08/6/24

Conjuring the Antidepressant Effect of Ketamine

Ketamine use and abuse has been getting several different kinds of media attention lately. The DEA and the Los Angeles police are investigating how Matthew Perry received the ketamine that killed him. Perry was undergoing ketamine infusion therapy under the care of a psychiatrist and an anesthesiologist. However, his last infusion therapy was 10 days before his death and wouldn’t explain the levels of ketamine found in his autopsy. The amount of ketamine in his blood was approximately that for general anesthesia during surgery and was listed as the primary cause of his death.

Ketamine is known as a “dissociative anesthetic hallucinogen” because it makes the person feel detached from their pain and environment. It distorts the perception of sight and sound, making the user feel disconnected and not in control. It can induce sedation (feeling calm and relaxed), immobility, pain relief, and amnesia—no memory of events while under the influence of the drug. Not surprisingly, ketamine has also been used in sexual assault. And an overdose can cause unconsciousness and dangerously slowed breathing, as it seems to have done with Matthew Perry.

Ketamine became a popular “club drug” known as Special K, Kit Kat, Super K, and others. It’s typically distributed at raves, nightclubs and private parties; and rarely sold on the street. The illegal use of ketamine in the U.S. is diverted or stolen from veterinary clinics or smuggled into the country from Mexico. It comes in a clear liquid that can be mixed into drinks, or as a white or off-white powder that is snorted or smoked, typically with marijuana or tobacco.

Ketamine produces hallucinations. It distorts perceptions of sight and sound and makes the user feel disconnected and not in control. A “Special K” trip is touted as better than that of LSD or PCP because its hallucinatory effects are relatively short in duration, lasting approximately 30 to 60 minutes as opposed to several hours.

The onset of effects is rapid and often occurs within a few minutes of taking the drug, though taking it orally results in a slightly slower onset of effects. Hallucinogen Persisting Perception Disorder (HPPD) has been reported several weeks after ketamine is used and may include experiencing the negative side effects that occurred while taking the drug initially. Ketamine may also cause agitation, depression, cognitive difficulties, unconsciousness, and amnesia.

In an interview, Elon Musk discussed his prescription use of ketamine. He said he uses a small amount once every week or so. “There are times when I have sort of a … negative chemical state in my brain, like depression I guess, or depression that’s not linked to any negative news, and ketamine is helpful for getting one out of the negative frame of mind.” He denied any misuse of ketamine, saying, “if you use too much ketamine, you can’t really get work done. I have a lot of work. I’m typically putting in 16-hour days … so I don’t really have a situation where I can be not mentally acute for an extended period of time.”

Ketamine is not an FDA-approved treatment for depression but some psychiatrists use it off-label. Ketamine infusion therapy, like that prescribed to Matthew Perry, is not covered by insurance, meaning it’s expensive. And not every psychiatrist is willing to prescribe it. A derivative of ketamine known as esketamine (Spravato) was approved in 2019 as a nasal spray. But receiving a ketamine infusion or Spravato requires close medical supervision in a clinic.

This expense and the “inconvenience” of medical supervision led to the proliferation of compounded ketamine products such as ketamine lozenges and tablets and nasal sprays from a multitude of online sources, allowing for the at-home use of ketamine, which seems to be what contributed to Matthew Perry’s accidental death. The FDA published an alert, warning of the potential danger of compounded ketamine products. “Compounded drugs are not regulated by the FDA, so there is no assurance the drugs purchased from a compounding pharmacy are what the companies claim they are.” They pose a higher risk to patients than FDA-approved drugs because they don’t undergo the FDA review for safety, effectiveness and quality.

Now there has been the publication of a phase 2 clinical trial for extended-release ketamine tablets for treatment-resistant depression in the journal Nature Medicine. The lead author of the study told Medscape, “Having a tablet formulation makes it possible for patients to be safely dosed at home and would increase the number of patients who could be treated at any one time.” He added that when formulated as an extended-release tablet, taking around 10 hours to release, most of the ketamine is metabolized in the liver. “The low ketamine blood levels mean patients experience few or no side effects.” The study reported the majority of side effects were of a mild or moderate intensity. The most common adverse events included dizziness, headache, dissociation, feeling abnormal, fatigue and nausea.

The design of the study eliminated non-responders before randomization in order to reduce the risk of study failure. This meant that of the 231 enrolled in the open-label enrichment phase of the study, (where participants took a daily dose of 120 milligrams of ketamine in the slow-release pill for five days) 63 exited the study as nonresponders and 168 continued as responders. The responders were participants whose MADRS (Montgomery-Asberg Depression Rating Scale) score was greater than or equal to 12 and had reduced their scores by at least 50% during the enrichment phase. These responders were then randomized into double-blind groups of four different doses and placebo. See the figure below from the original study.

A CNN Health article on the study reported that experts thought the study was an important first step, but the trial probably biased the results, making the drug look more effective than it would be in the real world. Dr. Gerald Sanacora, who was not involved in the study, said it’s very likely participants knew they were getting ketamine rather than the placebo, and expected it to work. “It is usually easier to guess correctly once you have been exposed to the active treatment and then receive the inactive treatment.” He thought further study in a larger population was necessary. The researchers acknowledged this design likely overestimated response levels, “and future unenriched clinical trials are needed to address this issue.”

Sancora went on to say there was “significant tension” between the potential benefits of ketamine and making sure the treatment can be given safely and responsibly. “This is a step in the right direction, but we clearly need more high-quality data before we can say much more about the overall efficacy and safety of the new form of treatment and especially the safety of doing this at home.” There was also a high dropout rate of the double-blind RCT phase of the study; and one completed suicide.

Of the 168 people who initially saw benefit from the pills, 100 didn’t complete the trial. Ninety-four left because they stopped being helped by their treatment. One person left because of an adverse event. Four others left for unspecified reasons. A 65-year-old man died as a result of suicide.

An independent review committee judged the suicide was a result of the patient’s depression rather than the treatment. Experts agreed it was difficult to know whether the drug played any role in the death, and said larger studies were needed to “tease out” any serious safety issues. “One of the challenges with oral ketamine, one of the reasons that we haven’t used as much for depression as IV, is that it can be sort of unpredictable, and how much is getting into the bloodstream?”

Reflect for a minute on the above reported information. One hundred sixty-eight participants were identified as responders to ketamine treatment for treatment-resistant depression. But 100 (59.5%) didn’t complete the trial; and 94 (55.9%) left because they stopped being helped.

What seems implied, but unspoken here, is that the high dropout rate in the study was fueled by participants recognizing rather quickly that ketamine no longer had an antidepressant effect for them. This suggests two concerns with the study. First, the double-blind part of the open-label enrichment phase was broken, raising the question of the credibility of the supposedly “random” design. Second, the rapid antidepressant effect of ketamine appears to dissipate quickly, raising a concern about the wisdom of ketamine as a long-term treatment for “treatment-resistant” depression. Remember, it is a Schedule III Controlled Substance.

Additionally, there was no significant difference of relief reported between the four treatment phase groups in the study. The CNN article noted while everyone still in the study at 14 weeks reported some relief from their depression, the results when compared with the placebo group were not significant; meaning the reported relief “could have been observed due to chance alone.” So, the antidepressant effect of ketamine could merely a pharmaceutical conjuring trick—now you have it, now you don’t.

See “Evaluating the Risks with Esketamine,” Repeating Past Mistakes with Esketaine,” “Voyages on the Starship Ketamine,” and others for more information on the concerns with ketamine and esketamine to treat depression on my website.

11/14/23

Voyages on the Starship Ketamine

Image by ThankYouFantasyPictures from Pixabay

On October 10, 2023, the FDA issued a warning about the potential risks of compounded ketamine products for the treatment of psychiatric disorders such as depression, anxiety, OCD and PTSD. The concern seems to center on the at-home use of ketamine compounds from a multitude of online sources, dispensing oral formulations such as ketamine lozenges or tablets. Not only is ketamine not FDA approved for the treatment of any psychiatric disorder, it has known safety concerns such as abuse and misuse, increased blood pressure, slowed breathing and “psychiatric events.” The FDA said these compounds should only be used “under the care of a health care provider.”

