• Psychedelic Medicine

DEPRESSION | +80 articles

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'Microdosing lifted me out of my depression'

Little research exists on the effects of tiny doses of psychedelics, but devotees of the practice report remarkable benefits.

Erica Avey, 27, microdosed on LSD for 8 months, using an analogue that was legal in Germany. "I started microdosing because I was in a really depressed stage of my life. It was for mental health reasons, mood balancing, mood management. It was hard for me to leave my apartment and do normal things as a human being," she said.

Depression or sadness are very common reasons for starting; Avey was unusual only in that she could be open about it. Her workplace knew and thought it was fine. "As long as I wasn't out of control or permanently high at work they were quite OK."

She took about 15 micrograms. "That was a good amount for me. Some people take as little as six," she said. She adopted a popular protocol, one day on, three days off.

It worked for her. "It definitely had the effect I wanted", she said. "It lifted me out of a pretty deep depression. I am still trying to wrap my head around what it has done to me in the long-term. I think it has changed me." She had been "pretty negative," she said, "mindlessly going through social media, plagued with obsessive thoughts."

"I am able to be more mindful of my emotions. If I am feeling sad, that is OK. I don't obsess anymore. I don't dwell on it. I don't get worked up about it."


She and others spoke of becoming more aware of the need to be active, cut down on alcohol and eat healthily. She talked of heightened energy and heightened awareness. In the beginning she felt more productive and creative, but later that became more of a problem.

"I was able to get all my work done, but around 2 to 3pm I would hit this wall of really needing to go out for a walk, a need to be moving," she said. Although it lifted her depression, she felt more anxiety. "There were one or two experiences when I did feel a bit overwhelmed. If people experience high levels of anxiety, I don't think this is for them."

Microdosing, for her, is a transformative psychological experience and she is not the only one who feels it is in danger of being misused in Silicon Valley. "To think of people using this just to write code faster does seem a bit superficial. But it might be good for them. They might re-evaluate their lives in ways."

It's not the answer to everything. She left her job and moved on. In a blog, Avey wrote: "There is no magic pill. Microdosing is not a good-time-guaranteed, or quick fix. Our minds are in conversation with our environments. We create and are created by our contexts. And in many cases, we don't need drugs, just a new environment."

Alex, 35, (not his real name) is a paramedic in the NHS and can tell nobody that he microdoses. Severely depressed, he turned down his GP's offer of antidepressants which he had 'tried before without success,' he said. He did a lot of reading and researching online before experimenting with microdoses of LSD.

"What struck me was that there was no discernible difference at first," he said. "I'd never tried LSD recreationally, so I had no idea what to expect. I stared at a blank wall every now and then just to make sure I didn't see any hallucinations, but there was nothing. Weirdly, it's not until the next day, in retrospect where you look back, that you realise you handled things, or reacted to things differently. It's so subtle it's easy to miss. But it definitely worked."

"I continued taking it for approximately three months. Sometimes I'd take a dose before work (around 9 mcg dose). I found that whilst it improved my concentration, I didn't want to become dependent on it for that purpose. Once I was out of that black hole cycle, I stopped taking it. But I will take it again if I need to."


Adam, 30, (not his real name) lives in Germany and has been microdosing on magic mushrooms for five months, on and off. He also follows the one day on, three days off protocol. He says he is stereotypical of those who microdose: "Someone who's been struggling with more or less intense depression all my life." Before he started, he was 'stuck in a rut,' he said. "I lost all interest in my everyday activities. I had no sense of pride or joy." He was drinking too much red wine after work to calm down.

"Microdosing," he says, "doesn't make me feel better. It forces me to reflect on things. It helped me to reshape my daily habits." He got back into exercise, running on the days he microdosed, going to the gym the day after. He ate and slept better.

"There are downsides. I can get a little anxious on dosing days, he said. "He talks of underestimating challenges, having to confront things and not duck them, whether thoughts or encounters with strangers. On microdosing days," he said, "he is exhausted and in bed by 10pm. The second day brings an afterglow," he said, "which is more pleasant."

He doesn't believe microdosing should be used to try to boost your career. "I am not a big fan of people promulgating microdosing to a bunch of CEOs to increase their work," he said.

https://www.theguardian.com/science/...-for-your-mind
 
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The complete guide to ketamine therapy for depression, from someone who’s tried it

by Allegra Ringo | allure | Oct 30 2019

Ketamine is an anesthetic that's used off-label for depression, but does it work?

When I entered the ketamine clinic for the first time, I started crying almost immediately. This was for two reasons: First and foremost, I was scared. After watching a documentary that introduced me to the subject and reading several accounts of ketamine infusion therapy, I knew a fair amount about the process. But the experience sounded strange, disorienting, and mysterious. Despite having done my research, I still didn’t feel like I had a good idea of exactly what it would feel like.

I was also crying simply from sadness. I’d been trying for almost 10 years to manage my depression with medications and therapy but felt worse than ever. The many medications I’d been prescribed over the years would work for a little while, then inevitably stop being effective, sending me into a progressive spiral that would worsen every time. I felt like I'd tried everything, but that wasn’t quite true. I hadn’t tried ketamine.

Ketamine has been used as an anesthetic since the1960s. In the 1990s and 2000s, researchers began looking into trying it off-label as an antidepressant. Fairly recently, it has come into use for people with treatment-resistant depression, as well as people with other diagnoses, like bipolar disorder and post-traumatic stress disorder (PTSD). (It’s also used for treating pain.) Ketamine clinics have opened in select states throughout the U.S., including California, where I live.

Ketamine is available in a couple of different forms: It can be administered through an IV or ingested via a nasal spray called esketamine. Esketamine is approved by the FDA for the treatment of treatment-resistant depression. IV ketamine is not, and thus treating depression with ketamine is an off-label use. Ketamine lozenges are also available to some patients.

I was about to give IV ketamine a try, and although I was terrified, the unknown was preferential to continuing on the same path I was used to because it came with a massive potential benefit: finally finding relief from my depression.

What ketamine can do for depression

Ketamine has been shown to be effective in treating symptoms of depression and can be especially helpful for treatment-resistant depression (TRD), which is generally defined as “inadequate response to at least one antidepressant trial of adequate doses and duration,” according to a study published by Harvard Medical School. If you’ve tried multiple antidepressant medications (possibly in combination with other treatments) without success, you might have treatment-resistant depression.

In several studies at Yale, more than half of the participants who were given ketamine infusions showed a significant decrease in symptoms associated with depression after only 24 hours. These results are significant for two primary reasons: One, these participants were people who had experienced no “meaningful improvement” on other antidepressants. Two, the alleviation of depression symptoms after just 24 hours is extremely fast compared to other antidepressants, which can take weeks to kick in. To a severely depressed person who might be experiencing suicidal ideation, a fast-acting treatment could make all the difference in the world.

John Krystal, the Robert L. McNeil Professor of Translational Research and chair of the Yale department of psychiatry, believes that ketamine is a promising treatment for depression for several reasons. First, it can be effective for people whose depression symptoms have not responded to other treatments. Second, as noted above, the effects are rapid. “People who are severely depressed, suicidal, and might otherwise need hospitalization may get better as quickly as 24 hours after their first dose,” says Krystal.

A third reason is that ongoing ketamine therapy can protect a patient against a return of depression symptoms. “The reason that this is so important is that even after trying many different treatments, as many as 30 percent of patients will remain significantly depressed,” Krystal tells me.

How it works

Robert C. Meisner is the medical director of the McLean Ketamine Service in the psychiatric neurotherapeutics program at McLean Hospital, the major psychiatric hospital for Harvard Medical School. In an article for Harvard, he writes that experts aren’t exactly sure how ketamine works to combat depression, but that one likely target is N-methyl-D-aspartate (NMDA) receptors in the brain. “By binding to these receptors, ketamine appears to increase the amount of a neurotransmitter called glutamate in the spaces between neurons,” Meisner writes. Then it activates connections in another receptor, called the AMPA receptor.

“Together, the initial blockade of NMDA receptors and activation of AMPA receptors lead to the release of other molecules that help neurons communicate with each other along new pathways,” writes Meisner. This process likely affects mood, thought patterns, and cognition.

Ketamine may also reduce symptoms of depression in other ways, such as reducing signals involved in inflammation. Meisner and other experts theorize that ketamine likely works in several different ways at the same time.

Potential risks of ketamine therapy

I asked Meisner about the risks of ketamine therapy, including whether ketamine can be addictive. “All of us who specialize in this area remain concerned about the potential for physiologic and psychological dependence,” he tells me. At his clinic, for example, a previous history of substance use usually means a patient will not be treated with ketamine (though there are some rare exceptions).

“It’s important to understand that even though you may suffer from treatment-resistant depression, ketamine may not be the wisest choice,” he says.

That said, Meisner and his colleagues have not seen a high volume of patients who show signs of ketamine addiction. “To the best of my knowledge, we have received only one consultation request over the phone in which the caller was seeking treatment with ketamine for reasons consistent with addiction,” he tells Allure. “Moreover, to the best of my knowledge, not a single one of our patients has gone on to develop physiologic or psychologic dependence to ketamine after completing our protocol.”

However, experts remain alert about any potential for abuse. Currently, there is an epidemic of oral ketamine abuse in parts of Asia. Ketamine as a street drug is quite a different experience from ketamine as a treatment for depression (and street drugs carry the risk of being cut with other substances), but epidemics like this are always cause for concern.

In addition, there are some basic physiological changes that happen when ketamine is administered, such as a rise in blood pressure. For many patients, this isn’t a problem, but if you have some preexisting conditions, it may pose a health risk. That’s why it’s so important to find a ketamine clinic that prioritizes safety.

The financial cost

Ketamine therapy isn’t cheap. When I was determining where to go for my ketamine infusions, I asked about pricing at several clinics. The range I found in the Los Angeles area was $450 per infusion (the lowest price I could find) to $750 per infusion. Anecdotally, the highest price I’ve heard of is $1,000 per infusion. The clinic I ultimately went with charged $750 for the first two infusions and $600 for all subsequent infusions.

In other U.S. states, the price varies, but it’s never exactly an inexpensive option. (A map of “active clinics in good standing” from the website Ketamine Clinics Directory lists the price of ketamine infusions at clinics across the U.S. The lowest price listed is $250 per infusion, at a clinic in New Jersey.) Many clinics recommend six initial infusions, though of course, they can’t make you do any more than you want to.

The other big question associated with cost is whether health insurance will cover it. All of the clinics I spoke to in Los Angeles billed out of network, meaning that my insurance company might end up covering some of it, but either way, I would have to front the cost. (After many months, I am still waiting to hear back from my insurance company about whether I will be reimbursed for any of my treatments.)

If you have health insurance, you’re at the mercy of your insurance company to determine whether they’ll cover any of your ketamine therapy. To be fair, this is true of most medical procedures that are still considered experimental. I haven’t found a clinic that is an in-network provider for any health insurance plans, although that doesn’t mean they don’t exist. If you don’t have health insurance, of course, you’ll be paying the cost yourself. This can add up to many thousands of dollars, depending on the number of infusions you receive. On the bright side, some ketamine clinics offer payment plans.

If you are able to find an academic center in your area, the pricing may be different. At this time, it’s difficult to find any comprehensive list of prices throughout the U.S., so it’s important to call around and ask for pricing information when you’re doing your research.

What it feels like

This remains the most difficult part of the ketamine process to describe. Even after seven sessions, I never got very good at describing what it feels like to undergo a ketamine infusion.

I spoke to a writer, who I’ll call Rebecca for the purposes of anonymity, who was prescribed esketamine after suffering from treatment-resistant depression for many years. She described her first two experiences of esketamine (which were a higher dose than her subsequent doses) thusly: “There was a physical sensation of heaviness but at the same time I felt separated from my body. Or it might be more accurate to say, separated from my consciousness. I was able to view certain things more objectively. Things that were upsetting suddenly seemed less important.”

This description rang true for me. If you’ve ever done a hallucinogen, like LSD or mushrooms, this probably all sounds familiar to you. Ketamine felt similar to other hallucinogens but way more intense, and for me, it lacked any feeling of euphoria, though I did find myself laughing during several of the treatments.

Now, let's talk results

Like almost anything, the effects of ketamine therapy vary greatly from person to person. Studies show that ketamine is associated with a rapid reduction in depression symptoms, including suicidal ideation. Overall, ketamine is promising in terms of its general effectiveness, as well as its fast-acting properties.

