In March 2019, the FDA approved ketamine, under the trade name Spravato (esketamine), for clinical use in treatment-resistant depression therapy. Alongside racemic ketamine, which is commonly used in ketamine infusion therapy, ketamine is the first hallucinogen approved for therapeutic usage in the United States.
Technically, ketamine is not a psychedelic but rather a hallucinogen and dissociative. (While ketamine has psychedelic effects, traditional psychedelics bind to the 5-HT2B receptor.) Still, advocates for psychedelic therapy recognize ketamine as a gateway for traditional psychedelics, such as psilocybin and LSD, to be considered for therapeutic usage.
To understand the proliferation of ketamine clinics across North America, the origins of this peculiar substance — one that went from battlefields to veterinary clinics to dance clubs in the span of two decades — must be discussed.
History of ketamine
In 1962, chemistry professor Calvin Stevens synthesized ketamine while researching alpha-hydroxyimine rearrangements. The first human tests were conducted on prisoners in 1964. Ketamine soon replaced phencyclidine (PCP) as the go-to anesthetic in hospitals. It was initially used on soldiers during the Vietnam War following FDA approval in 1970. Thanks to its success on the battlefield, ketamine was placed on the World Health Organization's List of Essential Medicines.
Ketamine has been used broadly as a sedative and anesthetic; to aid in emergency surgeries in war zones; as a bronchodilator for severe asthmatics; to treat certain types of seizures; and in postoperative pain management. Now, ketamine infusions and nasal sprays are being used for depression. Ketamine is also showing potential efficacy in treating chronic pain and suicidal ideation, though more research needs to be done.
Of all of those uses, ketamine has predominantly been used as an anesthetic in humans and animals. While it restricts breathing less than other similar medications, ketamine also produces hallucinations (thus, it's labeled as a dissociative anesthetic). The list of potential side effects from using ketamine is long, including nausea, double vision, breathing problems, impaired memory, liver enzyme abnormalities, urinary tract problems, and even increased depression — an alarming possibility given its growing use as an antidepressant replacement.
Small-scale studies on using ketamine to treat depression were conducted in 2000 and 2006. Further research confirmed its role in alleviating depressive symptoms, including the possibility that the antidepressant effects of a single dose can persist for weeks. In 2016, the FDA fast-tracked ketamine trials for depression.
A chair is seen in a therapy room at Field Trip, a psychedelic therapy clinic in Toronto, Ontario, Canada.Credit: Cole Burston/AFP via Getty Images
Ketamine infusion therapy
There has yet to be a consensus on how ketamine addresses depression. Antidepressants act on the body's serotonin and noradrenaline systems. Ketamine seems to interfere with an amino acid derivative, NMDA. As a 2017 study published in the journal Nature explains:
"Ketamine is responsible for blocking the N-methyl-D-aspartate (NMDA) receptor, which causes an immediate alleviation of depressive effects, while another metabolite in the drug helps the effects last for hours. This blockage is also what causes the hallucinogenic effects."
Small intravenous doses of esketamine — an enantiomer of ketamine and the substance actually approved by the FDA — seem to lift depressed patients out of their funk. So does Spravato, a nasal spray that can only be administered under supervision in a doctor's office or clinic.
Patients that have tried two different antidepressant medications with no success (the definition of treatment-resistant depression) can legally receive ketamine infusions or Spravato at clinics located all over the country. Since the therapy is generally not covered by insurance, treatments range from $300 to $2,000 per session; the Field Trip Treatment Program, which includes psychotherapy and six infusions, runs $4,700.
The process of ketamine infusion therapy is varied depending on which clinic you attend. Companies like Field Trip and organizations such as MAPS require psychotherapy sessions to coincide with infusions.
Unfortunately, therapeutic implementation has not always lived up to federal requirements. Reports of patients quitting antidepressants and psychotherapy to use esketamine as their primary source of treatment abound. Since medical professionals with no mental health training, such as nurse practitioners, anesthesiologists, and pain physicians, can legally administer ketamine, patients are left to process the drug's effects with little to no guidance.
Thus far, efficacy has been mixed. As STAT News editor Megan Thielking writes, people with minor depressive issues are likely better candidates for ketamine therapy than those with treatment-resistant depression, the very cohort the drug is purported to target.