Ketamine is a Schedule III controlled substance approved by the FDA as an intravenous or intramuscular injection to induce and maintain general anesthesia. It is not FDA-approved to treat any psychiatric disorder. It is a mixture of two-mirror-image molecules, R-ketamine and S-ketamine—arketamine and esketamine, respectively. The “S” form of ketamine (esketamine), known as Spravato, was approved by the FDA as a nasal spray for the treatment of major depression and adults with acute suicidal ideation or behavior in 2019. See “Red Flags with Spravato,” “Doublethink with Spravato?,” “Repeating Past Mistakes with Esketamine” and other articles on this website expressing concerns with esketamine/Spravato.

Spravato is also a Schedule III controlled substance and like ketamine, and has similar risks of adverse events. This led the FDA to require a Risk Evaluation and Mitigation Strategy (REMS) with esketamine, meaning that esketamine is required to be “dispensed and administered in medically supervised health care settings that are certified in the REMS and agree to monitor patients for a minimum of two hours following administration because of possible sedation and disassociation and the potential for misuse and abuse.” But ketamine and ketamine compounds can be legally prescribed off label to treat psychiatric disorders and do not have to have a FDA required REMS.

However, on February 16, 2022 the FDA published an alert describing the risks associated with the use of compounded ketamine nasal spray products. The FDA Adverse Event Reporting system (FAERS) and the medical literature identified five cases (reported between 2016 and 2021) of compounded ketamine nasal spray that resulted in psychiatric events “such as delusion, dissociation, visual hallucination, and panic attack as well as abuse and misuse.”

The reported concentrations of compounded ketamine nasal spray ranged from 125 – 200 mg/ml. Frequency of use varied from three sprays three times a day to six sprays eight times a day. The amount of medication administered to the patients with each spray is unknown. In most case reports, the patients self-administered the product at home, and it is unknown whether they were observed or monitored by a healthcare professional.

Because compounded ketamine nasal spray products are not FDA-approved, there is no FDA-approved dosing regimen for these products. There are also no data to support dosing conversion between Spravato (esketamine) nasal spray and compounded ketamine nasal spray.

The New York Times said the October 2023 alert sought to differentiate between the supervised use of ketamine as a therapy administered at clinics, and the “wellness centers” or online marketers that prescribe the drug via telemedicine so that buyers can take the drug at home. The alert included a caution that individuals receiving ketamine products from compounders and telemedicine platforms may not receive information about the potential risks associated with the product. “At-home administration of compounded ketamine presents additional risks because a health care provider is not available onsite to monitor for serious adverse outcomes resulting from sedation and dissociation.”

The pandemic-related boom in telehealth has given rise to a legion of online prescribers that dispense inexpensive ketamine lozenges, tablets or nasal sprays following a brief video interview. Some companies provide as many as 30 doses after one session, which experts say can lead to misuse.

Company executives in the compounding industry say they’d welcome government oversight. But they are concerned that a lack of flexibility in the FDA’s guidance could result in overly aggressive enforcement by state regulators. The manager of a compounding pharmacy in San Francisco said he is concerned these online sellers will ruin it for everyone. “Our fear is that regulators, if they perceive a threat to public health, will move to take this amazing medicine away and leave patients at risk.”

Psychiatric Times also expressed concerns with at-home ketamine therapy. They described a report by the All Points North Treatment Center in Edwards Colorado of 2,000 adults where 64% said they thought ketamine helped with their mental health symptoms. But 55% who tried at-home ketamine therapy also admitted accidentally or purposely using more than the recommended dose. The Editor in Chief of Psychiatric Times said, “Esketamine has to be administered in person by a trained health care provider. The use of at-home ketamine bypasses this safety net and puts individuals at risk, undermining the FDA’s REMS protocol to minimize risk and maximize safety and prevent diversion and abuse/misuse.”

There were reservations in 2019 with the approval process for esketamine, Spravato (see “Hype and Concern with Esketamine” and “Evaluating the Risks with Esketamine”). A NPR interview BEFORE the FDA approved esketamine predicted the problem the FDA is now attempting to address in its alert for “compounded ketamine products.” A doctor who prescribed ketamine to his patients said doctors would continue to offer a generic version of ketamine for depression because it would be cheaper than the cost of Spravato with its REMS. The generic form of ketamine was cheap, and could be taken at home with the assistance of a nasal spray, he said. “Any psychiatrist or physician can prescribe [it] without the restrictions that are going to be applied to esketamine.”

A Cunning Methodology

In a new study, Stanford researchers devised a cunning workaround to disguise the dissociative properties of ketamine. A major difficulty with doing clinical trials on psychedelic drugs like ketamine is the difficulty of providing a satisfactorily double blinded methodology. Participants can usually tell whether or not they were given ketamine or a placebo. The researchers “recruited 40 participants with moderate to severe depression who were scheduled for routine surgery, then administered a dose of ketamine or placebo when the participants were in surgery and under general anesthesia.”

They were surprised to find that both groups experienced the large improvement in depressive symptoms usually seen with ketamine. The senior author of the study he was surprised to see the result. He quoted some participants as saying their life was changed; they never felt like that before. “But they were in the placebo group.” Both the ketamine and placebo groups saw their depression rating scores drop by half and stayed roughly the same throughout the two-week follow-up of the study.

The researchers thought it was unlikely the surgeries and general anesthesia accounted for the improvement. They theorized the positive expectations of the participants played a key role in the effectiveness reported by them. “Those who had improved more in their depression scores were more likely to think they received ketamine, even when they didn’t, implying some preexisting positive expectations for ketamine.” The senior author said this was nothing new.

Placebo is probably the single most effective, consistent intervention in medicine, full stop. It’s seen in every trial, and we should probably be paying more attention to the factors that give rise to it.

However, he said the takeaway shouldn’t be that ketamine “is just a placebo.” He thought that was a disservice to placebos. He hypothesized there may be a physiological resonance between the placebo effect and how ketamine works. “There is most definitely a physiological mechanism, something that happens between your ears, when you instill hope.” He added that the results also suggest the psychedelic experience may not be crucial to the drug’s benefits, although it likely encourages more positive expectations.

Maybe with a non-hallucinogenic psychedelic analog you can get the same benefits without having to, you know, go to outer space.

07/18/23

Repeating Past Mistakes with Esketamine

Ketamine has been touted as effective treatment for depression. A recent study by Anand et al said ketamine was “noninferior” to ECT as therapy for treatment-resistant depression without psychosis. Commenting for Medpage Today, the lead author said it was surprising that ketamine was at least at least effective as ECT, which he said is the gold standard for treatment resistant depression. Commenting on the study, Robert Freedman, MD, said it was noteworthy that all the patients considered for the study were initially referred to ECT because it was thought that ECT was their best option. But he thought the results were not life-changing: “Ketamine treatment was effective, but by 6 months, a brief period in a lifetime of depression, the quality of life was no better with the agent than with ECT.”

A longer duration of treatment increases the likelihood of both drug dependence and cognitive adverse effects, including dissociation, paranoia, and other psychotic symptoms. ECT clinics have informed consent documents that list the various cognitive and other adverse effects of that treatment. A similar informed consent document for ketamine should caution patients and clinicians that temporary relief may come with longer-term costs.

Ketamine is a psychoactive substance that makes the “gold standard” of a double-blind research methodology (neither the participants nor the researchers know which treatment participants are receiving) difficult to implement. In a new study that has not yet been peer-reviewed, Lii et al gave volunteers with mild to moderate depression ketamine while they were preparing to go under general anesthesia, essentially blinding them to the psychedelic or dissociative effects. 38.6% guessed their assignment correctly—no better than chance—indicating the anesthesia had masked the drug’s dissociative effects.

Reviewing the study for Science, Claudia Lopez Lloreda reported both groups experienced a 15-point drop in their depression scores. About 40% of the participants still had more than a 12-point decrease 3 days after the ketamine infusion, “meaning they are in remission for their depression.” That improvement was similar to the antidepressant effects of ketamine in other studies. But the doses of anesthesia used in Lii et al were much lower than that used in the other antidepression studies.