However, that doesn’t mean it will be effective for every individual. Like any treatment for depression, there is, unfortunately, no way to test whether it will be effective for a given person. When intravenous ketamine does work, patients usually respond to it within one to three treatments. If a patient doesn’t respond at all to those initial treatments, further infusions are not likely to be effective.

In addition, most experts agree that ketamine works best as part of a larger treatment plan, which usually involves talk therapy and sometimes ongoing use of antidepressant medication. Meisner says "it’s important to remember that ketamine is not a magic bullet."

In my case, the first two treatments did not feel effective to me, although I experienced mild euphoria for short periods after each of them. After my third infusion, though, I began to feel significantly better. Many of my symptoms subsided, I felt “lighter,” and I laughed a lot more.

Between my third and sixth infusions, and for about a week afterward, I continued to feel relief from my previous symptoms. Unfortunately, that relief faded quickly. My symptoms returned about a week after I finished my sixth infusion. Ketamine’s effects are known to be relatively short-term; the staff at my ketamine clinic told me that most of their patients feel relief for about three months after completing six infusions. I was one of the people who experienced its effectiveness for a very short time. After trying a seventh infusion, I was prescribed ketamine lozenges, which are supposed to prolong the effects of the ketamine infusions. I do find the lozenges effective, though for very short periods. For me, their effects last about a day.

However, I spoke to other people who reported success with ketamine therapy. Rebecca, who takes esketamine for depression, has experienced a significant reduction in her symptoms.

Her first two doses were eight sprays each, taken under the doctor’s supervision, followed by a “maintenance dose” of two sprays a week, taken at home. Rebecca told me that she experienced immediate positive effects, that it boosted her energy levels and took the edge off her depressive symptoms. Before the ketamine treatment, her depression was causing her debilitating levels of “brain fog,” negatively affecting her memory and cognition. She feels that the esketamine, which she continues to take at home, is helping with that. She says that after about a month and a half of treatment, she’s cautiously optimistic.

How to seek out ketamine therapy

If you’ve been diagnosed with major depressive disorder (MDD), bipolar, or PTSD (or some other diagnoses, in some cases), and other treatments haven’t helped you, you might be a good candidate for ketamine therapy. However, it’s important to get an opinion from your psychiatrist first as to whether ketamine is a good option for you. “They may not be especially familiar with these emerging treatments, but they should understand your response to first-line antidepressants and be able to offer an opinion regarding the likelihood that further trials with more established medications will yield different results,” says Meisner.

Start by researching ketamine clinics in your area. Again, this map is a handy place to start, though it’s not comprehensive, and the quality of each clinic is not guaranteed. If you don’t feel up to doing this research, this is a great project to ask a non-depressed loved one to do for you. The person doing the research should determine a reasonable distance from where you live and call any ketamine clinics in that area. They should ask about price, insurance options, payment plans, and how many initial sessions the clinic recommends.

Many clinics recommend six infusions within a two- or three-week period, so if you do go ahead with treatment, be sure to schedule them when you can spare that time. My infusions lasted 55 minutes each, plus 15 to 20 minutes of recovery time afterward — you need some time before you are steady enough to walk again. You also can’t drive yourself home after an infusion, and you will feel fuzzy and possibly sleepy in the hours afterward, so schedule accordingly. Also worth noting: My clinic instructed me to fast for four hours before each infusion.

What to look for in a ketamine clinic

Additionally, many ketamine clinics will ask to be put in contact with a therapist, psychiatrist, or general practitioner who can confirm your diagnosis, so have that information ready. Meisner also stresses the importance of finding a ketamine clinic that’s evidence-based and data-driven, and that puts safety first. He has a few key recommendations for anyone considering ketamine treatment:

- Seek out a specialist who is “not only willing — but enthusiastically supports — close collaboration with your outpatient psychiatrist.” Collaboration of this kind can be time-consuming and is often not reimbursed but is extremely important with “emerging treatments” like ketamine.

- Find a specialist who is willing to be transparent about the uncertainties of ketamine treatment. “This is not a sub-field in which arrogance — of any kind — is a marker for competence,” says Meisner. “If you sense someone is overpromising, they probably are.”

- Be relentless about ensuring that the clinic has appropriate safety measures in place. “Don't be afraid to ask what specialists are on sight, and why they are qualified for a psychiatric use of a medication typically categorized as an anesthetic,” says Meisner. "For example: Are both a psychiatrist and an anesthesiologist present? What sort of training does staff have that qualifies them to administer ketamine? And crucially, what kind of monitoring is in place during treatment?"

In all honesty, I wanted ketamine to cure my depression instantly and forever. Deep down, though, I think I knew it couldn’t do that. Ketamine isn’t for everyone, and it isn’t a magic bullet. But it taught me that my brain, as hopelessly entrenched in sadness as it sometimes seems, has the potential to change, and that it’s possible for me to feel better. For those of us who have spent a long time suffering and who have been unable to find an effective treatment, ketamine therapy offers a ray of hope. For some of us, that hope can be life-saving.

 
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Could a combination of psychedelics and meditation treat depression?

by Lauren Sharkey | Medical News Today | Nov 4 2019

Mixing a specific type of meditation with a well-known hallucinogen may make for a new form of therapy that could aid those with depression, according to a new study.

People often still regard psychedelic psychotherapy as a controversial treatment. However, recent evidence suggests that hallucinogens may have benefits for depression and anxiety disorders when individuals use them with certain other therapies.

The reasoning behind this is still unclear, but one theory states that psychedelics can help quicken the realization and thought processes a person needs for their therapy to work.

Psilocybin, a psychedelic that people find in magic mushrooms, has been the subject of several studies. Its effects can range from assisting with social interactions to limiting a person's focus on themselves.

One such study, appearing in the Journal of Psychopharmacology in 2016, found that psilocybin, together with psychotherapy, produced antidepressant effects in patients with life-threatening cancer.

Researchers at Imperial College London found similar benefits in people with depression who had not responded to other treatments. Neuroimaging revealed the drug could turn off a part of the brain that is always on when a person is awake. Neuroscientists call this brain element the default mode network.

Earlier this year, the U.K. university opened the world's first center for psychedelics research. A trial currently underway at the center is comparing the effects of psilocybin with those of a well-known antidepressant.

In the meantime, according to new findings that now appear in the journal Scientific Reports, combining psilocybin with a form of meditation may produce even more positive benefits.

The power of mindfulness meditation

Mindfulness meditation is already known to have a similar psychedelic effect to psilocybin, including reducing self-focus and boosting feelings of self-transcendence.

In the latest study, a team from the University Hospital of Psychiatry Zurich in Switzerland has combined the two to look at the joint impact for the first time.

Some 39 Buddhist meditation practitioners took part in a 5-day mindfulness retreat. Guided by a Zen teacher, they stuck to strict schedules that lasted from 6 a.m. until 9 p.m.

The practice — known as sesshin — involves sitting meditation sessions, indoor and outdoor walking meditation, and mindful physical activities. Participants were silent throughout.

On the fourth day of the retreat, the researchers gave some participants psilocybin while administering a placebo to the remainder.

Blocking negative impacts

Using questionnaires and mindfulness scales, among other neurocognitive measurements, the team found that, after 4 months, psilocybin takers had more positive changes.

These changes related to aspects such as empathy, self-acceptance, and psychosocial functioning.

Notably, even before the 4-month follow-up, "psilocybin markedly increased the incidence and intensity of self-transcendence virtually without inducing any anxiety compared to participants who received the placebo," says Lukasz Smigielski, first author of the study.

In fact, researchers believe the skills gained during the meditation retreat helped guard against any negative impact from taking the psilocybin.

Predictors of a positive outcome included the depth of meditation and participants' optimism and openness.
Another treatment for depression?

The intensity of the retreat and expertise of the participants may have limited the application of the findings, however. It may take the average person longer to experience the full benefits of mindfulness meditation, and many individuals will not have access to a structured, retreat-type experience.

But, says study director Prof. Franz Vollenweider, "the findings could pave the way for 'new therapeutic avenues.' "

"One example,"
he notes, "could be "for the treatment of depression, which is often accompanied by increased self-focus and social deficits."

With millions of adults in the United States currently living with depression, according to the Anxiety and Depression Association of America, this novel method could provide many more research opportunities.

As with all such research avenues, however, it is likely to take time before psychedelic psychotherapy or psychedelic enhanced meditation wholly enter the mental health conversation.

 
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Taking a deep look at psilocybin for depression*

by Michelle Janikian | Psychedelics Today | Nov 13 2019

Psilocybin for depression is becoming a major avenue of clinical research. The Usona Institute is about to begin the largest psilocybin-depression study in the US. Part of the FDA’s drug approval protocol, this phase 2 clinical trial will test the magic mushroom compound in 80 individuals for safety and efficacy in treating major depressive disorder (MDD).

When Usona co-founder, Malynn Utzinger, MD presented at this year’s Horizons Conference, she explained that she and co-founder Bill Linton originally wanted to look at psilocybin for depression and anxiety in those with terminal cancer. But when they brought the idea to the FDA, the government organization basically said: "Why limit yourselves to depression in cancer patients?" And so they changed gears to research psilocybin for depression more generally.

“It is our duty to make sure a potentially effective medicine gets to the widest… group of medical need,” Utzinger said. She went on to explain that "depression affects 300 million people worldwide and is predicted to be the second-largest cause of medical morbidity by next year," to further show the need for this research.

Psilocybin depression studies

So could psilocybin help those millions of people? Usona is hopeful, especially among the large portion of people with depression for whom traditional treatment, like anti-depressant medication, does not work. They’ve recently secured 7 clinical trial sites that will conduct this research and give qualified participants psilocybin along with therapeutic support. The sites are located around the US and include Johns Hopkins University in Baltimore, the University of California San Francisco, Yale University in Connecticut, University of Wisconsin-Madison, private testing sites in Chicago and Miami, and NYU in Manhattan – which is also the first site to complete training of facilitators and begin recruiting participants.

People are very interested in trying this new depression treatment. In fact, Utzinger said in her talk that "over 6,000 people have volunteered for the 80 available spots in their phase 2 trial."

Although this is the biggest study in the US looking at psilocybin for depression, this isn’t exactly a new concept. Outside of clinical trials, folks have been reporting reduced depression symptoms from psychedelic experiences – and peak experiences in general – for a long time. In fact, a 2017 study that looked at lifetime psychedelic users in “naturalistic settings” (meaning outside of a trial) found them to be less “psychologically distressed” and suicidal than users of other substances.

Over at Imperial College London, their team of psychedelic scientists have been looking into this even further, trying to figure out how psilocybin works for depression, both on a psychological and neurological level. Clinical psychologist from the Imperial team, Rosalind Watts, PhD and her colleague Ashleigh Murphy-Beiner, spoke right after Utzinger at Horizons, and presented a paper Watts authored which gives practitioners a framework for facilitating psilocybin for depression therapy, called the “ACE (Accept, Connect, Embody) Model.”

Watts developed this idea after facilitating participants’ psilocybin experiences during Imperial’s first psilocybin for treatment-resistant depression trial. During “psilodep 1” 20 people were given psilocybin-assisted therapy, and 19 had decreased depression symptoms at week 1 and nearly half at week 5. Plus, none of their participants began a new course of anti-depressants until after week 5.

Now, she tells Psychedelics Today over the phone that Imperial is halfway through their second study on psilocybin for depression; they’ve seen 38 out of “65, possibly 70” participants in a trial that’s comparing psilocybin to an SSRI antidepressant for depression treatment efficacy.

Psilocybin for depression: the ACE model

The ACE Model (not to be confused with ACEs, or Adverse Childhood Experiences) highlights psilocybin’s ability to promote psychological flexibility as a key function in how this therapy works. Essentially folks move from a psychologically rigid place where they’re stuck ruminating on negative thoughts to a more flexible, open, and accepting place, post-psilocybin session.

Watts describes it to me in terms of a ski slope. That our minds, or our “default mode network” is like a skier who follows the same path in the snow until they’ve become deeply ingrained grooves. Then a psilocybin-assisted therapy experience is like a snowplow that comes in and evens out the entire mountain. And so folks are suddenly freed from their ruminative ruts and now have the option to ski anywhere (or think about anything) they please. “They feel that they can think a different way. That they can have new thoughts and see themselves slightly differently,” Watts says. “They can have a sense of space and freedom, mental clarity, not stuck in those deep groves.”