"Studies vary but have found response rates to ketamine as high as 70 percent among people with major depression who have failed a few other antidepressants. But the rate is lower for patients with extremely treatment-resistant depression, and how long any improvement lasts varies from one patient to the next."
Was ketamine approved too quickly?
While ketamine therapy is certainly promising, the FDA-approved trials raise a number of red flags. A recent analysis in The British Journal of Psychiatry concludes that we're moving too fast. Author Mark Horowitz writes:
"Out of the three short-term trials conducted by Janssen only one showed a statistically significant difference between esketamine and placebo. These were even shorter than the 6-8 week trials the FDA usually requires for drug licensing."
Trials usually last three months; the approved ketamine trials only lasted four weeks and barely showed efficacy above placebo. More concerning, the FDA allowed Janssen to submit a discontinuation trial with a study design flaw as evidence of efficacy — side effects were treated as evidence of relapse, not withdrawal symptoms. Even more alarmingly, six people in the esketamine group died during the trials, including three by suicide, two of which had previously shown no signs of suicidal ideation.
When Janssen stated that the problem wasn't esketamine but underlying conditions, the FDA accepted the reasoning even though no conclusive evidence was provided. This doesn't mean ketamine therapy isn't potentially therapeutic, though it does suggest that its approval by the FDA was rushed.
Psychiatrist Lori Calabrese, who offers ketamine infusion for depression and anxiety in her clinic, puts it best when stating, "The pace of ketamine treatment in real-world practices has outstripped what researchers are able to do and publish." Time will tell if this treatment proves more beneficial than dangerous in mental health treatments.
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Stay in touch with Derek on Twitter and Facebook. His most recent book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."
Are you a worrier? Do you imagine nightmare scenarios and then get worked up and anxious about them? Does your mind get caught in a horrible spiral of catastrophizing over even the smallest of things? Worrying, particularly imagining the worst case scenario, seems to be a natural part of being human and comes easily to a lot of us. It's awful, perhaps even dangerous, when we do it.
But, there might just be an ancient wisdom that can help. It involves reframing this attitude for the better, and it comes from Stoicism. It's called "premeditation," and it could be the most useful trick we can learn.
Practical Stoicism
Broadly speaking, Stoicism is the philosophy of choosing your judgments. Stoics believe that there is nothing about the universe that can be called good or bad, valuable or valueless, in itself. It's we who add these values to things. As Shakespeare's Hamlet says, "There is nothing either good or bad, but thinking makes it so." Our minds color the things we encounter as being "good" or "bad," and given that we control our minds, we therefore have control over all of our negative feelings.
Put another way, Stoicism maintains that there's a gap between our experience of an event and our judgment of it. For instance, if someone calls you a smelly goat, you have an opportunity, however small and hard it might be, to pause and ask yourself, "How will I judge this?" What's more, you can even ask, "How will I respond?" We have power over which thoughts we entertain and the final say on our actions. Today, Stoicism has influenced and finds modern expression in the hugely effective "cognitive behavioral therapy."
Helping you practice StoicismCredit: Robyn Beck via Getty Images
One of the principal fathers of ancient Stoicism was the Roman statesmen, Seneca, who argued that the unexpected and unforeseen blows of life are the hardest to take control over. The shock of a misfortune can strip away the power we have to choose our reaction. For instance, being burglarized feels so horrible because we had felt so safe at home. A stomach ache, out of the blue, is harder than a stitch thirty minutes into a run. A sudden bang makes us jump, but a firework makes us smile. Fell swoops hurt more than known hardships.
What could possibly go wrong?
So, how can we resolve this? Seneca suggests a Stoic technique called "premeditatio malorum" or "premeditation." At the start of every day, we ought to take time to indulge our anxious and catastrophizing mind. We should "rehearse in the mind: exile, torture, war, shipwreck." We should meditate on the worst things that could happen: your partner will leave you, your boss will fire you, your house will burn down. Maybe, even, you'll die.
This might sound depressing, but the important thing is that we do not stop there.
Stoicism has influenced and finds modern expression in the hugely effective "cognitive behavioral therapy."
The Stoic also rehearses how they will react to these things as they come up. For instance, another Stoic (and Roman Emperor) Marcus Aurelius asks us to imagine all the mean, rude, selfish, and boorish people we'll come across today. Then, in our heads, we script how we'll respond when we meet them. We can shrug off their meanness, smile at their rudeness, and refuse to be "implicated in what is degrading." Thus prepared, we take control again of our reactions and behavior.