All of this suggests that neither ketamine nor the anesthesia by themselves may do much to alleviate depression, says Theresa Lii, an anesthesiologist at Stanford and co-author of the study. Instead, simply going through the complex, orderly treatment procedure itself—during which participants receive attention and one-on-one interactions with doctors and psychiatrists—benefits people. By merely participating in this trial, she says, participants in both the ketamine and placebo groups may have created an expectation that they were going to get better—and they did.

Peter Simons, who reviewed the study for Mad in America, pointed out that on the secondary outcome measure of the study, by day 3 of the follow up, both the ketamine treatment group and the placebo group had a 40% remission rate. “By the end of a week, the placebo group had 57.9% of patients in remission, compared to just 31.6% of those who received ketamine.” After two weeks, the placebo group was still doing better. The researchers suggested the placebo effect may be responsible for supposed powerful antidepressant effects of ketamine. Quoting from the Conclusion of the >Lii et al study,

Secondary and exploratory outcomes also found no evidence of benefit for ketamine over placebo. These findings differ from those of prior antidepressant trials with ketamine conducted without adequate masking, where the large effect sizes reported may reflect expectancy bias [placebo effect]. Our results suggest that ketamine may actually be ineffective for the short-term treatment of MDD.

Introducing Ketamine’s Chemical Cousin: Esketamine

Mark Horowitz and Joanna Moncrieff asked, “Are we repeating mistakes of the past?” in their article for The British Journal of Psychiatry. They were primarily concerned with esketamine, a chemical cousin of ketamine, but they began with a summary of what is known about ketamine which has been licensed as an anaesthetic for five decades. They noted patients often report several unusual symptoms when recovering from ketamine anaesthesia, including delusions, hallucinations delirium and confusion; sometimes ‘out of body’ experiences. It commonly elevates blood pressure and heart rate, and has been associated with fatal heart failure and myocardial infarction as well as stroke and cerebral hemorrhage.

Used recreationally since the 1970s, ketamine or ‘special K’ produces a dissociative state characterized by a sense of detachment often referred to as the ‘K-hole.’ See “Falling Down the K-Hole.” It’s also addictive, quickly inducing tolerance. “Stopping regular use causes a withdrawal syndrome characterised by anxiety, dysphoria and depression, shaking, sweating and palpitations, and craving the drug.” The way it produces its psychoactive and addictive effects is not entirely clear.

Intravenous ketamine was shown to have “rapid-onset antidepressant effects” in as little as 2 hours. While some researchers have claimed it leads to a genuine, long-lasting antidepressant effect, this has not been established in randomized trials. Since ketamine was already licensed for use, Janssen applied to license one of its enantiomers, (S)-ketamine or esketamine, which is more potent than ketamine. After their application was approved, Janssen received patent exclusivity on the new drug application for several years; and the profit from that approval. See the following graphic, taken from Bloomberg Businessweek comparing ketamine and esketamine.

The FDA normally requires two positive efficacy trials to license a drug, showing a statistically significant difference between esketamine and placebo. But Janssen only had one trial that was statistically significant. The three efficacy trials lasted 4 weeks, shorter than the 6 to 8-week trials the FDA usually requires for drug licensing. Janssen also defined “treatment resistant depression” in a fuzzy way that included many current antidepressant users. Participants with treatment resistant depression could be those who had “failed” with two different antidepressants.

The only positive study wasn’t really that positive. It found a difference of 4 points on the Montgomery-Asberg Depression Rating Scale (MADRS) that favored esketamine over an inert placebo. This difference corresponded to less than minimal change (a reduction of 7-9 points on the MADRS); and was one-quarter the size of the placebo response. Participants were also unmasked/unblinded by the noticeable psychoactive effects of esketamine inflating the apparent difference between esketamine and placebo.

The FDA then allowed Janssen to submit the results of a discontinuation trial as evidence of efficacy. The study design was problematical as an efficacy trial because withdrawal effects from esketamine can be mistaken for relapse of depression. Ketamine is recognized as having withdrawal effects and both ketamine and esketamine are Schedule III Controlled Substances. Yet the study report suggested there were no evidence of a withdrawal syndrome on the Physician Withdrawal Checklist. It was not clear how items on the checklist were distinguished from identical items in the MADRS.

As half (48.7%) of relapses occurred in the first 4 weeks following esketamine cessation, the time most likely for withdrawal effects to occur, and as the relapse rate in the placebo group became ‘closer to esketamine with each week’, as highlighted by the FDA, confounding of ‘relapse’ by withdrawal seems likely.

The FDA also noted a concern that the positive results were driven by a single site in Poland. There was a 100% relapse rate in the placebo group, compared with a 33% relapse rate in all the other sites. “It has been demonstrated that if this outlier site is excluded there is no difference between esketamine and placebo (the P-value changes from 0.012 to 0.48), leading to the conclusion that the findings are ‘not robust’.”

There was also disturbing evidence with how the FDA rationalized data on six reported deaths during the licensing trials. There were three suicides occurring after the participant’s last dose of esketamine. The FDA attributed these deaths to “the severity of the patients’ underlying illness.” Yet two of the participants had no indication of suicidal ideation during the study, either at entry or the last visit. Data was not available for the third participant.

Others have argued that these cases might fit with a pattern of a severe withdrawal reaction, consistent with other reports of suicide associated with recreational ketamine, and are significant enough in number to constitute a worrying signal.

An increase in depression and suicidality was also observed during esketamine treatment. Six participants in the esketamine group of the short-term trials became more depressed, compared to only one in the placebo group. Five participants expressed increased suicidal ideation in the esketamine group, compared to two in the placebo group. Paradoxically, Janssen sought and received an expansion of the use of esketamine to include acutely suicidal patients. See “Doublethink With Spravato?”

Horowitz and Moncrieff concluded that history is repeating itself: “A known drug of misuse, associated with significant harm, is increasingly promoted despite scant evidence of efficacy and without adequate long-term safety studies.” But they are not the only individuals concerned with the potential problems with esketamine-related adverse events. Gastalon et al analyzed adverse events (AEs) reported in the FDA Adverse Event Reporting system (FAERS) between March 2019 and March 2020. They found 962 registered reports of esketamine-related AEs in one year, reinforcing worries regarding the safety and acceptability of esketamine. Signals (i.e., statistically significant disproportionality) were detected for disassociation, sedation, feeling drunk, suicidal ideation and completed suicide.

When the trials submitted to the FDA are examined, serious questions with regard to the approval process of esketamine can be raised. The post approval assessment of FAERS data seems to indicate that this sloppy process set up a post marketing examination of the real-world safety and acceptability of esketamine. And it seems Horowitz and Moncrieff legitimately asked if we were repeating with esketamine the past mistakes made with ketamine.

This is the latest of several previous articles I’ve written about my concerns with using ketamine and esketamine to treat depression. In addition to the above-linked articles see “Esketamine Craze,” “In Search of a Disorder for Ketamine,” “Hype and Concern with Esketamine,” “Evaluating the Risks with Esketamine,” “Safety Concerns with Esketamine” and more on my website: Faith Seeking Understanding.

04/5/22

The Psychedelic Pendulum and Psychiatry, Part 1

© rolffimages | 123rf.com. Opened door to another dimension.

In November of 2020, Oregon became the first state to legalize the use of psilocybin in therapeutic settings. Measure 109 created a two-year time period during which regulatory details were to be worked out by the Oregon Psilocybin Advisory Board (OPAB). These details would include issues like what qualifications would be required of therapists overseeing those who chose to use psilocybin. Significantly, psilocybin treatment will not be limited to individuals struggling with mental health issues. Anyone 21 or older who passes a screening will be able to access these psychedelic services for “personal development.”