It’s this same idea that her colleague at Imperial, Robin Carhart-Harris, PhD, made famous, that psychedelic experiences can “reset the brain” or “shake up the snow globe” allowing for new thoughts and perspectives. “It’s a disruption,” says Watts. “It’s actually that disruption that allows for a reset.” Yet, she explains that doesn’t happen so easily for everyone, and she doesn’t think it’s healthy for folks to go into these experiences with that expectation, because if they aren’t magically “reset”, they can be extremely disappointed.

“They’re often in very, very desperate states. Sometimes they haven’t been outside of their homes for years and their relationships have suffered and they’re feeling very isolated,” Watts says of the depression participants. “The amount of expectation and pressure that is on them for those experiences is huge.”

Therefore, in the ACE Model, they frame the whole experience in terms of a journey – rather than a reset – for participants, to try and lower the pressure and encourage the acceptance of all experiences as they come. That includes accepting challenging material that may arise as well as not making participants feel like a failure for “resisting” the medicine; in the ACE Model, it’s all part of the experience. And that’s where preparation and integration become critical to the whole healing process.

“It needs to be a therapeutic intervention where that person’s unique set of fears and hopes can be gently sat with, processed and held so that the person that’s sitting with them has some sense of the complexity of the whole scenario,” Watts explains. “Because so often the healing isn’t actually just in the trip, it’s in the environment, it’s in the relationships that you have in the room. And actually, often it’s as much about the narrative, the story you co-construct as the psilocybin.”

When all the pieces come together, when people feel fully supported and understood, then psilocybin can help folks out of depression by helping them see themselves and their lives more clearly. The process can also include planning actionable steps during integration that participants can take to improve happiness, like being less hard on themselves and spending more time with community or in nature.

Watts described the psilocybin healing process in a 2017 paper as people “moving from disconnection to connection” or “from avoidance of emotions to acceptance” and that’s very much part of what they try to instill during the therapy sessions. The ACE Model also includes guided meditation, and during a preparatory session they have participants visualize a journey, often a diving expedition where they’re encouraged to go deep into the dark parts of their mind in search of pearls of wisdom. The therapists remind divers that pearls are often found in scary, prickly oyster shells, so it may not always be easy, but the value will be great and worth the struggle.

This process of psilocybin-assisted therapy for depression is personal, and experts like Watts and Utzinger both point out its high rate of success is likely as much about the deep connections participants feel with their therapists as it is about the effects of psilocybin. Unlike taking anti-depressant medications for depression – which tend to numb people’s feelings – psilocybin and the therapy surrounding it encourage people to dig deep into their emotional worlds to try and heal themselves from the inside out.

The future of mushrooms for depression

Even though psilocybin-assisted therapy is working for people in initial studies, it’s often not a permanent fix. Watts says "many people from her trial have found that their depression symptoms come back after a few months." However, when I ask her about this, and about the potential future of legal mushrooms for depression therapy, she’s hopeful folks will have more options, including opportunities to do psilocybin sessions once every few months or so. She also adds that she thinks there’s "lots of room to develop integration practices for more long-term depression relief, which could include integration groups that go out and do meaningful activities together, like planting trees."

Obviously this is just the beginning of scientific research looking into this treatment. And hopefully, as law and science catch up with nature, there will be more options for folks to access this therapy for depression in the near future.

*From the article here :
 
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Are psychedelic drugs a new treatment option for people with depression?*

Neuroscience News | Virginia Commonwealth University | Nov 21 2019

After being relegated to the fringes of legitimate scientific inquiry for nearly five decades, an increasing number of researchers, including Javier González-Maeso, Ph.D., and Mario de la Fuente Revenga, Ph.D., both in the Department of Physiology and Biophysics at the Virginia Commonwealth University School of Medicine, are exploring whether psychedelics, or related compounds, could be a new treatment option for people with depression.

Major depression is one of the most common mental health issues in the United States, according to the National Institute of Mental Health, affecting an estimated 17.3 million adults. Treatment usually involves counseling/therapy, medication or a combination of both. However, these options take time to produce meaningful results and have high failure rates.

“Patients with depression need to receive antidepressants for weeks or even months to start to see the first therapeutic effects. Not only that—within that period of time, the risk of suicide goes up,” said González-Maeso, an associate professor.

Fast-acting antidepressant effects

Researchers in the U.S. and Europe have shown that a single dose of psilocybin, the psychoactive compound in so-called “magic mushrooms,” has fast-acting antidepressant effects—generally within hours. These effects also appear to last much longer than traditional antidepressants.

In one study cited by González-Maeso, 80 percent of people diagnosed with terminal cancer and depression who received a single dose of psilocybin continued to show improvements in their mood after six months.

That is because despite showing promise as a treatment for mood and substance abuse disorders in the 1950s and ’60s, the Drug Enforcement Administration cracked down on psychedelics such as LSD and psilocybin in 1970, making them some of the most tightly controlled substances in the country.

It took until the year 2000 for the Food and Drug Administration to grant permission for psilocybin research to resume, and it was only recently that positive results from these studies have made headlines.

Still, psychedelics are considered controlled substances that have “no currently accepted medical use and a high potential for abuse” and are classified as Schedule I drugs.

As a result, “it will take rock-hard scientific evidence before they can be used by physicians,” de la Fuente said.

A major component of that evidence will come from uncovering how psychedelic compounds produce antidepressant effects. This is exactly what de la Fuente and González-Maeso are trying to uncover—the underlying changes that psychedelics promote in the brain, both at a molecular and structural level.

Rewiring the brain

One possible mechanism behind psychedelics’ observed antidepressant activity that the pair is investigating involves changes to the way the brain is wired—a process involving the creation of new synapses.

Synapses are the most basic structures that neurons use to communicate with each other. Previous research has shown that people experiencing depression often have fewer synaptic connections, especially in areas of the brain responsible for regulating mood and cognition, such as the frontal cortex.

As part of their preclinical research, González-Maeso and de la Fuente have found that when mice are given a single dose of a psychedelic compound, it not only reduces behaviors associated with depression but also increases the number of synapses in their frontal cortexes. González-Maeso presented these findings at the inaugural meeting of the International Society for Research on Psychedelics in New Orleans in October.

“Psychedelics have been a banned field for decades,” de la Fuente said. “Now, with a more open attitude, we have all of the technological advances that we’ve accumulated over this time to apply to a growing field that almost nobody has explored before. From a scientific point of view, it is essentially the ‘promised land’ and will hopefully yield results that will make a real difference in the clinic.”

*From the article here :
 
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World’s first magic mushroom nasal spray for PTSD and depression

HEALTH EUROPA | 4 Dec 2019

PTSD and depression are two conditions that are being trialled for treatment with psilocybin.

A ‘magic mushroom’ nasal spray has been designed to make microdosing easier for people trying to treat their PTSD or depression.

Silo Wellness, an Oregon company with a team with roots in cannabis delivery modalities, has developed a magic mushroom nasal spray in Jamaica – where psilocybin is legal – for controlled, metered-dosing known as ‘microdosing’.

Magic mushroom nasal spray

The psilocybin nasal spray passes the gut, going directly to the bloodstream through the nasal mucus membranes and eventually the liver for metabolising. This saves the patient from feeling nauseous, as commonly experienced when taking psilocybin.

Board Advisor and Silo Wellness investor Becky Rotterman, a Missouri pharmacist, stated: “Many psilocybin patients, particularly women, complain of upset stomach or vomiting when taking high-doses of mushrooms."

“We want to bring this wonderful natural medicine first to Oregon and then the flyover states – to those who would be afraid to eat a handful of fungi and who feel more comfortable seeing their medicine in a familiar delivery modality, such as a metered-dose nasal spray.”


The correct dose

When a patient takes psilocybin the dosage is vital. Many people end up ‘stacking’, whereby the first dose takes some time to take effect so the patient consumes more, only to find they have taken too much later on. Microdosing alternatives with faster uptake speed are important in order to prevent accidental high-dosage experiences.

Silo Wellness founder, Mike Arnold, said he created the medicine dispenser after his first experience with psilocybin after he was advised by a doctor to try it.

He said: “I couldn’t help to think how fortunate I was to have an actual physician take me on my first trip rather than ‘some guy’ I know, but I realised that most first-time users don’t have that luxury."

“I reached out to my long-time colleague from the marijuana space, brilliant inventor Michael Hartman, and we agreed that we need to be able to give patients predictable dosing so they can self-titrate into the desired levels of sub-psychedelic or psychedelic treatment.”

“We solved the age-old problem with plant- and fungus-based medicine: How do you know how much is a dose?”
Hartman explained. “How do you avoid taking too much, like the cannabis edibles dilemma? We also managed to solve one of the common complaints of some mushroom users: taste and upset stomach.”

Healing trauma with magic mushrooms

Psilocybin is being trialled for the treatment of a number of physical and mental conditions, two of which are PTSD and depression. The psychoactive component is thought to stimulate receptors in the brain and potentially ‘rewire the brain’ by increasing neuro connectivity – helping to heal trauma from physical or psychological events.

COO, Scott Slay, said: “We are so grateful for the opportunity to have an actual and real first-to-market consumer product in magic mushrooms."

“I found mushrooms after returning from Iraq working in IED demolition and combat. The war changed me and the VA was ill equipped to help me transition and deal with my PTSD."

“I was heavily medicated. Mushrooms and DMT saved me. My life was renewed. I now have peace and purpose, and I can’t wait to share this opportunity with the world.”


Since psilocybin and other psychoactive compounds are found in nearly 200 known-species of mushrooms, humans have evolved around these beneficial chemical compounds.

Users of psychedelics have known for many years that small “micro doses” of mushrooms can give the user spiritual, medical, and therapeutic benefits without sending the user into a psychedelic ’trip’ as with high doses of mushroom biomass.

Psilocybin for depression has recently been given its second ‘Breakthrough Therapy’ designation by the FDA.

 
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Psilocybin better at treating depression than Ketamine, study

by Chris Moore | 8 April 2020

Ketamine received federal approval as a treatment for depression in 2017, but a new study suggests that psilocybin is even more effective.

Psilocybin may be more effective at treating depression than ketamine, according to new animal research conducted by Louisiana State University.

Just over a year ago, the US Food and Drug Administration (FDA) approved a new drug called esketamine, derived from the popular party drug ketamine, to treat depression. Ketamine, sold on the street as “Special K” or just “K,” is a dissociative that is legally used as a medical anesthetic and illegally used as a recreational drug. In recent years, a growing number of clinical studies have shown that small doses of ketamine can reduce the symptoms of treatment-resistant depression, and this research convinced the FDA to officially sanction this medicine.

But ketamine is not the only former party drug that shows promise at treating depression and anxiety. Dozens of new clinical research trials show that MDMA and psilocybin can effectively treat PTSD, depression, anxiety, and other disorders. The preliminary research is so promising, in fact, that the FDA is currently considering legalizing both of these drugs to be used under medical supervision within the next few years.

The present study, published last month in the ACS Chemical Neuroscience journal, conducted two experiments to determine whether psilocybin could be an even more effective treatment for depression and anxiety than ketamine.

In the first experiment, researchers placed mice in a Forced Swim Test (FST), an inescapable tank filled with water, once a week for five weeks. In a normal FST experiment, mice are forced to swim constantly, as there is no escape from the tank. Some mice eventually give up swimming, which researchers have identified as a depressive-like behavior.

Before conducting this experiment, researchers injected the rodents with either ketamine or psilocybin. During the first two weeks of testing, both groups of mice were less likely to stop swimming than a control group that was injected with saline. But, during the last three weeks of the test, the mice who were dosed with psilocybin continued to fight for their lives, while the ketamine group showed the same immobility rates as the control group.

In a second test, mice were placed in a maze that included both open and enclosed areas. Because rodents generally prefer enclosed areas, researchers identify the open areas as an anxiety-inducing environment that most mice choose to avoid. One group of mice was allowed to explore the maze before the trial began, but the other group of mice only saw the maze for the first time after they had been injected with the drugs.

The mice that were given psilocybin and early exposure to the maze were more eager to explore the open areas than any other group of mice. Mice that were given ketamine or saline, plus early exposure to the maze, were not as likely to enter the open areas. From this, researchers concluded that the mice given psilocybin were experiencing less anxiety than the other mice.

Interestingly, mice that didn’t receive early exposure to the maze did not show any increased interest in exploring the open areas, regardless of the drug they were given. Researchers concluded that this phase of the experiment demonstrated how important “set and setting” are to the psychedelic experience. Among the mice who received psilocybin, the ones familiar with the maze showed fewer signs of anxiety than those unfamiliar with the maze.

