the United States, two in Canada, and another two in Israel.

In May of 2021, they published the results of the first Phase 3 study in Nature. The data was in line with the breakthrough data from Phases 1 and 2. A remarkable 88% of patients responded favorably to the therapy. After three sessions of MDMA-AT, 67% of patients lost their PTSD diagnosis, with 33% of responders reporting full remission of symptoms. (To put those numbers in perspective, correlative responses in the placebo group were just 32% and 5%.) To make the results even more impressive, the average duration of prior PTSD for the participants in the study was 14 years.

A final and confirmatory Phase 3 study demonstrated even more promising findings. 87% of participants responded favorably to MDMA-AT, 71% no longer meet the criteria for PTSD, and an incredible 46% experienced full remission of their symptoms. PTSD patients given traditional drugs and therapies generally have about a 50% chance of a favorable response. This means that the portion of patients who experience full remission from MDMA-AT is roughly equal to the portion of patients who respond at all to traditional drugs and therapies.

The results have generated excitement in the media, veterans groups, even Congress. Signaling a potential sea change in mental healthcare, outlets including The Economist, The New York Times, The Wall Street Journal, and The New Yorker have all reported on MAPS and the burgeoning field of psychedelic medicine. On Capitol Hill, the support is strong and bipartisan: in March, United States Representatives Lou Correa (D-CA) and Jack Bergman (R-MI) announced that they were relaunching their Congressional Psychedelics Advancing Therapies (PATH) Caucus. Last November, U.S. Senator Cory Booker (D-N.J.) and U.S. Senator Rand Paul (R-KY) introduced the Breakthrough Therapies Act to “enable the Drug Enforcement Agency (DEA) to make the findings necessary to transfer breakthrough therapies involving Schedule I substances such as MDMA and psilocybin from Schedule I to Schedule II.”

In December of 2023, Lykos filed a New Drug Approval application for MDMA Assisted Therapy with the FDA – a historic submission representing decades of dedication and a watershed moment for the future of psychedelic medicine.

Anticipating the surge in demand if FDA approval is obtained, Lykos has been educating psychiatrists in MDMA-AT and working with institutions such as the Department of Veteran Affairs to deliver treatment to those most in need. Helena member Dr. Rachel Yehuda, Director of the Center for Psychedelic Psychotherapy and Trauma Research at Mt. Sinai and Director of Mental Health at the James J. Peters Veterans Affairs Center, became convinced that the treatment allowed people to break through “the immutable narrative of trauma” by creating a state of “maximum self-compassion … and minimal self-criticism.” Her lab at the VA has subsequently conducted a number of Phase 1 and Phase 2 trials in the treatment.

In January of 2024, The Department of Veterans Affairs (VA) announced a significant research initiative to explore the effectiveness of psychedelic compounds in treating PTSD and depression among veterans. The endeavor marks the first VA-funded research into psychedelics since the 1960s. Of the announcement, VA Under Secretary of Veteran Affairs Denis McDonough remarked, “our nation’s Veterans deserve the very best care, and the VA is constantly supporting innovations to deliver that.” VA Under Secretary of Health Dr. Shareef Elhnahel echoed McDonough’s support and underscored the “potential promise of psychedelics to treat mental health.”

The initiative indicates a paradigm shift in institutional reception for psychedelic therapies and reflects calls from veterans and Veteran Service Organizations such as the American Legion and Disabled American Veterans to expand research in the field.

In the “golden age” of the 50s and 60s, psychedelics were used to treat a wide range of conditions, including eating disorders, addictions, anxiety, and major depressive disorder. Lykos is committed to expanding its focus beyond PTSD. It is currently planning a Phase 2 study on MDMA-AT (with caregiver involvement) for treating anorexia nervosa restricting subtype (AN-R) and binge-eating disorder (BED). It has also published its Phase 3 findings on MDMA-AT’s effects on alcohol and substance abuse.

Beyond MDMA, Lykos will be well-positioned to explore alternative psychedelic treatments for a range of conditions. Recently, the FDA gave psilocybin a “breakthrough therapy” distinction for treatment of substance abuse. Esketamine has already been approved for treatment-resistant depression. (Under its brand name, SPRAVATO, it was Johnson and Johnson’s fastest growing product this year). Explorations are underway for the use of LSD and psilocybin in the treatment of physical pain.  A recent study of mice published in Nature suggests that psychedelics can “reopen” a “critical period” for learning social and emotional skills (“the social reward learning period”), which could prove life-changing for cult survivors.

The company is committed to enacting a global rollout, with a research entity in Europe and Phase 3 MDMA-AT studies in Canada and Israel.

Helena is proud to be the lead investor in Lykos’ Series A funding round, contributing to over $100 million raised in the last 12 months to support the launch of MDMA-Assisted Therapy.

The burden of PTSD on society is extensive – it affects millions of people each year, it can last for decades, and it has an incredibly high incidence of comorbidity. For those that suffer from chronic, debilitating PTSD, for their communities and loved ones, MDMA-AT offers help that is two to three times more effective than existing treatments, and exponentially faster-acting. Yehuda has said that she has seen MDMA-AT accomplish “in eight hours what one might do in the course of 10 years in psychotherapy.”

Helena’s decision to partner with the company was bolstered by the composition of the Lykos team, led by a group of experienced industry leaders. Jeff George, Lykos’ Board Chair, is Managing Partner of Maytal Capital, a healthcare-focused private equity and venture capital firm. He previously served as the global CEO for the Alcon and Sandoz division at Novartis Group. Lykos CEO Amy Emerson has been with MAPS since 2003 and led its pharmaceutical development from Phase 1 to Phase 3. And Lykos’ COO Mike Mullette formerly served as Vice President of North America for Moderna where he oversaw commercialization of the Company’s COVID-19 vaccine during the height of the pandemic.

Helena Managing Partner Protik Basu brings his extensive public health experience to bear as a MAPS PBC board member. Outside of his work at Helena, Basu chairs the Advisory Board at the Johns Hopkins School of Public Health. Helena also holds one Observer seat.