The first draft of rules recommended by the OPAB were made public in February of 2022. Manufacturers will only be permitted to cultivate one of about 200 different types of mushrooms containing psilocybin, Psilocybin cubensis. Some people were concerned with this recommendation, believing the board was also limiting potential benefits. “It is believed that different species promote different types of experiences.”

Psilocybe cubensis was chosen because it’s one of the most popular mushrooms consumed and one of the most studied. Advisory board members also thought that it would be best to start simple, with one mushroom. Other species might be introduced later.

The OPAB also recommended a ban on growing Psilocybe cubensis in wood chips. This is to prevent a rare condition known as wood lover’s paralysis that produces muscle weakness a few hours after hallucinogenic mushrooms grown in wood chips are consumed. Scientists don’t know why this condition occurs. “But it isn’t believed to happen with Psilocybe cubensis.”

The rules also prohibit the chemical synthesis of psilocybin. Measure 109 also requires the state to only license people to set up grow operations who have been Oregon residents for at least two years. Well, at least until 2025. These recommendations are attempting to allow small farmers to set up grow operations and limit the ability of large pharmaceutical companies to move in and potentially dominate the market.

There are other reasons for banning synthesized psilocybin. The synthesis requires using toxic chemicals that have to be extracted before sale so there’s no residue in the final product. Mason Marks, a member of the OPAB, said synthesizing psilocybin is a huge undertaking. “There was some sentiment that that might be maybe unrealistic or overly burdensome, at least initially to expect people to have that level of expertise or equipment in order to do that.”

Manufacturers will have to use clean, food-grade equipment in an area that can be locked. They won’t be permitted to make psilocybin products that may appeal to minors, like in the shape of cartoon characters. Psilocybin is only permitted to be used orally—not with an inhaler, a suppository or an injection. Students will have the opportunity to observe “non-ordinary states of consciousness.”

Facilitators (not therapists?) will have to take at least 120 hours of instruction, covering everything from the history of psilocybin use to safety concerns. They will have to have sufficient experience to teach classes for individuals interested in trying psilocybin. But what about ethical expectations and boundaries with clients under the influence?

Therapeutic facilitators of individuals doing psychedelic therapy from the time of its origins in the 1950s recommended two therapists, one male and one female. This was to minimize the possibility of sexual exploitation of the clients when they are under the influence of psychedelics. More about this in part 2 of the article.

These draft rules need to be discussed and adopted by the Oregon Health Authority. Other rules are still pending, such as how research with psilocybin should be conducted, and the conditions (i.e., schizophrenia) that would prohibit people from trying psilocybin treatment. There are more complicated issues that need to be decided as well. There’s a desire to permit microdosing psilocybin (taking one-tenth or one-twentieth of a normal dose), over a few days. This practice is thought to boost creativity and focus, as well as alleviate depression.

Oregon’s psilocybin system is scheduled to begin in 2023. The Oregon Health Authority will begin taking applications for licenses to manufacture, transport, deliver, sell and purchase psilocybin products on January 2, 2023.

Psychology Today has a page that introduces the reader to “Psychedelic-Assisted Therapy,” giving information on the most common psychedelic substances, their general effects and properties, as well as potential harms and proposed therapeutic uses. It also has a section on “Understanding Microdosing.” The most common psychedelic substances listed on the page were: psilocybin, LSD, ayahuasca, mescaline and MDMA. All but MDMA listed psychosis as a potential harm. Therapeutic uses being investigated include: PTSD, addiction to alcohol, tobacco and cocaine; anxiety associated with terminal illness; depression and general anxiety.

Dependence or substance misuse is not listed as a potential harm for any of the psychedelics, which do have a low risk for addiction. But the repeated therapeutic use of psychedelics increases the ritualized, long-term use of these drugs, and raises the possibility of misuse or dependence problems developing in users over time.

Information on microdosing said there was some evidence of positive effects performance and creativity, but it was mostly anecdotal. One 2018 study published in the journal Psychopharmacology, “Exploring the effect of microdosing psychedelics on creativity,” found support for its cognitive enhancing properties, but fluid intelligence was unaffected. The researchers concluded that while large doses of psychedelics can introduce several undesirable side effects, microdoses might be an alternative that could eliminate the risks of these side effects, while maintaining the benefits on emotion and thinking.

A 2016 study by Roland Griffiths et al, also published in the journal Psychopharmacology, found that when a high dose of psilocybin was administered to patients with a life-threatening cancer diagnosis under supportive conditions, there were “substantial and enduring” decreases in depressed mood and anxiety. It also resulted in increases in measures of quality of life, life meaning, the acceptance of death, and optimism. The effects were sustained for six months.

There has been a veritable flood of articles and research on the supposed benefits of psychedelics, particularly psilocybin and MDMA, over the last several years besides these two Psychopharmacology studies. In 2019, the FDA designated psilocybin therapy as a breakthrough therapy for Usona Institute, the second pharmaceutical company to gain such an approval in that year. The first company, Compass Pathways, is looking at how psilocybin may help with treatment-resistant depression, that is patients who have not improved after trying two different antidepressants. The significance of the second FDA breakthrough approval is related to how it expands the potential market from the relatively small population of individuals struggling with treatment resistant depression to the estimated 17 million with major depressive disorder, according to a statement by Usona:

This is a significant milestone for the over 17 million people in the US who suffer from MDD. Although there are several existing MDD treatments, Breakthrough Therapy Designation recognizes that psilocybin may offer a clinically significant improvement over these therapies. Psilocybin potentially offers a novel paradigm in which a short-acting compound imparts profound alterations in consciousness and could enable long-term remission of depressive symptoms.

Dr. Samoon Ahmad provided a helpful description of how psilocybin affects the brain in a Psychology Today article, “Understanding the Buzz About Magic Mushrooms.” He said psilocin, not psilocybin, seems to be the substance responsible for the psychoactive effects of “magic mushrooms.” Psilocybin and other psychedelics like LSD and mescaline activate the 5-HT1A and 5-HT2A receptors in the prefrontal cortex, which in turn has downstream effects on serotonin and dopamine. “The increase in dopamine is believed to be part of the reason for some of the psilocybin’s effects on mood, such as euphoria, and the commonly reported phenomenon of depersonalization.”

He said the probability of serious adverse events and abuse of psilocybin was low when compared to other classes of abused drugs. The association of the lifetime use of psychedelics and an increased likelihood of mental illness or suicidality “simply does not exist,” according to Ahmad. By associating “lifetime use of psychedelics” and an “increased likelihood of mental illness or suicidality,” Ahmad’s sidesteps how psychedelics can be destabilizing for some individuals who have a past history of psychotic disorders like schizophrenia. See Part 2 for more information on concerns with psychedelic psychotherapy.

Psilocybin can also produce side effects like hypertension, nausea, vomiting, anxiety, confusion and more. Ahmad also pointed out the importance of “set and setting,” the individual’s mindset and their environment.

A positive experience may inspire life-changing epiphanies and grant individuals a greater perspective on life. A negative experience may result in disturbing thoughts or hallucinations, which may lead to anxiety, disorientation, delirium, and, in extreme circumstances, temporary psychosis. Researchers have found that they can significantly diminish the likelihood of negative experiences by providing patients with more preparation and interpersonal support during the period of drug action.

There is still a risk if the interpersonal support is inadequate or inappropriate—not respecting clear, therapeutic boundaries between the support person and the client. And the preparation may not get the person ready for the actual psychedelic experience. Careful attention to the “set and setting,” the inner and outer environments of the drug event, is crucial for a positive experience.

Ahmad said research has shown that psychedelics hold a great deal of promise, “as long as they are administered in a controlled and clinical environment or under the guidance of individuals who are experienced in the use of psychedelics.” But stigma surrounds the use and research into these drugs. His hope is that there will be a loosening of restrictions and regulations in the U.S. as there is more research published, “and the case for the use of psychedelics becomes stronger.”