“The antidepressant-like and anxiolytic effects of psychedelics are measurable and significant in males of a rat experimental system that has been used by several other groups over many decades for the study of mood disorders in humans,” the study authors wrote. “These effects are evident many weeks after administration, are more persistent than those of ketamine, and are modulated by the rats’ experiences in the first week following administration.”

“The more persistent therapeutic effects of a single administration of psilocybin compared to ketamine in our experimental system support the notion that serotonin 5-HT2A receptor-directed therapeutic strategies may be superior to ketamine-based treatments in the clinic for depression,”
the study concluded.

 
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There are 3 types of ketamine. Which one works best for depression?*

by Dr. Erica Zelfand | DoubleBlind | 18 May 2020

Janssen Pharmaceuticals has patented a filtered version of ketamine called Spravato. But is their drug any better than generic ketamine?

The use of generic ketamine in the treatment of depression and suicidal ideation is not FDA approved, but that hasn’t stopped the new industry based upon off-label uses of the drug from blossoming, seemingly overnight.

When news broke that the world’s most popular anesthesia drug held promise as a treatment for depression, an explosion of interest in ketamine ensued. Several clinical trials were published exploring the drug’s efficacy in treating major depressive disorder (MDD), treatment-resistant depression (TRD), and suicidality, and numerous clinicians began providing off-label ketamine therapy to their depressed patients.

Until recently, Big Pharma was left out of the party, on account of two main roadblocks: One issue was that ketamine is a generic drug, meaning it cannot be patented, branded, or profitized. The other hurdle was FDA approval.

If the ketamine molecule could somehow be tweaked chemically, however, a pharmaceutical company could patent it as a new drug, dress it up with a catchy brand name, and charge top dollar for it. That’s exactly what Janssen Pharmaceuticals, a subsidiary of Johnson & Johnson, has done with Spravato, their S-ketamine (esketamine) nasal spray. After spending millions of dollars on studies and clinical trials demonstrating the efficacy of their new formulation, Janssen was able to secure FDA approval for the drug on March 5, 2019. This came on the heels of the FDA already having granted Fast Track and Breakthrough Therapy Designation to Janssen for S-ketamine as a remedy for treatment resistant depression (TRD) in patients concurrently taking oral antidepressant medication.

But does Spravato actually work any better than the cheap, widely available generic ketamine that has been around since the 1960’s? The jury is out.

In the meantime, many ketamine providers have been slow to welcome the “new K on the block,” choosing instead to stick with the affordable, generic ketamine they already know and use in a variety of dosages, forms, routes of administration, and contexts—not just as an off-label treatment not just for TRD, but also for other mood, pain, and personality disorders.

Understanding chirality, or “handedness”

To better understand the potential significance—or insignificance—of how Spravato differs chemically from other ketamine preparations, a quick explanation of the chemical concept of chirality is warranted.

Like many molecules, ketamine is made up of a 50:50 mixture of two differently oriented versions of the same molecule, known as enantiomers (or optical isomers). To understand the difference between enantiomers, consider for a moment your own hands. Though they are mirror images of one another, your two hands are not identical. If you placed your left hand on top of the right, you would find your thumbs pointing in two opposite directions. In other words, your hands are non-superimposable.

In chemistry, a molecule is said to be chiral if, like your hands, it exists in different forms that are non-superimposable mirror images of one another. These different orientations of a molecule (enantiomers) can exert subtly different pharmacological effects in the body.

Although Spravato (S-ketamine) is the only ketamine formulation currently approved by the FDA for the treatment of treatment-resistant depression, the medical community has been slow to welcome the “new K on the block.”

The two enantiomers of ketamine are known as S-ketamine (esketamine)—the right-handed orientation of the molecule—and R-ketamine (arketamine)—the left-handed version. A bottle of generic ketamine is a “mixed handed” (or racemic) solution, containing a mixture of both S- and R-ketamine, and it is this preparation that is found in hospitals and ketamine clinics across the globe.

Janssen, however, has found a way to isolate just S-ketamine by filtering the racemic molecule and discarding the R- enantiomer. And this right-handed solution (S-ketamine) is the only ketamine formulation currently approved by the FDA for the treatment of treatment-resistant depression.

The oldest trick in the book

Regarding Janssen’s development of Spravato, Dr. Wesley Ryan, Los Angeles-based ketamine provider board-certified in both general psychiatry and addiction psychiatry, says: “This is one of the oldest tricks in the book. We see this all the time with pharmaceutical companies patenting isomers of generic drugs.”

Examples of Big Pharma’s penchant for tweaking and rebranding molecules include the antidepressant escitazolam (from citalopram), the antibiotic levofloxacin (from ofloxacin), the reflux medication esomeprazole (from omeprazole), and the ADHD drug dexmethylphenidate (from methylphenidate).

Spravato comes in metered, single-use dose units of 56 mg and 84mg, which cost a patient or their insurance provider $590 and $885 USD, respectively. The first month of the recommended bi-weekly treatments therefore runs from $4,720 to $6,785 USD—and that’s before fees for the provider’s time and other administrative expenses. Racemic ketamine, however, costs under $4 USD for a 100mL bottle, an amount that can treat several patients. “You can’t ignore that it takes a lot of money to do the whole FDA approval process and conduct phase 2 and phase 3 clinical trials,” says Ryan. “But still, it’s an egregious price difference.”

The discrepancy in price between S- and generic ketamine, along with the cumbersome administration model mandated by the FDA (which includes longer office visits and requires a patient be concurrently taking oral antidepressant medication), has Ryan questioning if the expensive, Big-Pharma-backed “left handed” ketamine actually works any better than the cheap, widely available “mixed handed” racemate.

In other words: does left- or right-handedness matter?

Rat studies

According to studies done in rats, left- or right-handedness (chirality) does indeed matter, and “right handed” R-ketamine is the better of the two enantiomers in treating depression (in rodents, anyway).

The superiority of R-ketamine over S- in mitigating depression-related behavior in rodents has been confirmed in several studies, with R-ketamine yielding longer-lasting improvements. For example, in studies by Fukumoto et al., both S- and R-ketamine were eliminated from the rats’ blood at 48 hours post treatment, yet the rats treated with R- still had anti-depressive benefits after the ketamine had left their systems, whereas those that received S- returned to their baseline symptoms of depression.

R-ketamine has also been observed to induce synaptogenesis—the formation of new connections between brain cells—more robustly than S-ketamine. Considering that depression may be caused by the disruption of neural circuits in the brain, strategies that increase synaptic connectivity may be of great value in restoring mental health.
S-ketamine in humans

Pharmacologist Jason Wallach, PhD, at University of the Sciences in Philadelphia, however, warns against extrapolating rat studies onto humans. He tells me that the methods used to assess depression in rats “have very poor predictive validity” in people.

Clarity on the question of ketamine racemates can realistically come only from clinical trials performed on human participants.

While studies have demonstrated the efficacy of both S-ketamine and racemic ketamine in the treatment of humans with depression, no direct comparison between S- and R-ketamine in human subjects has been conducted as of yet. Nor are there comparisons of either enantiomer to the racemic mixture of both, although a protocol for a head-to-head study of S-ketamine and racemic ketamine in humans has been proposed.

"Nevertheless, there are a good number of randomized, controlled trials with both individually,” Wallach says in an email. “Overall the results with esketamine suggest it is comparable with racemic ketamine in all the classic endpoints and clinical profile.” The way he sees it, both S-ketamine and generic ketamine have merit in the treatment of depression.

A spokesperson for the Janssen Pharmaceutical Companies of Johnson & Johnson explains in an e-mail that “SPRAVATO® was studied in 28 clinical trials over eight years… with documented long-term safety and efficacy.”

But Erick Turner, MD, a psychiatrist with Oregon Health and Science University, disagrees: “When you look at the data [on S-ketamine], it’s actually quite anemic.” In his 2019 article in The Lancet, Turner points out flaws in the S-ketamine clinical trials, cautioning: “Clinicians and patients might wish to temper their expectations.”

Turner isn’t alone: A systematic review of S-ketamine reveals that phase 3 trials on the molecule have yielded mixed outcomes in patients, suggesting that S-ketamine might not be all it’s cracked up to be.

Why S- over R-?

Most of what we know about how ketamine works comes from the 50-something years of the drug’s use in the context of anesthesia. The drug blocks a channel in the brain known as the N-methyl D-aspartate receptor (NMDAR) and thus alters brain levels of glutamate, a neurotransmitter that stimulates nerve cells and thus allows for more effective communication between them. But the jury is still out as to whether or not NMDAR blockade explains ketamine’s effects as an antidepressant.

Because most of the currently approved antidepressant drugs affect the monoamine neurotransmitters—molecules like serotonin, dopamine, and norepinephrine—ketamine’s effects at NMDARs makes it a truly unique addition to psychiatry. This unique mechanism of action may, in fact, be what caught the FDA’s attention. When I called Janssen’s hotline for medical providers to ask why they chose S-ketamine for their new drug, a member of the company’s medical information group explained to me: “The higher NMDA receptor activity of S-ketamine allows a lower volume of solution to be administered via the intrasanal route compared to ketamine or R-ketamine.” In other words, S-ketamine has more NMDAR-blocking bang per spray than R- or racemic ketamine, thus allowing for lower dosage. But does that really matter in the context of depression?

Some folks think not, and in fact suspect the FDA may have gotten too excited about the novelty of the drug. “I think there was excitement about the novel mechanism,” says Turner, who previously worked as an FDA reviewer. “If this had been any other antidepressant like an SSRI or an SNRI, I don’t see the FDA being convinced enough to approve it.”

A review of ketamine enantiomers in Therapeutic Advances in Psychopharmacology identifies some perks of S-ketamine over R-, namely that it causes less drowsiness, lethargy, agitation, and memory problems.

But at least three other papers argue the opposite case, stating that R-ketamine causes fewer side effects than S-, namely dizziness, dissociation, and sensory deficits. R-ketamine’s weaker activity at NMDARs also likely explains its lower potential for abuse in rats. Again, we can’t superimpose rat data onto humans, but the suggestion of this study is that R-ketamine may be more addictive than S-.

“Misty,” a woman in her 30’s who uses street ketamine to manage her generalized anxiety disorder (GAD), premenstrual syndrome (PMS), and chronic headaches, reports that she gets the best results from a 50:50 blend of S- and R-ketamine. Unable to afford above-board, prescribed treatments supervised by a physician, Misty has been self-treating with insufflated (read: snorted) ketamine every 4-6 weeks for about two years now. While there is no guarantee that the powders she buys are pure, she has played around with various ratios of the enantiomers and cannot say which one stabilizes her mood and headaches better in the weeks that follow. She does report, however, that R-ketamine alone causes more vivid mystical visualizations, but the “come down feels choppy and edgy.” She describes S-ketamine as “smoother” and more of a “body experience” and floating sensation, “almost like an opioid.” Misty finds that the lack of visualizations that come with an S-ketamine session, however, limits how deep she is able to go in her healing, explaining that “the visuals help me illustrate the feelings.” Combining R- and S-ketamine allows Misty to have a smooth yet mystical experience that affords her weeks of mood-stabilizing benefits at a time.

The matter of insurance coverage

FDA approval of S-ketamine has paved the way for insurance coverage of ketamine therapy, but anesthesiologist Shawn DeRemer, MD and nurse anesthetist Gregg White, CRNA, two of the owners of Evolve Health in Portland, Oregon, report that insurance reimbursement has been an uphill battle. White explains: “Insurance companies typically don’t want to want to spend $2,000 a week for an ongoing treatment,” and elaborates that insurers typically require that a patient try and fail three or more psychiatric medications from two or more drug classes before they’ll cover the cost of Spravato therapy.

In fact, the cost of Spravato therapy is so high that England’s National Institute for Health and Care and Excellence (NICE), which serves the National Health Service (NHS) of England and Wales, does not recommend the drug.

A spokesperson for the Janssen Pharmaceutical Companies of Johnson & Johnson, however, tells me in an e-mail: “The average total annual cost of SPRAVATO® is generally comparable with other innovative, specialty mental health drugs, like the long-acting injectables for treatment of schizophrenia, and is not reflective of discounts and rebates that may be provided to Medicare and commercial insurers or through Janssen support programs.”