The Stoics cast themselves into the darkest and most desperate of conditions but then realize that they can and will endure. With premeditation, the Stoic is prepared and has the mental vigor necessary to take the blow on the chin and say, "Yep, l can deal with this."
Catastrophizing as a method of mental inoculation
Seneca wrote: "In times of peace, the soldier carries out maneuvers." This is also true of premeditation, which acts as the war room or training ground. The agonizing cut of the unexpected is blunted by preparedness. We can prepare the mind for whatever trials may come, in just the same way we can prepare the body for some endurance activity. The world can throw nothing as bad as that which our minds have already imagined.
Stoicism teaches us to embrace our worrying mind but to embrace it as a kind of inoculation. With a frown over breakfast, try to spend five minutes of your day deliberately catastrophizing. Get your anti-anxiety battle plan ready and then face the world.
Jonny Thomson teaches philosophy in Oxford. He runs a popular Instagram account called Mini Philosophy (@philosophyminis). His first book is Mini Philosophy: A Small Book of Big Ideas.
While the physical effects of COVID-19 have dominated headlines for the last 13 months, mental health effects are considered a simultaneous pandemic that could outlast the virus. Children have generally been resilient against the novel coronavirus (though at least one variant is hitting that demographic harder). In terms of depression and anxiety, however, children are on par with adults.
Emergency hospital visits for mental health issues in the 12-to-17-year-old demographic have jumped 31 percent since the pandemic began. Younger children have fared only slightly better: a 24 percent increase for children ages 5 to 11. In Germany, one in three children has suffered anxiety or depression over the past year. On top of this, children are having trouble learning in remote education environments.
However, at least one demographic fared better than normal, at least during the early phase of lockdowns. According to a new study, published in the Journal of the American Academy of Child and Adolescent Psychiatry, middle school children from a predominantly Latinx community with higher-than-normal levels of mental distress experienced a reduction in symptoms.
Children with previous mental health problems saw reduced internalizing (behaviors including being withdrawn, nervous, lonely, unwanted, or sad), externalizing (behaviors including lying, acting irresponsibly, breaking the law, or displaying lack of remorse), and other problems.
Those without mental health issues benefited as well, at least in terms of internalizing and overall behavior; there was no change in attentional issues or externalizing.
The researchers began tracking 322 children (average age 12) in January 2020, before the pandemic took hold in America. They were studied until May 2020. While this only represents a sliver of time in lockdown, senior author Carla Sharp, a psychology professor at the University of Houston, says the results have important clinical implications.
"First, promoting family functioning during COVID-19 may have helped protect or improve youth mental health during the pandemic. Further, it is important to consider cultural factors, such as familism and collectivism in Latinx communities that may buffer the early effects of disasters on mental health to COVID-19 stress."
Seven-year-old Hamza Haqqani, a 2nd-grade student at Al-Huda Academy, uses a computer to participate in an E-learning class with his teacher and classmates while at his home on May 01, 2020 in Bartlett, Illinois.Photo by Scott Olson/Getty Images
Many have decried what we've lost during this past year. Indeed, the issues are many and complex. Yet we've also seen reductions in environmental damage (including noise pollution) and increased savings. We also have a greater awareness of how factory farming helps viruses proliferate. And, despite the obvious challenges of earning a living with so many businesses and industries shuttered, this time has afforded some an opportunity to reconnect with their family.
Study co-author Jessica Hernandez Ortiz says this research could inspire new avenues of addressing mental health issues in children.
"Our findings underline the importance of the family environment and Latinx collectivist values of community connection for promoting child resilience and brings into stark focus the possibility that school environments may exacerbate mental health difficulties. Removal from that context into a less pressured environment immediately and positively impacts mental health."
Since the study ended shortly into the pandemic, the novelty of family togetherness could have diminished as families became economically strained and realized that spending all their time together was more taxing than initially imagined. That said, humans are social animals that require regular contact with family and peers. The latter group might not have been available, but at least for some children, their families filled in the gaps, especially for those that did not thrive in a traditional school environment.
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Stay in touch with Derek on Twitter and Facebook. His most recent book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."