Dr. Ahmad and researchers like Roland Griffiths (see this Google scholar link for “Roland Griffths psilocybin”) are representative of those who see the potential for psychedelic therapy, particularly with psilocybin. Rick Doblin and his organization MAPS (Multidisciplinary Association for Psychedelic Studies) are attempting to bring MDMA to market as a treatment for PTSD see this Google scholar link for “Rick Doblin MDMA”). British researchers including Robin Carhart-Harris and David Nutt want to treat depression with psilocybin. Michael Pollan, author of a best-selling book on psychedelics, How to Change Your Mind, thought there has been a sea change in attitudes towards psychedelics. In “The Psychedelic Revolution Is Coming,” he said, “Given the mental health crisis in this country, there’s great curiosity and hope about psychedelics and a recognition that we need new therapeutic tools.”

But what are the risks in turning to psychedelics like psilocybin and MDMA as the next great hope in psychiatric drug treatment? As Andrew Jacobs noted in his NYT article, “The Psychedelic Revolution Is Coming,”

The question for many is how far — and how fast — the pendulum should swing. Even researchers who champion psychedelic-assisted therapy say the drive to commercialize the drugs, combined with a growing movement to liberalize existing prohibitions, could prove risky, especially for those with severe psychiatric disorders, and derail the field’s slow, methodical return to mainstream acceptance.

We’ll look at some of the concerns others see with the growing move towards psychedelics as the newest fad in the pursuit of therapeutic tools in Part 2 of this article. For more information on psychedelics as therapy, see the following articles on this website: “Psychedelics Are Not a Magic Bullet,” “The Long, Strange Trip of Psychedelic Psychiatry,” “Give MDMA a Chance?,” and “Psychedelic Renaissance?”

02/22/22

Risks of Ketamine for Suicide Prevention

As 2021 drew to a close, there was another study published online that evaluated ketamine’s value in mental health therapy. As other research has shown, this metanalysis found that ketamine could quickly relieve depression and thoughts of suicide. But the rapid response was usually short-lived. While there was some evidence it helped with other disorders, the evidence base was of a small number of primarily non randomized trials with short follow-up periods, which require confirmation and extension.

The study, “Ketamine for the treatment of mental health and substance use disorders,” was published in the British Journal of Psychiatry Open. The write up of the study in Medical News Today, “What 83 studies say about ketamine and mental health,” was generally positive. However, one of the study’s co-authors thought it was best administered in a clinical environment. In such a setting, people can be provided with “preparation and psychological support during and after the ketamine infusions” which can reduce the risk of adverse events. This is a methodology that follows similar attention to the “set and setting” in psychedelic drug research.

Commenting on the study, Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford, thought the research to date was not enough to determine whether ketamine was effective enough to be worth it. He said, “I haven’t seen enough real data to say that we [have] got a huge winner here.” One of his concerns was that he thought ketamine worked through an opioid mechanism, acting significantly with mu opioid receptors. In certain forms and situations “it’s highly addictive.” Opioid drugs had been used to treat depression until the mid-1950s, but were largely abandoned because of concern about abuse.

Schatzberg was the senior author of a 2018 study in The American Journal of Psychiatry that showed how ketamine activates the opioid system. The study was created after the authors saw research that suggested drugs that only worked on the brain’s glutamate system weren’t very effective antidepressants.

Speaking to NPR about the study, Schatzberg said: “We think ketamine is acting as an opioid. . . That is why you’re getting these rapid effects.” The researchers commented their findings challenged the current understanding of ketamine’s mechanisms of action and its antidepressant properties.

They designed their study to investigate whether ketamine activates mu opioid receptors. This meant they treated patients with depression in two ways. First, depressed patients were given an infusion of ketamine alone. Second, depressed patients were given naltrexone, which blocks the effects of opioid drugs, before they received their infusion of ketamine. This was not a blinded study for ketamine; it is essentially impossible to design a double-blinded study with drugs like ketamine that have dissociative side effects.

An analysis of a dozen patients who got both treatments showed a dramatic difference. Seven of the 12 saw their depression symptoms decrease by at least 50 percent a day after they got ketamine alone. But when they got naltrexone first, there was “virtually no effect.”

Dr. Schatzberg gave a talk on “Clinical Use of Ketamine in Suicide Prevention” for McLean Hospital and discussed the above research. In the slide below, taken from his talk, you see a clear antidepressant effect with the ketamine plus placebo group (K+P). When the same patients get naltrexone first (K+N), there is no evidence of a ketamine effect. The “B” graph shows the dissociative effect of ketamine was not blocked in the ketamine and naltrexone group, while the antidepressant effect was.

The anti-suicide effects of ketamine were also blocked by naltrexone, as shown in the graph below, taken again from Dr. Schatzberg’s McLean talk. This led the researchers to conclude, “the antidepressant effect of the ketamine is being mediated in some way through mu opioid receptors.”

Schatzberg noted how there have been five reports since 2018, three of which have been published, all of which show that mu opioid antagonists block ketamine’s behavioral effects. “We can show that ketamine works through an opioid effect.” He then asked, if this effect could be harnessed. In further research, Schatzberg and others looked at buprenorphine, which is a partial mu opioid agonist. At high doses (16-24 mg per day) it has an antagonist effect, blocking typical opioid effects. But very low doses, under 2 mg, have been used to treat refractory depression.

There was a 1995 study by Bodkin and Cole that investigated the potential for low doses (less than 2.0 mg per day) of buprenorphine to treat refractory depression. Its findings suggested a potential role for buprenorphine in treating depression. There was also a 2016 Israeli study by Yovell et al that looked at whether ultra-low doses of buprenorphine (.2 mg-.8 mg) could treat severe suicidal ideation.

At two weeks, Yovell et al had a dramatic reduction in suicidal ideation as assessed by the Beck Suicide Ideation Scale. This was true at the end of two weeks and at the end of four weeks. At the end of week 4, the buprenorphine was discontinued, reportedly without withdrawal symptoms at a one-week follow-up appointment. “It is possible that in this opioid-naïve population, the short duration and low dosages protected against dependence.” See the graph below taken from the Yovell et al study.

Notice that the dramatic reduction in suicidal ideation was not evident until after one week of ultra-low dose buprenorphine. Contrasting this to the rapid, within one day, antidepressant response noted above, raised a research question Schatzberg and other are currently investigating. Can you get a more immediate anti-suicide effect if you first pre-treat buprenorphine patients with ketamine?

Schatzberg and a team of researchers are looking at 60 patients with major depression and active suicidal behavior. They are repeating the Israeli experiment, but adding it after a ketamine infusion. All patients receive an open label, intravenous infusion of ketamine. Two days later, patients are randomized to receive ultra-low dose buprenorphine or placebo for 4 weeks. This research is ongoing; no results were discussed or presented in Schatzberg’s talk.

Given the previous research, it seems likely these researchers will demonstrate a rapid antidepressive reduction in active suicidal behavior. Combining ketamine and buprenorphine as Schatzberg does in this experiment will simultaneously engage two systems that seem to mediate depression and suicidal ideation—the endogenous opioid system and the glutamatergic system. However, we need to keep in mind that both of the drugs in Schatzberg’s experiment, ketamine and buprenorphine, are classified as Schedule III Controlled Substances.

The Yovell et al study suggested that ultra-low doses of buprenorphine were successfully discontinued without withdrawal. But wasn’t that after a single treatment? Studies of ketamine’s rapid antidepressant effects indicate the changes are temporary and require repeated therapeutic interventions in order to maintain an improvement in mood. In time, could tolerance and withdrawal become evident with ultra-low dose buprenorphine as it has already been shown with ketamine?

Considering the ultimate risk of suicidal ideation leading to completed suicide, it would seem to be an acceptable risk-benefit ratio as a therapeutic intervention for suicidality. But as an ongoing, repeated cycle to treat major depression, the ketamine-buprenorphine combination does not appear to be an acceptable risk to me. In time, the patient could add physical dependency concerns with ketamine and buprenorphine to his ongoing struggle against depression.

I look forward to the completion of Schatberg’s study and hope the publication of the results will address this concern. For more information on ketamine, see this review of research by The Mental Elf and other articles on this website: “Ketamine to the Rescue?”, “In Search of a Disorder for Ketamine,” and “Is Ketamine Really Safe & Non-Toxic?”