Jill Carter, DNP, another owner of Evolve Health, shares the story of a patient who was doing well on Spravato, but whose insurance authorization expired at the year’s end. After switching to racemic nasal spray, the patient’s depression returned, and Carter appealed to their insurance to allow the patient to resume treatment with Spravato.

So which enantiomer works better?

Researchers, providers, and patients alike want to know what form of ketamine is best, delivered through which route of administration. The opinions on the matter are seemingly as varied as the many protocols for administering the drug.

Carter explains that the best treatment choice is unique to each patient. In her experience, however, acutely suicidal patients are typically best served by intravenous (IV) infusions of the racemate.

DeRemer is more decisive: “I think Spravato works better than intranasal or IV racemate.”

White also thinks that patients achieve longer-lasting antidepressant benefits from Spravato than from racemic ketamine, but admits, “each patient responds differently to the modality and the mixture.”

Nonetheless, racemic ketamine has some considerable benefits over S-, with price being just one. Whereas S-ketamine is available only as Spravato nasal spray, racemic ketamine can be administered in a variety of dosing protocols and routes of administration, including oral, sublingual, nasal, rectal, intravenous, and subcutaneous and intramuscular injections.

The FDA-mandated risk evaluation and mitigation strategy (REMS) program requires that Spravato be administered only under medical supervision at approved treatment facilities. While generic ketamine is usually administered in the office as well, some lower-dose racemic preparations, like nasal sprays and lozenges prepared by a compounding pharmacy, can be prescribed for at-home use.

REMS also requires that patients be monitored for two hours after receiving Spravato, only allows for intranasal delivery of the drug, and further limits the dosage that patients can receive to 56 or 84 mg.

“The mystical-type experiences that can happen at higher doses are correlated with greater improvements and greater change. I don’t know if people get that on Spravato.”

Ryan finds that results are dose dependent, however, and is thus concerned that REMS’s dosage restrictions may limit patients’ responses to Spravato. He also nods to the emerging field of psychedelic medicine, adding,“The mystical-type experiences that can happen at higher doses are correlated with greater improvements and greater change. I don’t know if people get that on Spravato.”

Spravato is approved for use only in patients with a primary diagnosis of treatment resistant depression (TRD) who are concurrently taking oral antidepressant medication. Generic ketamine, however, is currently being used off label not only for TRD but also for bipolar depression, anxiety, obsessive-compulsive disorder (OCD), addiction, alcohol withdrawal, post-traumatic stress disorder (PTSD), complex regional pain syndrome (CRPS), and other forms of chronic pain, borderline personality disorder (BPD), refractory headaches, and a variety of other ailments.

Ketamine is clearly a unique addition to the psychiatric formulary. As for exactly how well it works, the mechanism(s) by which it does so, and which form of the molecule is best: time will tell. In the meantime, the majority of ketamine providers will likely stick to the adage, “If it ain’t broke, don’t fix it” and continue using affordable, generic, racemic ketamine as an off-label treatment for mood disorders.

*From the article here :
 
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Karolinska Institutet

How Ketamine Combats Depression

Ketamine increases the number of serotonin 1B receptors and binds to serotonin 1B receptors, reducing the release of serotonin and increasing the release of dopamine.

The anesthetic drug ketamine has been shown, in low doses, to have a rapid effect on difficult-to-treat depression. Researchers at Karolinska Institutet now report that they have identified a key target for the drug: specific serotonin receptors in the brain. Their findings, which are published in Translational Psychiatry, give hope of new, effective antidepressants.

Depression is the most common psychiatric diagnosis in Sweden, affecting one in ten men and one in five women at some point during their lives. Between 15 and 30 percent of patients are not helped by the first two attempts at therapy, in which case the depression is designated difficult to treat. Studies have shown that low doses of the anesthetic drug ketamine are rapid-acting on certain sufferers, but exactly how it works is unknown. A nasal spray containing ketamine has recently been approved in the USA and EU for patients with treatment-resistant depression.

Researchers at Karolinska Institutet in Sweden have now imaged the brains of study participants using a PET (positron emission tomography) camera in connection with ketamine treatment.

“In this, the largest PET study of its kind in the world, we wanted to look at not only the magnitude of the effect but also if ketamine acts via serotonin 1B receptors,” says the study’s first author Mikael Tiger, a researcher at the Department of Clinical Neuroscience, Karolinska Institutet. “We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression.”

In the first phase of the study, 30 people with difficult-to-treat depression were randomly assigned to either a ketamine-infusion group (20 individuals) or a placebo (saline) group. It was a randomized double-blind study, so neither patient nor doctor initially knew who received the active substance. The participants’ brains were imaged with a PET camera before the infusion and 24-72 hours afterward.

In the next phase, those who so wished (29 individuals) received ketamine twice a week for two weeks. The result was that over 70 percent of those treated with ketamine responded to the drug according to a rating scale for depression.

Serotonin plays a key role in depression and low levels are thought to be linked to more serious disease. There are 14 different kinds of receptors for this neurotransmitter on the surface of neurons. For their PET imaging, the researchers used a radioactive marker that binds specifically to serotonin 1B receptors. They found that the ketamine operated via these receptors in a formerly unknown mechanism of action. Binding to this receptor reduces the release of serotonin but increases that of another neurotransmitter called dopamine. Dopamine is part of the brain’s reward system and helps people to experience positive feelings about life, something that is often lacking in depression.

“We show for the first time that ketamine treatment increases the number of serotonin 1B receptors,” says the study’s last author Johan Lundberg, research group leader at the Department of Clinical Neuroscience, Karolinska Institutet. “Ketamine has the advantage of being very rapid-acting, but at the same time, it is a narcotic-classed drug that can lead to addiction. So it’ll be interesting to examine in future studies if this receptor can be a target for new, effective drugs that don’t have the adverse effects of ketamine.”

https://neurosciencenews.com/ketamine-depression-16478/
 
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We can no longer ignore the potential of psychedelic drugs to treat depression

by Robin Carhart-Harris | The Guardian | 8 Jun 2020

The world is experiencing a devastating physical health emergency. But the coronavirus pandemic has also seen a renewed focus on our psychological wellbeing. Loneliness, uncertainty and grief may be intensifying an already acute mental health crisis, and in the US there has been a 20% spike in the number of prescriptions for antidepressant and anti-anxiety drugs during lockdown. Demand for key antidepressants is threatening to exceed supply in the UK – where prescriptions have already more than doubled over the last decade.

I head the Centre for Psychedelic Research at Imperial College London, the first of its kind, supported by about £3m in philanthropic donations. For 15 years, my research has focused on how drugs such as LSD, psilocybin, DMT and MDMA work in the brain, and how they may be useful in treating disorders such as depression. Like the present pandemic, a psychedelic drug experiences can be transformative – of the individual – and of society. Both illuminate the extent to which the condition of the world we inhabit is dependent on our own behaviours. And these, in turn, are a consequence of how we feel, think and perceive.

The Centre was founded in April 2019. A few months later, Johns Hopkins University in the US announced a supersized version, floated by $17m. If you have read Michael Pollan’s book How to Change Your Mind or seen the first episode of Gwyneth Paltrow’s Netflix series, The Goop Lab (titled The Healing Trip), you may be aware that such developments reflect a rising interest, and investment, in the mental health application of psychedelic drugs.

One reason for this is that a decades-long struggle to resurrect medical research in the area is beginning to bear fruit. In London, we have spearheaded work showing how psilocybin ( or “magic mushrooms”) can be used to assist psychotherapy for difficult-to-treat depression, making a significant difference when conventional antidepressants and talking therapy have not. Right now, we are crunching data from a much larger depression trial that compares psilocybin-assisted therapy with a six-week course of a conventional antidepressant drug, a “Prozac-like” selective serotonin reuptake inhibitor (SSRI). Preliminary analyses indicate game-changing results.

There hasn’t been a breakthrough in mental healthcare for some time, and psychedelic therapy works very differently to current treatments. Conventional drug treatments have dominated psychiatry for decades, and although many people prefer psychotherapy, it is more expensive, harder to access and arguably no more effective than the drugs.

These drugs haven’t changed much since their discovery, and come with side effects that put people off taking them. Where SSRIs are concerned, their antidepressant action seems to rely on a moderation of the stress response – but it is a palliative rather than curative action, which requires having the chemical in the body for several months or longer.

Psychedelic therapy is a much more comprehensive treatment package. It entails a small number of psychologically supported dosing sessions, flanked by assessment, preparation, and integration (talking through one’s experience afterwards). Psychedelics appear to increase brain “plasticity,” which, broadly speaking, implies an accelerated ability to change.

One view is that a psychedelic experience is a consequence of an especially intense surge of plasticity that opens a window of opportunity for lasting therapeutic change. The same windows may open up during other extreme states, such as experiencing trauma, stress-induced breakdown, a spontaneous spiritual experience or coming close to death. The difference with psychedelic therapy, however, is that the experience is carefully prepared for, contained and mediated. If not done this way, the use of psychedelics can be dangerous.

The impact of successful psychedelic therapy is often one of revelation or epiphany. People speak of witnessing “the bigger picture,” placing things in perspective, accessing deep insight about themselves and the world, releasing pent-up mental pain, feeling emotionally and physically recalibrated, clear-sighted and equanimous. This is very different from people’s descriptions of the effects of SSRIs, where a contrasting feeling of being emotionally muted is not uncommon. It would be premature to disclose the findings of our head-to-head trial prior to proper scientific review, but on top of impressive tolerability and antidepressant effects with psilocybin-assisted therapy, we are seeing remarkable changes in patient-relevant outcomes. These include increased quality of life, “flourishing” (feeling well rather than just “not depressed”), the ability to feel pleasure again and normal sexual functioning. The value of something new and different is often hard to gauge until it is placed alongside something more familiar, and our new study does this.

Those driving efforts to get psilocybin therapy licensed hope to be able to market it across North America and Europe within the next five years. As was the case with medicinal cannabis, however, it is quite possible that use could begin to scale up prior to formal licensing. Before Covid-19, a small but buoyant market existed for plant-based psychedelic retreats or ceremonies in pockets of Europe, as well as Central and South America. There have been a number of initiatives to liberalise policies on psychedelic use in the US, and the most ambitious is the psilocybin service initiative in Oregon, which aims to phase in legal, regulated psilocybin therapy through Oregon’s health system, from this year. Whatever one’s view on these developments, allying them with research is imperative if we are to advance scientific understanding, and ultimately inform and safeguard the individual.

Despite this progress, the idea of “psychedelics for mental health” will be petrol on flames for some. Stigma is attached to both mental illness and psychedelics, and so full entry into the mainstream won’t go unchallenged (and rightly so). If the 1960s is anything to go by, there may be passions to temper at both ends of the spectrum, as psychedelics evangelisers could stoke as much trouble as opponents – which is why a dispassionate, scientific approach is so important.

Like all tourism, the psychedelic variety will have taken a big hit in the pandemic, but it is unclear whether home use has been affected, either in prevalence or quality. “Hardly the best time for a trip,” one might think – but psychedelics are sensitive to the slippery subtleties of context. Many of the insights these compounds awaken are of a Buddhist sort, and although timelessly relevant, they feel particularly so today: the self as illusory, suffering as inevitable, attachment as a common cause of suffering, impermanence as fundamental, and slowing down, contemplation, breath, and community as potent resources.

Sars-Cov-2 is a virus that attacks the respiratory system and can kill. We all breathe, and we will all die, but our instinct is to forget and escape these truths. Two of this pandemic’s silver linings are that it has invited an expanded consciousness – and that people have slowed down. Many will have noticed their breath, contemplated their own and other’s impermanence, and felt grateful for care, love and life. If psychedelic therapy does fulfil its potential, it will be providing the same essential lessons. The extent to which we listen will be up to us.

Robin Carhart-Harris is head of the Centre for Psychedelic Research at Imperial College London.

 
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University of Wisconsin

Combining therapy with psilocybin results in a large reduction of depression and anxiety

by Beth Ellwood | PsyPost | 18 Jun 2020

A recent meta-analysis published in Psychiatry Research provides tentative support for psilocybin in the treatment of depression and anxiety.

Researchers have made important advancements when it comes to the treatment of depression and anxiety, including both pharmacological and behavioral interventions. Nevertheless, existing treatments often have ill side effects or are ineffective for certain patients, pointing to the need for more treatment options. Study authors Simon Goldberg and his team wanted to investigate one possible new treatment option.

“Researchers have recently resumed investigating psychedelic compounds as a novel treatment approach,” the authors say. “One such substance is psilocybin, a plant alkaloid and 5-HT2A receptor agonist.”

