Esketamine Approved by the FDA for Treatment Resistant Depression

Marco Stojanovik

Following a review of clinical trial results and consultation with external advisors, the Food and Drug Administration (FDA) has granted approval for Spravato to be used in patients with treatment-resistant depression in the United States. Spravato is a nasal spray produced by Janssen Pharmaceuticals Inc. that contains esketamine hydrochloride, a chemical mirror to the anaesthetic and dissociative psychedelic ketamine.

“There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition,” said Tiffany Farchione, M.D., acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research. “Controlled clinical trials that studied the safety and efficacy of this drug, along with careful review through the FDA’s drug approval process including a robust discussion with our external advisory committees, were important to our decision to approve this treatment.”

Trials consisted of short-term and long-term studies in which one group of patients were given esketamine nasal spray alongside a traditional antidepressant, while a placebo group received saline and a traditional oral antidepressant. Individuals taking esketamine showed significantly more improvement, occurring in less than 24 hours after the first dose, and a greater length of time to relapse of depressive symptoms than those taking placebo.

Medical ketamine treatments in the US date back to 1970 when the FDA first approved its use as an anaesthetic.  Many ketamine clinics have since emerged though to offer intravenous (IV) administrations ‘off-label’ – meaning for a different medical use than the FDA has approved and not covered by health insurance plans –as a fast-acting treatment for severe depression. This follows the results of numerous published studies since 2000 showing significant decrease in depression symptoms in patients who felt no meaningful improvement on other antidepressant medications.

“This is a game changer,” said John Krystal, M.D., chief psychiatrist at Yale Medicine and one of the pioneers of ketamine research in the US. He calls ketamine “the anti-medication” medication working differently than those used previously to treat depression.

In other treatments SSRIs – serotonin reuptake inhibitors – are used based on the ‘chemical imbalance’ hypothesis that people with depression have a deficit of serotonin. However, this hypothesis may not fully explain depression with growing research showing a link to a build up of proteins in the brain under stress. This makes neurons less adaptable and less able to communicate with other neurons.

Ketamine works by triggering glutamate production, which prompts the brain to form new neural connections to repair the damage. The new pathways give patients the opportunity to develop more positive thoughts and behaviours.

While SSRIs tend to work as long they are in your system and can be difficult to come off, the effects of ketamine continue afterwards. ”It’s the reaction to ketamine, not the presence of ketamine in the body that constitutes its effects,” said Dr. Krystal.

Although esketamine works similarly to ketamine – its mirror molecule – Janssen Pharmaceuticals opted to pursue approval by the FDA for its use rather than ketamine for a number of reasons. Importantly, its chemical makeup allows it to bind more tightly to the glutamate receptors, making it two to five times more potent, meaning patients need a lower dose. It was also patentable and therefore profitable in contrast to ketamine that is widely used. And it escapees the baggage associated with ketamine as a ‘club drug’.

Still, the approval comes with a number of regulations.  The drug must only be administered as a nasal spray in a certified clinically supervised setting and used in conjunction with oral antidepressants. It can only be given to patients who have not responded successfully to two previous antidepressant treatments.

Because of the risk of sedation and dissociation, patients must stay in the doctor’s office for at least two hours of monitoring after receiving their Spravato dose until the doctor determines the patient is ready to leave. The Spravato never leaves the facility.

In all, this is a significant advancement for helping people struggling with treatment-resistant depression and an exciting step in the discovery of the medical potential of ketamine and other psychedelic drugs.

With efforts underway in the US could Australia follow next to decriminalize magic mushrooms?

Marco Stojanovik

On June 4th Oakland followed Denver to become the second city in the US to decriminalize psychoactive plants and fungi, including mushrooms, cacti, iboga, and ayahuasca. This means the city’s law enforcement will no longer investigate or prosecute people for their use, sale, and distribution. Now instead, proponents argue that resources can be freed to pursue violent offenses.

According to Oakland councilmember Rebecca Kaplan this policy is consistent with ongoing criminal justice reforms. “We need to continue to act to help end mass incarceration and the war on drugs,” she said.

Advocates for reform cite a growing body of research suggesting that psychedelic drugs are safe and therapeutically beneficial with low potential for addiction. Studies around psilocybin especially suggest that it can effectively treat obsessive-compulsive disorderdepression,  end-of-life anxietyaddiction, and cluster headaches, and that it can help people quit smoking and deal with alcohol dependence. There’s also growing evidence that the drug can induce mystical states that promote positive changes in personality such as openness, optimism, and sociability.

“This is getting the word out about the healing power,” said councilmember Noel Gallo. “Many people in communities of color and communities of trauma are not getting access.”

