AsianScientist (Mar. 28, 2023) — Would you go on a trip to treat your depression? Not the kind involving a car ride or a plane flight, but a pill or a shot to the arm. Although it might sound far-fetched, scientists are looking into that very possibility—the potential of mind-altering drugs, known as psychedelics, in managing depressive disorders.
From ‘magic mushrooms’ to lysergic acid diethylamide (LSD) to ketamine, there is an emerging scientific interest in uncovering just how these substances work, and whether they could undo the neurological knots behind mental health disorders that affect millions today. Psychedelics are known for the temporary but strong alterations they cause to our thoughts, moods and senses. While they’re mostly recognised as hallucinogens—creating visual and auditory experiences—they can also create a sense of euphoria, calm and heightened sensory awareness, leading to their popularity as recreational drugs in many countries; legally or otherwise.
However, the effects of psychedelics can be double-edged. Professor Kenji Hashimoto, clinical neuroscientist at the Center for Forensic Mental Health, Chiba University, Japan, has been studying ketamine’s effects on the mammalian brain for more than a decade.
“Ketamine has strong antidepressant effects, but repeated use could lead to potential abuse or addiction, with severe side effects such as psychosis, dissociation, and out of body experiences, not unlike those seen in schizophrenia,” Hashimoto told Asian Scientist Magazine.
Ketamine studies in mice in labs like Hashimoto’s have suggested that it taps into parts of the brain that release a flood of dopamine, a feel-good neurotransmitter, in a similar way to addictive drugs such as methamphetamine. As such, while ketamine has been approved for safe use as a surgical anaethestic since the 1970s, it remains a highly controlled substance in most countries.
Filling The Gaps
Despite those risks and the availability of other drugs for depression, an increasing number of scientists are putting premium on psychedelics. “The thing about depression is that while we have many antidepressant medications, they still don’t meet the medical needs of many patients,” said Hashimoto. “On the other hand, ketamine’s antidepressant effects might be the biggest breakthrough in depression research in the last 60 years.”
Globally, depression affects about 280 million people. It’s more than simply ‘feeling down;’ the persistent sense of fatigue, isolation, low self-worth, hopelessness, loss of pleasure from daily life, and suicidal thoughts can be crippling, even life-threatening. For some people it comes and goes, while for others it’s a chronic disability.
One unmet need in depression treatment is speed. Standard drugs in use, such as selective serotonin reuptake inhibitors (SSRIs) and serotonin-norepinephrine reuptake inhibitors (SNRIs), often take at least a couple of weeks to kick in. For a patient struggling with effects of conditions such as major depressive disorder (MDD), that wait can be far too long. When your brain makes the act of getting out of bed feel like scaling Mount Everest, it can be difficult to take a pill on a schedule regular enough for it to be effective.
In addition, studies have estimated that current antidepressants are ineffective for one-third of patients. “SSRIs and SNRIs tap into serotonin receptors in the human brain, but not all cases of depression involve that mechanism,” said Hashimoto.
He added that for those with severe depression, the slow-acting effects of conventional antidepressants rarely help in crises situations involving suicidal ideation, where time may be of the essence.
For Hashimoto, psychedelics like ketamine may offer a means to fill those treatment gaps. Since 2000, clinical studies from Yale University in the US and a range of other institutions have shown that ketamine produces “rapid acting, sustained antidepressant effects” in patients who didn’t benefit from other antidepressants, said Hashimoto.
Pharmaceutical companies have begun to ride the tide of evidence as well, with the first commercialized ketamine treatment, esketamine, approved in 2019 by the US FDA and the European Medicines Agency (EMA) for adult patients with treatment-resistant MDD.
Rebooting The Brain
One theory for how psychedelics reduce depression is that they essentially turn parts of the brain associated with depressive symptoms off and on again, allowing the brain to realign those circuits and restore healthier connections between the interlinked brain cells that process our thoughts.
“Psychedelics induce the brain to change transiently in ways that appear to allow a reset to take place and permit alterations in previously ‘stuck’ ways of thinking and feeling about things,” said Jerrold Rosenbaum, director of the Center for the Neuroscience of Psychedelics at Massachusetts General Hospital, USA, in a 2021 Harvard Health commentary. “It’s like rebooting your computer.”