Goldberg and associates conducted the first meta-analysis to examine clinical trials investigating the effects of psilocybin among individuals with heightened anxiety or depression.

The analysis included four studies published between the years 2011-2018 and a total of 117 subjects. Three studies took place in the United States and one in the United Kingdom. The samples had an average of 29 participants, and were largely female (58 percent) and White (86 percent). All participants had clinically relevant anxiety or depression symptoms, or a combination of both.

One trial had a single-group, non-controlled design where all participants were administered a dosage of psilocybin. The three remaining trials employed a random design where roughly half the participants received a psilocybin dose and half received a placebo (the control group). In addition to the drug treatment, all four studies incorporated behavioral interventions and support throughout the trial.

Results of the meta-analysis indicated that participants in all four studies showed large reductions in anxiety and depression after receiving psilocybin dosages. Furthermore, the effects of psilocybin were significant even at the six-month follow-up. For the three double-blind studies comparing placebo and psilocybin conditions, the effects of psilocybin on anxiety and depression were also found.

While the results provide support for psilocybin in the treatment of anxiety and depression, the authors discuss several limitations with the analysis. First, as only four studies were included, the observed effects may not be reliable. Additionally, most studies had a high risk of bias, including detection bias caused by insufficient blinding of participants.

One possible avenue for future research is in the treatment-resistant population. “Additional large-scale studies examining the effects of psilocybin on treatment-resistant depression may be warranted, as only one of the four studies focused on this population,” the authors say.

“Nonetheless,” the researchers conclude, “the current meta-analysis suggests psilocybin in combination with behavioral support may provide a safe and effective treatment option for reducing symptoms of anxiety and depression. This is an area for additional careful, scientific study.”

 
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Psychedelic drugs reduce depressive symptoms by helping individuals accept their emotions

by Eric Dolan | PsyPost | 13 Aug 2020

New research provides preliminary evidence that psychedelic drugs can improve mental health by making individuals more accepting of distressing experiences. The study, published in Frontiers in Psychiatry, adds to a growing body of literature that indicates that using psychedelics can result in sustained improvements in depressive symptoms.

“Psychedelic therapy has shown promise as a novel treatment for a range of mental health concerns, including major depressive disorder, distress associated with a life-threatening illness, and substance use disorders,” said study author Richard Zeifman, a PhD student at Ryerson University and research intern at the Centre for Psychedelic Research at Imperial College London.

“In contrast with the traditional pharmacological interventions, the effects of psychedelic therapy appear to last months and even years after treatment has ended. Understanding how psychedelic therapy leads to long-lasting mental health improvements across a range of conditions is not yet fully understood but is important for enhancing and delivering psychedelic therapy to individuals that may benefit from it.”

The researchers were particularly interested in the transdiagnostic construct known as experiential avoidance, meaning the tendency to avoid unpleasant thoughts and feelings. People who score high on a measure of experiential avoidance agree with statements such as “I would give up a lot not to feel bad” and “I go out of my way to avoid uncomfortable situations.”

For their study, the researchers used online advertisements to recruit a sample of 104 individuals who planned to use a psychedelic substance and a second sample of 254 individuals who planned to attend psychedelic ceremonies. Both samples completed measures of depression severity, experiential avoidance, and suicidal ideation one week before and 4 weeks after using their psychedelic substance of choice.

Zeifman and his colleagues found that the use of psychedelics in both ceremonial and non-ceremonial settings was associated with decreases in experiential avoidance, which in turn was associated with decreases in depression severity and suicidal ideation 4-weeks after psychedelic use. Psilocybin/magic mushrooms, LSD, and ayahuasca were the most commonly used substances in the study.

“Our findings suggest that one of the reasons that psychedelic therapy has positive therapeutic effects is that it helps individuals to be less avoidant and more accepting of their emotions, thoughts, and memories (even though such experiences may be distressing in the short-term),” Zeifman told PsyPost.

“More broadly, our results provide further support for the negative mental health effects associated with avoidance. This can be summed up with a saying that is often used in the context of psychedelic therapy, that ‘The only way out is through.'”

But the study — like all research — includes some caveats.

“There were important limitations to our study, including that our study was not conducted in the context of a controlled clinical trial or within a clinical sample. Accordingly, we are currently conducting research where we are comparing the effects of psychedelic therapy versus a traditional antidepressant (called escitalopram) on experiential avoidance. This research will help to further examine the possibility that psychedelic therapy leads to change through different mechanisms than do traditional pharmacological interventions for depression,” Zeifman said.

The study, “Post-Psychedelic Reductions in Experiential Avoidance Are Associated With Decreases in Depression Severity and Suicidal Ideation“, was authored by Richard J. Zeifman, Anne C. Wagner, Ros Watts, Hannes Kettner, Lea J. Mertens, and Robin L. Carhart-Harris.

 
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Should you microdose to treat depression?

by Ben Angel | Entrepreneur Media | 8 May 2020

Speaking with a psychopharmacology expert to find out whether psychedelics are ready for their mainstream moment.

If you asked 100 people about psychedelics, you’d most likely get 100 opinions based on their firsthand experience, strong condemnation or stories from their adventures at Woodstock in the ’60s. No matter what people might know or think they know about psychedelics, the 40-year moratorium that closed down related research in the '70s is now coming to an end. Psychiatrists are beginning to realize that strategic, supervised use of these psychopharmacological drugs is helping people with mental disorders including obsessive-compulsive disorder, post-traumatic stress disorder, alcoholism, depression and cluster headaches. Still, are there enough scientific studies to warrant the use of these drugs in mainstream society?

I’ll admit that talk of psychedelic therapy to treat depression makes me nervous. In researching my book, Unstoppable, I looked at other key triggers that can mimic psychological disorders like depression and anxiety, such as inflammation, nutritional deficiencies, hormonal changes, side effects from medications, gut imbalances and food sensitivities. The reality is, depression is complex. What works for one may not work for another. Any successful treatment must first identify the root cause of one’s depression successfully, which can be a complex process if not done under the right medical care. A psychedelic treatment isn’t suddenly going to fix a nutritional deficiency, for example, but it may help target other symptoms and behaviors that correspond with depression. This is why it was critical to set my own biases aside and speak to an expert.

I was fortunate enough to interview Dr. Domenick J. Sportelli, who is board-certified by the American Board of Neurology and Psychiatry for General Psychiatry and fellowship-trained and Board Certified in Child and Adolescent Psychiatry. He also specializes in human behavior and psychopharmacology. I wanted to get the most current information on the use of psychedelics in treatment for depression, anxiety and PTSD, so I first asked him first to clarify what psychedelics were.

“The term 'psychedelic substance' refers to an exogenous substance [derived outside the body] that, when taken into the body in various ways, physiologically, neurologically and psychologically manifest an internal personal experience of altered states of consciousness," he explains. "This includes perceptual distortions, hallucinations, synesthesia [a mixing of the senses], altered sense of time and space, as well as potentially inducing what researchers call a 'mystical experience' — a sense of oneness, of noetic experience and an undefinable but profoundly spiritual quality.”

Is there enough evidence to support psychedelic therapy?

Sportelli wants to make clear that the most researched psychedelics — LSD, psilocybin (mushrooms), peyote, MDMA, DMT and ketamine — have different mechanisms of action and even induce subtle, subjective experiential differences. Although each is grouped under the term “psychedelics,” they are quite disparate.

Dr. Sportelli is cautiously optimistic about the multitudes of large-scale, university-based testing and prior research compiled decades ago, but worries about the abiliity to circumvent bureaucracy and conduct safe, credible and substantial testing today. He does add that recent testing of psilocybin, LSD, ketamine and MDMA in particular has generated cause for optimism, and that they will likely have a place not only in continued, diverse research design and protocol, but eventually in therapeutic use.


What types of depression can psychedelics treat?

If we were to look at the onset of most mental illnesses, the majority start to become evident between the ages of 11 and 24, according to the National Institute of Health. With only 42 percent of people getting treatment, most typically do not seek out assistance until a secondary mental illness occurs several years later.

When asked how broadly psychedelics might be able to help treat people with depression, Sportelli concedes that, “Unfortunately, research hasn’t determined the level of scientific data to specify the type of depression or mood disorder that psychedelic therapy will benefit.” But he does add that research and data are beginning to show statistically significant improvements in mood, reduced anxiety, change in positive personality traits over time, the possibility of reducing addictive behaviors, reduction in suicidal tendencies and increased personal insight.


Do psychedelics treat the symptoms or the cause?

According to Dr. Sportelli, depression stems from a mix of genetic, biological, neurological, psychological and sociological factors. Recent research has demonstrated how the chemical breakdown of psilocybin closely resembles that of serotonin, and indicated the promising interplay of select hormone transmission. Dr. Sportelli stresses the critical role that these drugs might offer in mood disorders is at the forefront of the pharmaceutical quest for treatment.

“We have never seen substances like these that can potentially change the way that we look at our life and change perspective with lasting results," he says, noting that they might be able to help "supercharge psychotherapy."


Is this ultimately a recommend reatment, and where does one turn for it?

“At this time, in the U.S., I would only recommend this treatment be a part of, and under the close supervision of, a university-based IRB [Institutional Review Board]-monitored clinical trial,” Sportelli emphasizes. Before any psychiatric treatment, Dr. Sportelli also recommends a full medical and neurological evaluation to rule out any of the multitudes of medical circumstances that can manifest as a primary mood disorder, and reiterates that significant and often profoundly adverse outcomes associated with such powerful, mind-altering chemicals need to be weighed further as well. That’s why, as part of any regulated trial, all the necessary medical workups would be completed before participation.

Is the stigma around psychedelic therapy warranted?

Sportelli acknowledges that there is a safety concern associated with psychedelics, and does not condone their recreational or illict use. But he does believe that regulated clinical trials, judicious and ethical research methodology and the progression for therapeutic intervention should not be overlook based on previous stigma and possible misclassification.

I’ve never been one to throw the baby out with the bathwater. After interviewing Dr. Sportelli, I hold hope for the future, but also a concern for those who may seek out this kind of treatment without an accurate medical diagnosis. My number-one hesitation remains — that is we simply do not have the studies to show which types of depression psychedelic therapy successfully treats, which may result in people attempting to use a hammer when in fact they need a nail.

Either way, if you are to venture into this arena, find someone who specializes in it. The risk of going it alone could come at too high a price.

 
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Psilocybin + Mindfulness for depression: Complementary actions starting to emerge

by Lily Aleksandrova, MSc, PhD | Psychedelic Science Review | 20 Oct 2020

Both have long-lasting positive effects on mood, social skills and neuroplasticity. Combining them may potentiate and prolong mutual therapeutic effects.

Current treatment options for those suffering from depression are inadequate at best. This is especially true for the one-third of all depressed patients who are labelled as “treatment-resistant” after failing to respond to two or more traditional antidepressant drugs. On top of their low response rates, classical antidepressants are plagued by a slow onset of action and various side effects. These realities highlight the urgent clinical need for better antidepressant treatments to address a global pandemic of a different kind.

Psilocybin and mindfulness meditation represent two promising alternative approaches in the field. Emerging data on psilocybin’s safety and efficacy in depression led to its FDA (US Food and Drug Administration) designation as a breakthrough therapy in 2018. Psilocybin is converted in the body to its active metabolite, psilocin, which binds to the serotonin 5-HT2A receptor. It can help depressed patients break down negative, rigid patterns of thinking through deep personal insights and flexible cognition.

Mindful meditation (MM) is the mental practice of focusing on being in the present in a relaxed, non-judgmental, and accepting way. Mindfulness-based cognitive therapy has been reported to be effective in treating depression, and in preventing symptom relapse. Through persistent practise, patients learn to develop mental strategies for better emotional self-regulation and stress coping.


Antidepressant efficacy of psilocybin and mindfulness

Emerging evidence now suggests that depressed patients may benefit from the combination of psilocybin and MM.

A recent review published in Frontiers in Psychiatry pooled data from 93 relevant published studies. By looking at six clinical markers of depression, Heuschkel and Kuypers broke down the antidepressant effects of psilocybin and MM individually. At the time, there were no published clinical data on the use of psilocybin and MM in conjunction, leaving them to hypothesize about potential complementary effects based on what is known about their individual effects. The potential benefits of this combination therapy, and the need for future studies on this topic, were underscored.