The question of meaning remains one of life's greatest inquiries. Is religion necessary for deriving meaning? Can a modern, secular Buddhist approach work better, in which meaning is derived in moment-by-moment perception instead of reserving faith for a revelation at some future point?
These questions won't be answered here, though new research from Brazilian researchers has found that religion alleviates depressive symptoms in believers. Published in the journal Trends in Psychology, the researchers asked 279 volunteers (72 percent female) to respond to an online questionnaire that focused on intrinsic religiosity, meaning in life, and levels of anxiety and depression.
The team concludes, "intrinsic religiosity has a protective effect against depression symptoms; however, it occurs indirectly, via meaning in life."
The authors note that 4.4 percent of the global population suffers from depression, with women 1.5 to 3 times more likely to experience depressive symptoms. Religion, it appears, provides a bedrock for communing with the sacred. They define religion as the general "beliefs, practices, and rituals related to the sacred and vary according to each religious tradition." Intrinsic religiosity, the focus of this research, skews toward individual relationships with the sacred, not utilitarian values—the extrinsic dimension.
Religion Is Nature's Antidepressant | Robert Sapolsky
The question of meaning in life and religion has been a hot topic of late. Leigh Stein recently pinpointed the emerging trend of influencers being treated as moral authorities, to which she pointed to decreasing faith as a potential reason: void of traditional religion, people are searching for meaning in digital spaces.
She writes that 22% of millennials now identify as "nones." The broader religious landscape in America has shifted dramatically in the last generation. According to a 2019 Pew poll, American adults claiming Christianity dropped 12 points in the last decade. Overall, 26% of adults identify as "none."
"None" is an umbrella term signifying an atheist, agnostic, or someone not interested in anything in particular. Sometimes this includes dabblers who pull from a variety of traditions without feeling invested in one. Stein noticed that wellness influencers have rushed in to fill a void, intentionally or not. As she writes,
"I was once one of those millennials who made politics her religion; I lasted three years as a feminist activist and organizer before I burned out in 2017. That's when I began noticing how many wellness products and programs were marketed to women in pain, and how the social media industry relies on keeping us outraged and engaged. It's no wonder we're seeking relief."
Shadi Hamid occupies a similar place, though he identifies tribal political affiliations as the replacement for religion—specifically, to replace meaning. He claims a quarter of American adults qualify as "none," noting that less than half are traditionally religious, i.e. Christan church attendees, based on a 2019 Gallup poll. Hamid argues that this pivot occurred when religion left our lives.
"As Christianity's hold, in particular, has weakened, ideological intensity and fragmentation have risen. American faith, it turns out, is as fervent as ever; it's just that what was once religious belief has now been channeled into political belief. Political debates over what America is supposed to mean have taken on the character of theological disputations. This is what religion without religion looks like."
Credit: sutichak / Adobe Stock
Hamid believes the Left and Right channel their political-religious hybrids differently: the woke Left repurpose original sin, atonement, ritual, and excommunication as pathways to creating a more just society while the Right has stripped much of the religion from their religion in order to focus their existential angst into blood and soil themes. QAnon, for example, is essentially a religious doctrine, requiring of its devotees the same leaps of faith.
Stein looks at the politicization of religion—really, the religiosity of politics—as a failure of imagination. Why, she wonders, have people put their faith in memoir-selling, supplement-slinging influencers instead of people who have actually accomplished something in their lives other than turnkey marketing campaigns? Why would we turn to so-called leaders incapable of even attempting to answer life's big questions, or at the very least offer solace in the face of uncertainty, the classical role of religious leaders?
"There is a chasm between the vast scope of our needs and what influencers can provide. We're looking for guidance in the wrong places. Instead of helping us to engage with our most important questions, our screens might be distracting us from them. Maybe we actually need to go to something like church?"
The research team in Brazil might agree. One defining symptom of depression is an inability to foresee a better future. The global number might be 4.4 percent, but in America, the number is closer to 8 percent. America, now considered the twelfth wealthiest country in the world, ranked third in terms of depression. Money is never going to buy happiness.
Will religion? While the track record is spotty, this new research entertains an intrinsic sense of belief in the sacredness of life as a natural antidepressant, as Robert Sapolsky phrased it. During a time of growing unease, the suspension of disbelief might be what the doctor ordered—for some at least.
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Stay in touch with Derek on Twitter and Facebook. His most recent book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."