06/15/21

Evaluating the Risks with Esketamine

Esketamine, Spravato, was approved by the FDA for treatment-resistant depression in February 2019. Then on August 3, 2020, it was also approved to treat depressive symptoms in adults with major depression and symptoms other than suicidal ideation. But there have been a series of articles critical of the approvals, noting as Joanna Moncrieff and Mark Horowitz did in the BMJ, that it was licensed on flimsy evidence. They said: “The scientific community should instead be calling on the European Medicines Agency to resist the proposal to unleash another chemical on the unsuspecting public that has unproven benefits and untested harms.”

Research led by Chaira Gastaldon of the University of Verona caught the attention of Medscape Medical News in: “Serious, ‘Unexpected’ Adverse Events from Nasal Esketamine.” Gastaldon told the European Psychiatric Association 2021 Congress that esketamine “may carry a clear potential for serious and unexpected adverse events that were not reported by approval trials.” She noted that adverse events (AEs) like rapid-onset euphoria, dissociation and feeling drunk indicate there is a risk for misuse similar to ketamine. Esketamine (S-ketamine) is the left-handed isomer of ketamine.

Gastaldon and her fellow researchers collated records from the FDA Adverse Event Reporting System (FAERS) database for March 2019 to March 2020. Analysis showed that several AEs were significantly associated with esketamine when compared with other drugs. Serious treatment-related AEs were significantly more common among women; patients given higher doses of esketamine; those also taking other medications such as mood stabilizers, antipsychotics, and benzodiazepines. Gastaldon said these findings were important because esketamine was approved as an add-on medication, meaning it is to be used along with other antidepressants. Gastaldon, emphasized that these AEs were expected because they were also found in the approved trials for esketamine.

Robert McIntyre of the University of Toronto, who was not involved in the study was the lead author of an expert opinion article published in The American Journal of Psychiatry, “Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression.” The researchers concluded that while intranasal esketamine demonstrated efficacy, safety, and tolerability for up to one year in adults with treatment-resistant depression, the evidence for its long-term safety and tolerability was insufficient. He noted there is always a calculus in medicine; what are the risks and what are the benefits of a treatment. He acknowledged there is something to be concerned about at this point. “But at this stage, by no means would I say that the risk would warrant not considering giving this to a patient with depression.”

Along with other researchers, Gastaldon critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science. In “Esketamine for treatment resistant depression: a trick of smoke and mirrors?”, Gastaldon et al. questioned whether the rapid change in depression scores was due to improvement in depression or just a temporary effect of the drug on brain mechanisms. In other words, had “esketamine just modified some brain processes that impacted the depression scores, as many psychoactive substances are able to induce.”

For esketamine, understanding whether this rapid change in depression scores is due to an improvement of depression or just to a temporary effect of the drug on some brain mechanisms is of paramount relevance, as depression is a recurrent condition, and TRD is a particularly severe form of depression with symptoms persisting over long periods of time. It would be important to know if this acute effect is maintained in the long- term. For esketamine, however, long-term data are completely lacking.

Given that data on the safety of ketamine indicated the risk of abuse and associated harms, the FDA determined that a Risk Evaluation and Mitigation Strategy (REMS) was needed to see if the benefits of the drug outweigh the risks. REMS are a drug safety program required of medications with serious safety concerns. Gastaldon et al. argued that this action implied that esketamine was approved without knowledge of the potential negative consequences of esketamine prescribing. The results of the REMS could help in addressing some safety issues, “but this will require a long time and exposure of many persons with depression to this new agent.”

Reanalysis of the three efficacy trials revealed that the risk of dissociation was around 25%, almost seven times higher in the esketamine group as compared to placebo. “Again, we argue that further evidence on safety is urgently needed, given these preliminary signs suggesting that esketamine may not be safer than ketamine.”

Gastaldon also was the lead author on, “Post-Marketing Safety Concerns with Esketamine,” published in Psychotherapy and Psychosomatics. The authors concluded esketamine carries “a clear potential” for serious adverse events. “Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine [Effexor].” Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, and benzodiazepines were more likely to suffer from serious AEs.

Only the abstract of “Post-Marketing Safety Concerns with Esketamine” was available to me without paying $39 to Psychotherapy and Psychosomatics. However, Mad in America looked at Gastaldon et al.’s analysis of the FDA adverse event reports in, “New Research Questions Safety of Esketamine for Depression.” Rare AEs, not reported in regulatory trials of esketamine, such as self-injurious ideation, depressive symptoms, panic attack, paranoia and mania were detected. The most frequently reported adverse events (AEs) 5% or above were: Dissociation (9%), Sedation (7%) and Drug ineffectiveness (5%). The researchers concluded:

This study showed that the esketamine safety profile in the real-world population might be slightly different from that described in regulatory trials, and therefore further data from clinical practice would be required to better understand the safety profile of esketamine and provide an evidence-based framework for rational prescription. More real-world research is urgently needed, including pragmatic clinical trials, observational studies, and individual-participant meta-analyses on rare and unexpected AEs.

Concerns with esketamine are nothing new. There were problems noted with the FDA approval of Spravato, including only modest evidence of its effectiveness in limited trials; and no information provided on the safety of Spravato beyond 60 weeks, despite its potential for abuse. One member of the FDA advisory committee that ultimately approved Spravato thought its benefit was almost certainly exaggerated; another thought true treatment-resistant patients were weeded out of the trials. The FDA lowered the criteria bar for determining “treatment resistant depression.” Now patients had to fail to respond to two different antidepressant pills, not two different classes of antidepressants. This change meant that 49 of the 227 participants included in Janssen’s only successful efficacy trial failed just one class of oral antidepressants, not two.

Erick Turner, a member of that advisory committee, wrote about concerns he had about the efficacy of esketamine and its FDA approval for The Lancet. He noted seven concerns, including a lax definition of treatment-resistant depression, an 81% of response to esketamine with placebo, and a failure to formally demonstrate rapid onset. “In any case, only about 10% of patients who received esketamine achieved a rapid clinical response.” He wondered whether the novel mechanism of action encouraged leniency with the concerns he listed.

See “Hype and Concern with Esketamine,” “Doublethink with Spravato?” and “Red Flags with Spravato” for more on these concerns.

Not to be deterred by these findings, a group of employees of Janssen, the company that brought Spravato (esketamine) to market, responded to Gastaldon et al. in “Comments to Drs. Gastaldon, Raschi, Kane, Barbui and Schoretsantis.” Their reply was also published in Psychotherapy and Psychosomatics. They acknowledged the work of Gastaldon et al. in identifying potential safety signals related to esketamine. But they thought Gastaldon et al.’s interpretation of their findings was overstated.

In summary, our comprehensive surveillance has not revealed any new safety signal and confirms that Spravato® [esketamine] product labeling adequately addresses esketamine’s risks. Additionally, data are being collected in a prospective long-term safety study (NCT02782104). Janssen remains committed to ongoing esketamine safety monitoring via robust risk management and pharmaco-vigilance surveillance programs, including REMS, to ensure that up-to-date safety information is available to prescribers and patients.

It seems to me that this is the heart of the problem. Supporters of esketamine see its safety monitoring and REMS as providing “up-to-date safety information” to prescribers and patients. Critics see the need for a REMS as pointing out that esketamine was rushed to market without first gathering information on its potential long-term negative consequences. The drug companies themselves are responsible for managing and reporting the results of a REMS to the FDA. Can Janssen be trusted to not strategically massage the data found by NCT02782104 in order to present a favorable outcome with esketamine?

01/5/21

In Search of a Disorder for Ketamine

Interest in getting ketamine approved to treat depression persists, even after the approval of esketamine (Spravato) in March of 2019. The rapid reversal of depression symptoms was first shown with ketamine. But as it was a generic drug, there was no financial motivation for the pharmaceutical industry to invest in its potential. There is still a mystery in knowing exactly how ketamine exerts its effects. Now there is some who theorize it may help with alcoholism.