The clinical/physiological markers of depression discussed were: 1) negative affect, 2) impaired cognition, 3) social deficits, 4) impaired neuroplasticity, 5) altered brain network activity, and 6) elevated stress hormone/inflammatory levels in the brain.

Briefly, the pooled data revealed that psilocybin and MM both exert long-lasting positive effects on mood, social skills, and neuroplasticity, with different effects on executive functioning, brain network activity, and stress hormone/inflammatory responses. It is expected that the two approaches will have synergistic actions by potentiating and/or prolonging mutual therapeutic effects.


Combination may maximize the therapeutic benefits

The limited but encouraging clinical data supports the combination of psilocybin and mindfulness meditation for treating depression. Importantly, according to Heuschkel and Kuyper’s analysis, MM seems to facilitate psychedelic-induced peak experiences or “breakthroughs,” which are positively correlated with treatment response. MM may also extend the psychedelic “afterglow,” or the persisting feeling of elevated and energetic mood often reported in the days to weeks following a trip. Additionally, MM can provide a better sense of control during the acute psychedelic experience, thus minimizing adverse drug events. Psilocybin can, in turn, open up a window of opportunity for successful MM-based therapy as sustained increases in both mindfulness and neuroplasticity are observed following a psychedelic treatment.

It is important to note that complementary or synergistic effects of the two treatments were speculative or anecdotal at the time of Heuschkel and Kuyper’s paper. Since then, the first double-blind study of the combination of psilocybin and MM was published. The small trial suggests, as predicted, that psilocybin can amplify the positive effects of mindfulness meditation practice while MM reduces the likelihood of a bad trip.

One thing is clear, more placebo-controlled, double-blind, randomized trials are needed to determine whether psilocybin-assisted mindfulness-based therapy is effective for treating depression. Trials could compare psilocybin with MM to each treatment alone, MM along with classical antidepressant drugs, or the combination of conventional pharmacotherapy and psychotherapy. Time and future research will tell.

 
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Karolinska Institute in Sweden

First psilocybin-for-depression clinical trial launched in Sweden

Psilocybin Alpha | October 16, 2020

The Swedish Medical Products Agency and Ethical Review Authority have approved the first clinical trial investigating psilocybin-assisted psychotherapy for depression in the European nation, which will be conducted at the Karolinska Institute and funded by the Osmond Foundation and Norrsken Foundation.

The randomized, placebo-controlled, double-blind phase 2b study seeks to reveal the efficacy of psilocybin-assisted psychotherapy for the treatment of depression. Patients are given one dose of psilocybin, or a placebo, plus 5 weeks of therapeutic support.

“With this study, we will investigate a novel treatment approach for depression, and learn more about acute and long-term efficacy. In addition, we will gain further insight into how psilocybin exerts its effect by using brain imaging techniques,” said Johan Lundberg, principal investigator.

Due to the fact that the Osmond Foundation adheres to Open Science protocols, we should expect to see a great deal of transparency around methodology and results. The Foundation also collaborates with the Usona Institute, who is sponsoring a Phase 2 psilocybin for major depressive disorder study in the United States. Usona is supplying the psilocybin for Osmond’s study.

Lundberg explained: “A previous study without a control group indicates that two doses of psilocybin, administered in a clinical environment with therapeutic support, can provide a rapid and relatively long-lasting alleviation of depression compared to existing drugs. These results need to be confirmed through randomized placebo-controlled studies, which is why we have chosen to conduct this trial.”

The study will be hosted at the Karolinska Institute, a research-led medical university in Stockholm, and is funded by the Osmond Foundation and the Norrsken Foundation: both of which are non-profits. The Osmond Foundation has a specific focus on psychedelic medicine, and seeks to unveil the treatment potential of such substances via clinical trials.

In terms of timelines, the clinical trial is set to recruit patients this month, October 2020. We will be following developments closely.

 
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Ketamine said to 'help people dislike themselves less'*

by Abigail Calder, MSc | Psychedelic Science Review | 27 Oct 2020

New research shows that ketamine reduces self-dislike, loosening the rigid prejudice toward oneself that can constitute depression.

In the 1990s, a team of Yale scientists was working to understand the role of glutamate signaling in depression. Glutamate is one of the brain’s most important neurotransmitters ‒ the chemicals that neurons exchange to communicate ‒ and something seemed to be amiss with it in depressed patients.

Ketamine was their chosen research tool. It blocks the NMDA glutamate receptor, which would allow scientists to study whether depressed patients responded strangely to changes in glutamate activity. And they did ‒ though not like the researchers expected. “To the amazement of our patients and ourselves,” the team later wrote, “ketamine produced rapid, profound, and surprisingly durable antidepressant effects.” Twenty years later, scientists are still trying to figure out why.


A new kind of antidepressant

Ketamine does not do what conventional antidepressants do. Instead of merely increasing the brain’s concentration of serotonin, its blockage of NMDA receptors sets off a complex molecular domino effect. The result may be that ketamine enhances the brain’s ability to form new connections and re-organize itself in response to its surroundings, a property scientists call neuroplasticity. This enhanced neuroplasticity, particularly in the prefrontal cortex, might be what drives depression into remission.

And ketamine is not the only drug capable of this: Classic psychedelics, such as psilocybin and LSD, also likely enhance cortical neuroplasticity, with similarly striking improvements in depressive symptoms. Although ketamine lacks the characteristic interaction with 5-HT2A receptors and is therefore not classified as a psychedelic, it has important things in common with them: It induces a strange hallucinatory state, it stimulates neuroplasticity through complex downstream effects on glutamate receptors, and it produces antidepressant effects that well outlast intoxication.

But what does this mean for a patient’s mental life? Depression has a complex cognitive pathology which manifests differently for different people ‒ so what exactly is it that ketamine improves? Medical doctors and scientists at the University of Bern in Switzerland aimed to find out how ketamine changes patients’ thinking and improves their mental health.


Ketamine targets self-dislike

This study took place in a hospital treatment center where 26 depressed patients were receiving ketamine infusions. All of them had been through at least three different treatment attempts with no relief. Using standardized questionnaires, Hasler et al. measured the severity of their depression before ketamine treatment, 24 hours afterward, and seven days later.

Before coming to the good news, one unfortunate fact leaps off the page: ketamine alone did not help everyone. The single dose evaluated in the study sent only 34.6% of the patients into remission, although the good news is that nearly all of them stayed there for at least a week. People can vary enormously in their responses to psychedelics and related substances, such as ketamine and MDMA, and these results are a clear reminder of it.

Returning to the patients who did improve, ketamine appeared to target particular symptoms: More than anything else, it made people dislike themselves less. Patients’ scores on the questionnaire measuring self-dislike were one standard deviation lower after ketamine treatment, which is not only a significant difference but also a large and meaningful one. Self-dislike is one of depression’s most common and terrible manifestations. Depression can compel people into an uncontrollable narrative about how worthless they must be, and when taken to its terrible extreme, self-loathing can motivate self-destruction. These negative biases are not easy to break, making it all the more incredible that one ketamine infusion can end them, if only temporarily.


Paradigm shifts in the mind and at large

Treatments like ketamine – and classic psychedelics – seem capable of inducing a paradigm shift in a patient’s mind, particularly with supportive therapy. In this study, ketamine helped some patients see themselves more positively, loosening the rigid prejudice toward oneself that can constitute depression. Soberingly, these changes do not seem to last on their own. But medical researchers are working on a way to help them persist: Once a patient has reached a healthier state they may still have to maintain it, but that is much easier than trying to claw one’s way out of disorder. For this reason, combining ketamine with therapy in the future may be the most effective way to use the brief “window of plasticity” that it can open.

Likewise, some scientists believe that ketamine is heralding a paradigm shift in the entire field of depression treatment, and it may be the first of many neuroplasticity-enhancing drugs to be synergized with therapy. Instead of replacing neurotransmitters purported to be “missing” in depression, these drugs enhances the brain’s ability to change, allowing new perspectives to break through the oppressive influence of negative cognitive biases. Instead of taking two weeks to be effective, they act rapidly – sometimes immediately. And instead of taking an antidepressant every day for perhaps the rest of their lives, patients may only need them between once every few weeks and once, period.

This is new territory, and researchers are still working out the proper indications for different experimental treatments. But both ketamine and psychedelics appear to target the same physical pathway: they change the brain’s ability to change. This alteration may not only be beneficial on its own but may also accelerate progress in therapy. Combining single doses of psychoactive, neuroplasticity-enhancing drugs with therapy represents a growing paradigm shift in how people view and treat depression. Not all depressed brains benefit from dumping more serotonin into their synapses. Perhaps some instead need a dose of flexibility.


*From the article here :
 
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Ketamine provides lasting relief from severe depression

The Royal's Institute of Mental Health Research | Apr 15 2019

For many people with severe depression who have tried medications but not found anything that helps, ketamine can be a life changing intervention.

Small doses of ketamine (an anesthetic agent that has been widely used for over 45 years) rapidly lowers depressive symptoms in 50 to 60 per cent of patients. What’s more, it can reduce suicidal ideation almost immediately. In some cases, patients who have had ketamine infusions during depressive or suicidal episodes reported feeling positive impacts either immediately after the infusion or within 24 hours afterwards.

While the effects of ketamine treatment were proven to be strikingly fast, they were not long-lasting.

That is, until now.

In a ground-breaking new study, Dr. Pierre Blier, Director of Mood Disorders Research at The Royal’s Institute of Mental Health Research (IMHR) and his research team were able to demonstrate that not only can ketamine be effective in rapidly treating those with severe depression or suicidal ideation – but that it can also have significant and prolonged effects.

According to results published in the American Journal of Psychiatry, repeated ketamine infusions (small doses delivered intravenously) can have sustained antidepressant effects for patients with treatment-resistant depression. The study showed that those who responded to ketamine went on to experience sustained reductions in depressive symptoms with once-weekly maintenance infusions.

“This is the first study that has shown we can decrease the frequency of ketamine infusions once somebody has had a response—and still maintain the antidepressant effects,” says Dr. Jennifer Phillips of the IMHR’s Mood Disorders Research Unit.

How did the study work?

The goal of this study was to understand how to best administer ketamine to maximize and prolong its antidepressant effects, to help make treatments as accessible and effective as possible.

Based on the results, the research team was able to show for the first time the rapid antidepressant effects of a single ketamine infusion could be re-instated and sustained with repeated infusions (something that is quite atypical of traditional medications for depression). Results also showed that individuals who do not respond to a single ketamine infusion could still respond to the treatment over time with repeated infusions.

In the last phase of the study, the team tested a truly novel strategy: those who responded to the three times per week infusions then received just once-weekly infusions for an extra four weeks. From this, the research team was able to conclude that ketamine’s antidepressant effects could be maintained in all patients when reducing the frequency of infusions.

“Through this study, we were able to test a much more practical way of administering ketamine in a clinical setting,” says Dr. Phillips.

Dr. Blier, who has been studying ketamine’s effect on depression since 2010 – and was the first clinician in Canada to give small doses of ketamine to patients – adds that the results of this study could be revolutionary for research and clinical practice.

“The moral of the story for clinicians and patients is that if ketamine doesn’t work the first time – don’t give up!" he says.

Dr. Blier recommends instead that individuals are given at least two weeks with repeated infusions before evaluating the effectiveness of the treatment. In this most recent study, for instance, he says that "while the majority of patients responded after three infusions – some required up to six before showing positive results."

 
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Multiple clinical trials have demonstrated that even a single subanesthetic
dose of intravenous ketamine has a rapid-acting antidepressant effect.


Use of acute and maintenance IV ketamine in outpatients with depression*

by Sheila Jacobs | Psychiatry Advisor | 3 Nov 2020

In real-world patients with treatment-resistant depression (TRD), long-term intravenous (IV) ketamine therapy is well tolerated and is associated with modest improvement in the 16-item Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR16) score. A retrospective chart review was conducted among patients with TRD who were being treated on an outpatient basis at the Intravenous Ketamine Clinic for Depression at Massachusetts General Hospital (MGH) in Boston, Massachusetts. Results of the study were published in the Journal of Affective Disorders.

The investigators sought to examine outcomes experienced among outpatients treated at the MGH ketamine clinic between October 2018 and November 2019. A total of 85 patients with TRD were enrolled in the study. At every visit prior to administration of IV ketamine, participants’ symptom severity was measured via use of the QIDS-SR16.

Patients’ initial dose of ketamine was typically 0.5 kg/mg. which was infused over 40 minutes. In the induction phase, IV ketamine was administered 2 times weekly for 3 weeks. This was followed by a maintenance phase, in which a variable dose and administration schedule were used. Response to IV ketamine was defined as a ≥50% reduction in the total QIDS-SR16 score from baseline.