With similar campaigns occurring in Oregon, Iowa and across California, activists hope this is the beginning of a wider national movement in the US towards legalisation.

In Australia, however, misinformation, prejudice, and academic conservatism have stalled psychedelic research and moves towards their medical use and decriminalisation. Since 2011, the non-profit organization Psychedelic Research in Science & Medicine (PRISM) has been working to interest universities and the psychiatric fraternity in Australia to begin psychedelic drug trials to much resistance.

 “Australia has a rather isolated group-think mentality, unfortunately,” says Dr Martin Williams, President of PRISM. “Our political class are just very, very scared and they’re very risk averse. Universities likewise.”

A decades-old stigma remains around these substances as illicit drugs. Traditional framing focuses on their potential risks and adverse consequences and sidelines their therapeutic potential. With a stigma-induced public resistance it’s politically divisive and unwise for policymakers to support reforms.

A lack of support on the part of for-profit pharmaceutical companies has also hindered progress. Many of these patent-free psychedelics need only a few doses to provide long-term effectiveness, in contrast to standard SSRI anti-depressants which require long-term ongoing use. The potential for profit is massively reduced.

Nevertheless, attitudes are changing. In December 2017, Dr Margaret Ross, the palliative care clinician at St Vincent’s Hospital in Melbourne, discovered Williams efforts and contacted him about working together on a trial with her patients who have not responded to anti-depressant or anti-anxiety therapies.

Gaining the financial support of $1 million from philanthropists Tania de Jong and Peter Hunt through their charity Mind Medicine Australia (MMA) and the necessary regulatory approvals from the federal and state authorities the trials began this year in April.

Terminally ill patients are being given a single dose of synthetic psilocybin – the psychoactive compound in mushrooms – in conjunction with therapy sessions. The aim is that these patients will be given a new perspective on their lives, easing the anxiety and depression which often overcomes as death approaches.  According to the hospital three in every 10 palliative care patients can experience extreme distress in their final months.

Dr Margaret Ross speaks at our recent Mushroom Day event in Sydney.

Dr Paul Liknaitzky, a psychology researcher at Deakin University and one of MMA’s scientific advisers, explains that the drug works by disabling the ‘default mode network’ – the ‘resting state’ of the brain associated with a person’s typical way of thinking. The default mode networks of people who have depression tend to become hyperactive repeating the same negative thoughts. By disabling this it is hoped that patients can detach themselves from their thoughts and concerns to gain an altered look on their situation approaching death.

The results of similar research in the US have been promising. Studies at New York University and Johns Hopkins University found that a single dose of psilocybin assisted by psychotherapy significantly reduced anxiety, depression, and existential distress in terminally ill cancer patients. Six months after 51 patients were treated at Jon Hopkins University, 80 percent showed significant decreases in depressed mood, while 83 per cent reported increased life satisfaction and 67 per cent reported the experience as one of the top five spiritually meaningful experiences in their lives.

“The US study was really profound: some people were able to transcend their ideas about dying. It really relaxes those old rigid ways we have built up in the way we look at the world,” Dr Margaret Ross explains.They had remission of symptoms [of psychiatric distress]. It was rapid, it was dramatic, and it was beyond impressive, because it lasted for up to six months.” 

The Australian trial seeks to build upon the studies in the US from cancer sufferers to those with other terminal conditions.

“Our plan is not to replicate research that has been done overseas,” says MMA’s de Jong. “We’re investing in being ready for when, and if, the regulators overseas reschedule these medicines.”

She’s referring to the push for a rescheduling of psilocybin to allow for its use as a prescription medicine. In the US the team of researchers at John Hopkins are proposing that the drug be reclassified from the most restrictive Schedule I to Schedule IV, making it available for prescription albeit within a clinical settingMeanwhile, MMA hopes to see it reclassified from an Australian Schedule 9 substance to Schedule 8 allowing its prescription with explicit government approval.

If the Australian trial, along with others occurring internationally, confirm the promising results of the initial studies, rescheduling could occur within the next five years. The campaign for Oakland and Denver style decriminalisation may be a long one in Australia. Yet, the progress being made in medical trials here and around the world leave one optimistic that the stigma is fading and widespread acceptance of their therapeutic potentials is nearing closer.

APS @ The Rainbow Serpent Festival

The Australian Psychedelic Society attended the
Rainbow Serpent Festival

This January the APS crew have been having a good ole time at the Rainbow Serpent Festival.

This year we hosted a panel discussion alongside PRISM: Psychedelic Research in Science & Medicine and Mind Medicine Australia.
We also hosted a stall where we collected thousands of signatures for the Students for Sensible Drug Policy Australia campaign for pill testing #BeHeardNotHarmed.
We can’t wait for the next one!