Soon after the FDA approval of Spravato in 2019, a team of researchers at Weill Cornell Medicine revealed how ketamine induced changes in the brain circuits of mice. Carlos Zarate, who was not involved in the study, said: “It’s a remarkable engineering feat, where they were able to visualize changes in neural circuits over time, corresponding with behavioral effects of ketamine.” He thought the work would help guide what treatments should be doing before they are moved into the clinical setting. The study used cutting-edge technology to visualize and manipulate the brains of stressed mice. Mice subjected to stress display the equivalent of depressed behavior and with antidepressant treatment, they often improve.

In the new study, the researchers used light microscopes to observe tiny structures called spines located on dendrites (a neuron’s “input” wires) in the mPFC [medial prefrontal cortex] of stressed mice. Spines play a key role because they form synapses if they survive for more than a few days.

STAT News said the medial prefrontal cortex is an area of the brain that is thought to be involved in depression. Research has suggested chronic stress can affect the number of synapses in the brain. The Weill Cornell researchers wanted to see if ketamine could reverse those effects. “So they looked at what are known as dendritic spines, tiny projections that shoot off branches of neurons known as dendrites. Most dendritic spines contain functional synapses, so scientists consider them a sign of a connection between two neurons.”

After giving the mice a dose of ketamine, the effects on behavior were rapid. They were more likely to attempt to escape from an unpleasant situation, preferred sugar water over plain water and explored a maze. All three behaviors are indications the mice are not stressed. However, the effects on synapse formation were slower. New synapses did not appear until around 12 hours after a dose of ketamine. This suggested ketamine’s rapid effect was not dependent on the formation of new synapses.

The researchers then used a tool that caused the newly formed synapses to collapse. Within two days, some of the behaviors of the mice reverted back to the behaviors evident during chronic stress. This suggests the new synapses and their continuation are critical to maintaining at least some of ketamine’s effect on behavior.

Zarate noted one limitation of the study was there was only a single dose of ketamine, rather than the multiple doses that occur with human treatment. Might the spines remain after weeks of repeated treatments? “Ongoing effects with repeated administration, we don’t know.” That will be the next question asked in further research.

One caution to remember there is a big difference between stressed mice and depressed humans. Anna Beyler, a neuroscientist of the University of Bordeaux, France, also added: “There’s no real way to measure synaptic plasticity in people, so it’s going to be hard to confirm these findings in humans.” Stay tuned for more mice research.

However, ketamine research is not focused solely on depression. There was a study published in Nature Communications that investigated how maladaptive reward memories (MRMs) are associated with developing and maintaining the overconsumption of alcohol: “Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories.” The researchers found that a single infusion of ketamine combined with motivational enhancement (MET) counseling can help heavy drinkers curb their drinking. Ninety people who drank an average of four to five pints of beer a day were recruited for the study.

These findings demonstrate MRM reconsolidation interference by ketamine and rewriting of reward structures surrounding alcohol. The subsequent, lasting clinical benefits observed suggest that this one-session intervention approach should be pursued in the future treatment of alcohol related disorders.

The study’s lead researcher, Ravi Das said to Merrit Kennedy of NPR: “When people become addicted, they’re learning that kind of behavior in response to things in their environment.” He added that those memories can be long lasting and become ingrained. “Current treatments don’t target those.” Das and the other researchers thought ketamine might be able to target a heavy drinker’s memories of drinking triggered just before they received a dose of ketamine. The results were said to be a dramatic decrease in the amount of alcohol consumed. “Given the high levels of problematic drinking in the current sample, one may reasonably expect similar effects to be observed in a more severely dependent/treatment-seeking population and there is now a strong rationale to conduct such clinical trials in formally diagnosed populations.”

Peter Simons reviewed the study for Mad in America, “Ketamine for Harmful Drinking: A Look at the Data.” One of the first things he noted was while the article claimed “ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories,” the results were more nuanced and not as positive as presented. “In fact, the group that did not receive ketamine had lower levels of alcohol use throughout the study.” The researchers based their experimentation on a memory-based theory of how problem drug abuse develops. According to the theory, memories of the rewards associated with drug use are triggered when a person sees the drug, which causes them to want more of it.

The theory underlying this study is that ketamine may cause short-term memory loss. But the research did not directly test this idea. Rather, the researchers looked at a broader idea—that a ketamine infusion may reduce problematic drinking.

There were three groups in the study. One group received a placebo instead of ketamine and also the alcohol memory task (RET+PBO), another ketamine and alcohol memory task (RET+KET), and the third group had no memory task and ketamine (NO RET +KET). The researchers found that the ketamine infusion and alcohol task group drank far less than their baseline levels. But they also began the study with a significantly higher baseline of drinking than the other two groups. All three groups did better over time and the group that received ketamine and the alcohol task (RET+KET), did worse than the other groups until the nine-month end point of the study, when all three groups were drinking about the same amount of alcohol. The researchers interpreted their findings as meaning that ketamine successfully reduced the amount of alcohol drank by the study’s participants. See the following chart.

However, as Peter Simon noted, “This finding is what would be predicted by chance.”

One statistical phenomenon that occurs by chance is called regression to the mean. In that phenomenon, groups that start at an abnormally high (or low) point on any scale are more likely to return to the average over time. For instance, let’s say an event occurs—like a wedding, or a holiday celebration, during which you drink much more than usual. You are most likely to return to your regular drinking amount afterward. And that’s what we see here.

The researchers do acknowledge this possibility, saying in their study, “We cannot rule out regression to the mean as a contributing factor to the observed reduction in alcohol consumption.” Yet they denied that regression to the mean was responsible for their results, calling that commonly occurring statistical phenomenon “highly unlikely.” Asserting the significance of their findings, the researchers said the lasting clinical benefits observed suggested this intervention approach should be pursued in the future treatment of alcohol use disorders.

There is another limitation to the significance of the findings in how they conceived harmful alcohol use. The researches understood problem drinking as fundamentally a learned behavior problem. “Overconsumption disorders such as harmful drinking, alcohol and substance use disorders (AUDs, SUDs), which represent leading causes of global preventable mortality and morbidity, are fundamentally acquired or learned behaviours.” Such a conception of substance use disorders is reductionistic. There is a clear element of learned behavior in the development of a drinking problem, and there is clear evidence of there being a physiological element for many individuals with alcohol use disorders (See “The Genetic Connection”).

Following the thinking of Carleton Erickson in The Science of Addiction, there is a distinction between what earlier editions of the DSM called drug abuse and drug dependence. “According to these criteria, drug abuse is intentional, ‘conscious,’ or voluntary. Drug dependence is pathological and unintended.” Alcohol dependent people have a dysregulation of the mesolimbic dopamine system and typically cannot stop drinking without intensive intervention. There is an overlap between individuals with an alcohol abuse problem and those with an alcohol dependence problem, illustrated by this chart derived from the first edition of The Science of Addiction:

Alcohol Abuse	Alcohol Dependence	Alcohol-Seeking
Mild		Little/None
Moderate		Some
Severe	Mild	A Lot
	Moderate	Even more
	Severe	All the Time

Alcohol Dependence was a continuous and compulsive pattern of use, often with tolerance and withdrawal symptoms, suggestive of a physical dysregulation. Most alcohol abusers “never become addicted in any meaningful sense.” The abuse/dependence distinction for substance use disorders was part of the DSM diagnostic system before the DSM-5. The DSM-5 collapsed the distinction between abuse and dependence, establishing a continuum of alcohol use disorder instead of two separate disorders of alcohol abuse and alcohol dependence. As a result, the above noted diagnostic distinction between abuse and dependence was lost or became unclear. The ability to discern diagnostically between learned substance problems and substance problems driven by physical dysregulation was muddled in the DSM-5.

Only individuals who were never formally diagnosed with a substance use disorder were included in the study. So, this meant that individuals who were most likely to exhibit symptoms of physical dependence, such as withdrawal, cravings and an inability to limit or control their alcohol use, were excluded from the study. Was the subject pool of participants unintentionally made up of individuals most likely demonstrate the study’s results? Were the individuals in the study heavy drinkers who were not on the way to developing what was called an alcohol dependence disorder? What works with undiagnosed heavy drinkers may not work with individuals who are alcohol dependent, who have a moderate or severe form of alcohol use disorder.