Overall, 47 percent (40 of 85) of the patients who initiated treatment discontinued during or immediately following the induction phase. At the time this report was published, 4 percent (3 of 85) of the participants were still on induction therapy, and 50 percent (42 of 85) of patients had transitioned to the maintenance phase after having completed the induction phase. Among these participants, 17 percent discontinued treatment during the maintenance period and 28 continued on maintenance therapy.

During maintenance therapy, the mean ketamine dosage was 0.91 ± 0.28 mg/kg. In total, 18 percent (15 of 82) of participants responded to induction therapy and 7 percent (6 of 82) of them remained in responder status during the maintenance phase — that is, at the time of data analysis. Discontinuation of ketamine because of side effects was reported in 3 patients.

The study has several limitations including the fact that this is a retrospective chart review and patients were followed naturalistically, with the possibility to continue or change antidepressants and their psychotherapy regimen according to recommendations from the treating psychiatrist. Also, the high dropout rate may have been influenced by the cost of ketamine infusions, since this treatment is not currently covered by insurance.

The investigators concluded that notwithstanding the considerable out-of-pocket costs incurred and the low response rates in QIDS-SR16 scores, nearly half of all the real-world outpatients with TRD continued maintenance treatment with ketamine because of the perceived significant improvement. Large comparative effectiveness studies on the subject are warranted, in order to identify the role played by ketamine in the depression treatment algorithm, as well as to better distinguish the optimal dosing and frequency of treatment needed in patients with TRD.

*From the article here :
 
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Ketamine vs. Antidepressants: What the research tells us

by Elena Schmidt | The Third Wave | 12 Nov 2020

In the last 20 years, modern medicine has mapped the human genome, reduced HIV mortality by 80%, and diminished heart disease deaths by 40%. Yet in the last century, psychiatry has made virtually no progress in alleviating depression—the leading cause of disease in the industrialized world. In fact, prescription drugs often exacerbate the very symptoms they claim to assuage.

As depression continues weaving its insidious web, those who suffer need hope. Fortunately, a growing wave of research points to ketamine therapy as a viable alternative. But could psychedelic ketamine infusions be safer and more effective than antidepressants?


The facts about depression
Yet modern medicine continues to tout similar prescription drugs and theories from the 1960s.

How we got here

In the early 1900s, doctors attempted to solve melancholia—the first term for depression—through electroshock treatments and herbal remedies. After decades of failed attempts, they accidentally stumbled on a new hypothesis. While administering tuberculous drugs, doctors observed surprising mood-elevating effects in their patients. Based on the discovery, they developed a theory that monoamine drugs, which affect noradrenaline, serotonin, dopamine, and norepinephrine, could also alleviate depression. As a result, pharmaceutical companies in the 1950s began developing new antidepressants drugs to target these biochemicals.

Tricyclic Antidepressants (TCAs)

TCAs are the earliest known monoamine antidepressant drugs, which work primarily by boosting happy hormones, such as serotonin and norepinephrine. While effective at elevating mood, TCAs may also cause severe side effects, including significant drops in blood pressure, difficulty urinating, sexual dysfunction, and tremors. As a result, TCAs have primarily been replaced by antidepressants that are supposedly safer and more effective. Despite the rhetoric, research shows patients are only negligibly more satisfied with today’s alternatives.

Monoamine Oxidase A Inhibitors (MAOIs)

Along with TCAs, psychiatrists often prescribed MAOIs to treat the chemical imbalances they believed caused depression. MAOIs work by blocking monoamine oxidase, the enzyme that diminishes happy hormones in the brain. While successful at a chemical level, MAOIs are incompatible with the standard American diet of red wine and beer. Mixing the two can trigger a spike in blood pressures as well as seizures. Starting in the late 1960s, pharmaceutical companies began developing SSRIs.

Selective Serotonin Reuptake Inhibitors (SSRIs)

SSRIs are the most recent psychiatric medicine, touted as a revolutionary approach to boosting serotonin levels. But the fact is scientists don’t truly understand how SSRIs work on a neurochemical level. When compared to TCA antidepressants, research shows SSRIs do not exhibit statistical improvements in treating depression. According to a meta-analysis of multiple antidepressant medications, SSRIs are only slightly more effective than placebos. Moreover, depressed people who take SSRIs report a slew of unwanted effects, from sleep issues to anxiety to suicidal behavior and severe dependency. The facts speak for themselves. The time was yesterday for mental health professionals to consider ketamine therapy as an alternative treatment for depression.

Ketamine therapy and consciousness

Mounting evidence shows ketamine may work by modulating glutamate, a neurochemical in the brain associated with depression. Ketamine is also known to have “neuroplastic effectiveness,” which can create new brain pathways.

Through this mechanism, ketamine can rewire the brain and change the mind by allowing people to dissociate from worry and detach from formerly limiting beliefs, opinions, and habits. Ketamine creates shifts in perspective everyone knows they need but can’t seem to access through brute prescription force. Even with a conservative dose, ketamine can yield physical and mental perception changes that allow patients to explore hidden parts of their consciousness.

The numbers tell the story
  • The first placebo-controlled double-blind ketamine therapy trial in 2000 showed that subjects treated with ketamine experienced a significant reduction in depressive symptoms. The placebo group did not.​
  • A second randomized controlled trial in 2006 showed a single ketamine injection could produce significant depression relief within 110 minutes in more than 70% of patients.​
  • In that same study, one-third achieved clinical remission in 24 hours.​
Another study with treatment-resistant patients found ketamine diminished suicidal thoughts within 24 hours.

More than just medicine

At legal ketamine clinics across the country, patients are receiving infusions and experiencing altered states of consciousness. Some even report “leaving the body” and reliving past experiences, such as their birth. This dissociative property directly results from ketamine’s ability to modulate glutamate and is precisely why people experience immediate relief. But IV therapy alone is not sufficient to transform euphoric shifts into permanent state changes.

Rapid onset is a serious advantage of ketamine therapy, but patients can relapse just a few weeks after their last injection. For ketamine therapy to be more effective than SSRIs, patients need more than an IV drip and a bill from their local clinic. According to the therapists and researchers at Mindbloom, people need guided psychedelic experiences, followed by psychedelic integration therapy over several weeks.

Mindbloom offers guided psychedelic therapy using clinically prescribed ketamine. Generally, Mindbloom’s clinicians prescribe four infusions every 1-2 weeks over four weeks to start. The team designs these sessions to inspire inner exploration, followed by personalized integration plans that include talk therapy and journaling. “Trust, let go, be open” is Mindbloom’s mantra. Their goal is to offer real hope for depression, representing a new chapter in mental health.

The bottom line

When mainstream psychiatrists purport to treat severe depression by manipulating a few biochemicals, they ignore the brain’s wildly complex structure and function. They also ignore the humans beyond their biology, the trauma they may be suffering, and their ability to self-heal. Through mind altering ketamine therapy, depressed people have a viable alternative for relief.

 
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Psilocybin delivers 'remarkable' relief in severe depression

by Batya Swift Yasgur, MA, LSW | Medscape | 5 Nov 2020

Psilocybin, the psychedelic compound in "magic mushrooms," rapidly improves symptoms and produces remission in as little as two sessions for patients with major depression, new research suggests.

Results of a small randomized trial showed that treatment with psilocybin was associated with a greater than 50% reduction in depressive symptoms in 67% of study participants. In addition, 71% showed improvement at 4-week follow-up, with more than 50% achieving remission.

"The finding that the majority of people whom we treated showed efficacy was quite a remarkable and gratifying finding and really sets the stage for psilocybin as a treatment for major depression," senior investigator Roland Griffiths, PhD, Oliver Lee McCabe III Professor in the Neuropsychopharmacology of Consciousness, Johns Hopkins University School of Medicine, Baltimore, Maryland, said in a statement.

"Perhaps the most exciting aspect of this as a new therapy is that psilocybin works as a therapeutic intervention with a single session or a few sessions, and then the effects are enduring. In contrast, most conventional treatments for depression...are given chronically and also have chronic side effects," Griffiths, who is also director of the Johns Hopkins Center for Psychedelic and Consciousness Research, added.

The study was published online November 4 in JAMA Psychiatry.


Growing evidence

As previously reported, psilocybin improves depressive symptoms for patients with cancer. "However, these patients might be regarded as having a "reactive depression" to their life-threatening illness," said Griffiths.

"This study built on that previous research by asking the question, is psilocybin effective in patients who have major depressive disorder, which is a much larger population?" he said.

In addition, prior studies of psilocybin-assisted therapy had no control group, lead author Alan Davis, PhD, adjunct assistant professor in the Psychedelic Research Unit, Johns Hopkins University, told Medscape Medical News.

The researchers created a control condition by randomly assigning 24 individuals who were currently experiencing a moderate or severe major depressive episode to receive either immediate treatment.

Participants had long-standing depression, with a mean of 22 months in the current depressive episode. They were required to avoid using other antidepressants for 4 weeks prior to screening and up to 4 months following enrollment.

Patients were also required to be medically stable; have no personal/family history of psychotic or bipolar disorders; no past-year alcohol, substance, or nicotine use disorder; and no substantial lifetime or recent use of ketamine or classic psychedelics.

Participants received eight preparatory meetings with two session facilitators before the first psilocybin session and then 2 to 3 hours of follow-up meetings after the psilocybin sessions. In addition, they received 13 sessions of psychotherapy.

After completing these preparatory sessions, they underwent two psilocybin sessions, administered a mean of 1.6 weeks apart.

Participants in the DT group were assessed for depressive symptoms weekly for 8 weeks prior to entering the treatment protocol.


"Surprising" findings

Participants in the IT group exhibited significantly lower depression scores on the GRID-HAMD at 1 and 4 weeks after the second psilocybin session in comparison with patients in the DT group during the corresponding weeks.
Group
Baseline mean (SD)
Week 5 mean (SD)
Week 8 mean (SD)
IT​
22.9 (3.6)​
8.0 (7.1)​
8.5 (5.7)​
DT​
22.5 (4.4)​
23.8 (5.4)​
23.5 (6.0)​

An analysis of outcomes showed that for all 24 participants, at 1 and at 4 weeks following the psilocybin intervention, had a "clinically significant response" in depressive symptoms; 60% and 56%, respectively, met criteria for remission.

Importantly, participants experienced no serious adverse effects.

Griffiths said he was "surprised" by the findings. "We knew that psilocybin would be effective in reactive depression of the type associated with illness, but we did not know that this would be the case in the large number of individuals who qualify for having major depressive disorder," he said.

Davis said "the finding represents a large effect of this treatment among people with major depressive disorder — an approximately 4 times larger effect compared to studies of antidepressant drugs."

Davis noted that psychotherapy was an "essential" component of the study protocol. "It is likely that the combination of psychotherapy and psilocybin is what makes this treatment efficacious and that this treatment will always have a psychotherapy component and will not be FDA-approved as a stand-alone medication."

Tipping Point

Commenting on the study for Medscape Medical News, Collin Reiff, MD, clinical assistant professor, Department of Psychiatry, New York University Grossman School of Medicine, New York City, noted that "because psychedelics are still stigmatized, the publication of this study in one of the highest-impact journals in all of psychiatry suggests that research into psychedelics is now in the mainstream and that the academic psychiatry research community is paying close attention to what is happening." He described this as a "tipping point."

Reiff, who was not involved with the study, noted that research had been conducted on psychedelic compounds until the 1960s, "when they left the research lab and went mainstream, leading to the shutting down and subsequent dormancy of the research for the next 30 to 40 years."

"Psychedelic research is undergoing a renaissance and no longer regarded with as much skepticism, but it is important to take our time doing this research so we do not repeat what happened in the 1960s,"
said Reiff.

In an accompanying editorial, Charles F. Reynolds III, MD, endowed professor in geriatric psychiatry at the University of Pittsburgh Medical Center (UPMC), Pittsburgh, Pennsylvania, questioned "for whom psychedelic-assisted psychotherapy is appropriate (or not), particularly in patients with depression who are suicidal of have a history of suicide attempt."

Reynolds, who is also director of the Aging Institute of UPMC wrote, "personalizing the management of depression has to entail an understanding of the multiple contexts in which depression occurs, including genetic, developmental, psychosocial, cultural, medical, neurocognitive, and spiritual."

*From the article here :
 
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