Swiss physician Paracelsus knew chemicals that heal in small doses can be toxic in large doses. The 16th-century "father of toxicology" spent his career investigating the effects of chemistry on human biology—and consciousness.
Psychedelics offer some of the most profound changes in consciousness known to humankind. As with the work of iatrochemists (chemists that provide chemical treatments for disease, a discipline vocally championed by Paracelsus), modern researchers recognize that understanding the dosage requirements of psychedelics is essential for determining efficacy. While overdosing can be psychologically damaging, psychedelics are generally not deadly, making them ideal for study.
Most people don't worry about overdoing LSD or psilocybin, however. The current trend is almost homeopathic in nature. Microdosing has become the productivity pastime of the Silicon Valley set, with knowledge workers swearing that minute quantities of LSD help them focus. Given the legal status of psychedelics, however, research has been scarce, though growing.
Imperial College London's Centre for Psychedelic Research has led the way in clinical trials. Director Robin Carhart-Harris has published over 100 papers on the effects of psychedelics on a variety of mental health issues. The center recently produced one of the first large-scale studies on microdosing, with a caveat—the psychedelics were self-supplied (to skirt legal issues) and the psychological results self-reported.
Psychedelics: The scientific renaissance of mind-altering drugs
For the study published in eLife, the team recruited 191 citizen cosmonauts to microdose either LSD or a placebo over the course of several weeks and note the psychological effects. Volunteers were already microdosing LSD, so there was no true control. Each volunteer was given instructions on creating their own low-dose gel capsules, some containing LSD, others not. Then they mixed the capsules in envelopes so they didn't know if they were taking the real thing or not.
The trial design was ingenious: each capsule featured a QR code that was scanned after the addition of ingredients but before they were placed in the envelope so that researchers knew what they were ingesting.
The problem: volunteers sourced their own LSD. Lack of quality control could have had a profound effect on the results.
The results: LSD microdosers reported feeling more mindful, satisfied with life, and better overall; they also noticed a reduction in feelings of paranoia.
The catch: the control group felt the same thing, with no statistical difference between the groups.
Lead author Balázs Szigeti comments on the findings: "This suggests that the improvements may not be due to the pharmacological action of the drug but can instead be explained by the placebo effect."
Credit: Alexander / Adobe Stock
Psychedelics are notoriously difficult to control for given the intensity of the experience. Yet there is precedent for the above findings. A 2019 study found that 61 percent of volunteers that took a placebo instead of psilocybin felt some psychedelic effects, with a few volunteers experiencing full-on trips.
"Several stated that they saw the paintings on the walls 'move' or 'reshape' themselves, others felt 'heavy. . . as if gravity [had] a stronger hold', and one had a 'come down' before another 'wave' hit her."
The Imperial team believes the expectation of a trip might have been enough to produce similar results. Senior author David Erritzoe is excited for future studies on the topic, believing they tapped into a new wave of citizen science that could push forward our knowledge of psychedelic substances.
"Accounting for the placebo effect is important when assessing trends such as the use of cannabidiol oils, fad diets or supplements where social pressure or users' expectations can lead to a strong placebo response. Self-blinding citizen science initiatives could be used as an inexpensive, initial screening tool before launching expensive clinical studies."
As investments into the psychedelics market explode, with one company reaching a $2 billion valuation, a recurring irony appears in the long arc of psychedelics and research: the power of our minds might be enough to feel greater life satisfaction and a deeper sense of mindfulness. If that's possible with a placebo, we have to question why the rush to create more pharmacology is necessary.
This is, mind you, a separate conversation over the role of psychedelics and rituals for group bonding. The function of group cohesion around consciousness-altering substances will continue to play an important role in many communities.
Of course, we should continue to explore the efficacy of psychedelics on anxiety, depression, suicidal ideation, PTSD, and addiction. Pharmacological dependence is a stain on the psychiatry industry. Whether or not psychedelics can be prescribed for daily use remains to be seen, but we know a moneyed interest is expecting a return on investment—the above company, ATAI Life Sciences, raised $157 million in its Series D round.
When it comes to wellbeing, some things money just can't buy. How we navigate the tricky terrain of mainstreaming psychedelics remains to be seen.
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Stay in touch with Derek on Twitter and Facebook. His most recent book is "Hero's Dose: The Case For Psychedelics in Ritual and Therapy."