To try and extract the medical benefits of psychedelics without their side effects, neuroscientists are looking into the molecules, cells and metabolic machinery they affect in the brain. Some aim to design ‘lookalike’ molecules resembling those in psychedelic compounds that could hit the same depression-related brain receptors without triggering hallucinations; a research group at the Chinese Academy of Sciences has been testing a synthesized compound for 5-HT2A, a key receptor targeted by LSD and magic mushrooms.
At his own laboratory in Chiba University, Hashimoto has been working on a ketamine derivative, arketamine, as an alternative to both ketamine and esketamine. While esketamine is currently approved for treatment-resistant MDD, it must be taken under trained medical supervision, as it can still cause psychoactive effects.
On the other hand, studies pioneered by Hashimoto’s team found that arketamine had more potent antidepressant effects compared to esketamine in mice—with little signs of induced psychosis. “Clinical trials with arketamine for depression are now underway by pharmaceutical companies in the US, China and Japan,” said Hashimoto.
In Asia, as with many regions of the world, the use of psychedelics is both historical and complicated. Cultural depictions of such substances go back for millennia. An ancient Hindu text, the Rig Veda, describes the use of soma, a plant-based elixir, to reach ‘divine’ heights of experience. In China, pre-Han era literature such as the Songs of Chu similarly describe fantastical ‘spirit journeys’ that come with imbibing lingzhi (spirit mushrooms).
Their use in medical contexts also has deep roots in tradition. Ayurvedic practitioners include a range of psychotropic herbs for treating mental health disorders such as anxiety and depression, while the 16th-century Chinese pharmacopoeia Compendium of Materia Medica lists at least 10 medicinal herbs with known hallucinogenic effects.
In modern Asia, national regulators have prohibited the use and distribution of most psychedelics on grounds of being public health risks. A few such as ketamine have been exempted for medical purposes or carry tightly controlled research permits.
“Unlike in the US and Europe, it isn’t easy to perform clinical studies of psychedelics in patients with psychiatric disorders in Asian countries,” said Hashimoto. He added that his research on ketamine in animal models was supported by grants from the Japanese government and pharmaceutical companies.
However, regulatory mindsets might slowly be changing. In 2022, Thailand’s Narcotics Control Board (NCB) announced a partnership with the country’s Khon Kaen University to investigate the potential of psilocybin based compounds from het khee khwai (buffalo dung mushrooms) in depression treatment. While currently a restricted narcotic, small quantities thereof remain a discreet tool for rural doctors in treating insomnia.
If the collaboration’s clinical trial results line up with those from similar North American and European studies on depression, the farming of het khee khwai could be legalized for medical products, according to the Thai government.
Small-scale clinical studies with psychedelics have also begun to be reported from more Asian countries. In 2019, researchers from the Ranchi Central Institute of Psychiatry, India, conducted a small trial of low dose, intravenously administered ketamine for a group of 25 men with severe depression, noting “robust and rapid effects on depression.” A team from China Medical University’s Shengjing Hospital also found that adding a single dose of ketamine to caesarean operations reduced the odds of postpartum depression in new mothers for at least a week after delivery.
In Singapore, where drug laws are among the world’s strictest, an esketamine nasal spray has been authorized in hospital settings for treatment-resistant patients with MDD. An oral tablet version of the spray is also currently under clinical trial locally.
“The clinical effectiveness of ketamine in alleviating depression is dependent on proper dosage; unauthorized consumption is harmful,” emphasized Johnson Fam, senior consultant psychologist at Singapore’s National University Hospital, the institution leading the trial. “[Trial] patients must be referred from doctors and screened; they can’t have a history of substance abuse. The tablets must be consumed under direct observation in the hospital and prohibited from home use.”
Back at Chiba University, Hashimoto’s team continues to explore the molecular mechanisms behind arketamine and expand the research on it to cover other neurological disorders including Parkinson’s disease, Alzheimer’s disease and multiple sclerosis.
“There’s still a lot we don’t know about the molecular mechanisms behind its antidepressant effects,” said Hashimoto. “Regardless, I hope that arketamine will be approved not only by the US FDA, but other countries such as Japan and China for depression treatment and other psychiatric disorders, since depression is also a common symptom of many other illnesses.”
This article was first published in the print version of Asian Scientist Magazine, January 2023.
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Copyright: Asian Scientist Magazine. Illustration: Chin Yi Ting/ Asian Scientist Magazine