For more information on DSM diagnosis and substance use, see: Misdiagnosing Substance Use. For more information on ketamine, see: Ketamine to the Rescue?, Family Likeness In Depression Drugs? or Psychedelic Depression.

05/7/19

Psychedelic Renaissance?

Spravato (esketamine), a chemical cousin of ketamine (Special K), was recently approved by the FDA as a fast-acting antidepressant. MDMA is now in a Phase 3 clinical trial for PTSD. Psilocybin has received a breakthrough therapy designation for treatment-resistant depression by the FDA. Clinical research into the therapeutic effects of psychedelics has resumed for a variety of conditions, including depression, substance abuse and individuals living with serious medical conditions like cancer. This has led to calls for increasing the availability of psychedelics by loosening the regulatory restrictions that currently limit the drugs’ use for research.

In his book, How to Change Your Mind, Michael Pollan said beginning in the 1990s, a small group of scientists, psychotherapists and so-called “psychonauts,” have sought to resurrect what they saw as a wrongful termination of research into the therapeutic value of psychedelics. “A new generation of scientists, many of them inspired by their own personal experience of the compounds, are testing their potential to heal mental illnesses such as depression, anxiety, trauma and addiction.” Others are using psychedelics in conjunction with brain-imaging technology to explore the links between brain and mind. “The hoary 1960s platitude that psychedelics offered a key to understanding—and ‘expanding’—consciousness no longer looks quite so preposterous.”

Psychedelics are currently classified as Schedule I controlled substances, meaning they have a high abuse potential; no accepted medical use; and have safety concerns, even under medical supervision. Some advocates are calling the DEA to place them into Schedule III, along with ketamine, anabolic steroids and buprenorphine. Writing for Scientific American, Rick Strassman described his own research with DMT in the 1990s. One of the most difficult impediments he faced was DMT being Schedule I.

After nearly two years of close work with FDA and DEA, an effective system developed allowing our studies to proceed. My subsequent applications to use psilocybin and LSD were much more quickly and easily approved. The New Mexico project’s success established the current American regulatory framework that has allowed for the current burgeoning of human studies with psychedelics.

Psychedelics have unique characteristics that make it difficult to fit them into the criteria used to define schedule placement. “Their safety and efficacy exist only within highly structured specialized treatment settings.” Outside of that structure, psychedelics retain their ability for abuse and are capable of debilitating, psychological damage. “How one understands the psychedelic drug state determines the assessment of risks and benefits, and thus drives recommendations for rescheduling.” William Richards, the clinical director for the John Hopkins University psychedelics research program, publicly advocates for the increased availability of the drugs, referring to their ‘inherent spirituality’ in lectures and talks.

Glorifying psychedelics’ benefits and rendering innocuous their adverse effects therefore may explain the Hopkins group’s recent publication of a paper suggesting rescheduling psychedelics into Schedule IV—the most liberal recommendation yet to appear.

Strassman suggested a new category—IA—that would acknowledge psychedelics’ abuse potential, while allowing for their use. “The security requirements established by the DEA for possession of psychedelics for clinical research—background checks of those handling the drugs, secure storage, regular inventory, etc.—would be the same as for Schedule I substances.” Significantly, only those with specialized training would be permitted to administer psychedelics to humans. With such a regulatory structure in place, He thought the clinical promise of psychedelic drugs could be realized without exposing patients to unnecessary risk. “It would also ensure that we maintain scientific rigor, intellectual honesty and high ethical standards as we continue investigating how these drugs produce their fascinating effects.”

One study published in the Journal of Psychopharmacology did produce some interesting effects with psilocybin. Two randomized controlled trials with late-stage cancer patients suggested that a single, high dose of psilocybin had “clinically significant and long-lasting effects on mood and anxiety.” There were no serious adverse events; no participants abused psilocybin; no cases of prolonged psychosis or hallucination. “No participants required hospitalization.”

Single moderate-dose psilocybin, in conjunction with psychotherapy, produced rapid, robust, and sustained clinical benefits in terms of reduction of anxiety and depression in patients with life-threatening cancer. This pharmacological finding is novel in psychiatry in terms of a single dose of a medication leading to immediate anti-depressant and anxiolytic effects with enduring (e.g. weeks to months) clinical benefits. Even though it is not possible to attribute causality of the experimental drug (in terms of sustained clinical benefit) after the crossover, the post-crossover data analyses of the two dosing sequences suggest that the clinical benefits, in terms of reduction of cancer-related anxiety and depression, of single-dose psilocybin (in conjunction with psychotherapy) may be sustained for longer than 7 weeks post-dosing, and that they may endure for as long as 8 months post-psilocybin dosing. The acute and sustained anti-depressant effects of psilocybin in this trial are consistent with a recently published open-label study of oral psilocybin treatment in patients with treatment-resistant depression (TRD) in which psilocybin (25 mg) was associated with 1 week and 3 months post-psilocybin anti-depressant effects.

Reflecting on the results of the study, Stephen Ross, MD, the director of Substance Abuse Services at the Langone Medical Center, said it possibly provides a new model in psychiatry. “This is potentially earth shattering and a big paradigm shift within psychiatry.” David Nutt, MD, PhD, of the Imperial College London said the studies were the “most rigorous controlled studies to date” using psilocybin. Others urged caution applying and interpreting the results. Jeffrey Lieberman, MD, from Columbia University said:

[W]e cannot tell if the anxiolytic and antidepressant effects of the drugs are direct results of their serotonergic effects or secondary to the mystical altered state of consciousness that they produce. Since other serotonergic agonists (eg, lisuride) do not produce this psychedelic experience it has been suggested that psychedelic drugs must bind to the 5-HT2A receptors in a special way or exhibit functional selectivity or receptor bias.”

A study of the abuse potential for psilocybin confirmed low abuse and no physical dependence potential. The study used all 8 factors required to guide the FDA and DEA recommendations for the Controlled Substance Act (CSA). They suggested placement as a Schedule IV Controlled substance. There was “no clear evidence of physical dependence and withdrawal in preclinical or clinical studies, or among those who chronically used illicit products.” The authors said the lack of therapeutic and mechanistic studies of psilocybin and other psychedelics stems from the lack of federal funding for the research and the barriers imposed by a Schedule I classification, not a lack of interest among researchers.

While some psychedelics like psilocybin may be viable therapeutic options, there simply isn’t enough modern controlled trials. James Rucker, MD, MRCPsych, PhD, of the King’s College London Institute of Psychiatry, said: “Psychedelics deserve to be investigated in modern, controlled trials if we are to know whether they are useful treatments in psychiatry, or not . . . At the moment there isn’t enough high-quality evidence to make that judgment.”

The biggest barrier to their wider use likely stems from the lack of research. Buy there are additional obstacles in doing the research. Most pharmaceutical companies aren’t interested because of the legal obstacles with Schedule I substances and because it’s not profitable to develop treatments with these drugs. The FDA approval of esketamine as a new molecular entity (NME) is the exception. Another problem is the impossibility of using a placebo control or blinding because of the identifiable effects from psychedelics. Finally, there is the challenge of obtaining sources of psilocybin that meet the standards required for the clinical trials. Rucker said:

I think everyone in this field is interested in one thing — that psychedelics get a fair hearing by Western medicine by undergoing well-funded, well-designed controlled trials . . . Then we will know whether they have any benefit, and we can judge whether this benefit is suitably balanced against any harm they might do. Until then we won’t know, and that is a worse state of affairs than knowing.

Benjamin Bell, from John Hopkins University, wrote “The psychedelic renaissance is here.” He is a proponent of psychedelic medicine, and gave a clearly biased history of how research into psychedelics was “turned off,” after Timothy Leary made the phrase “turn on, tune in, drop out” famous. “Researchers in the field are posed at the precipice of progressing forward with revolutionary studies and may conscientiously move our culture forward with them. But moving the culture will require awareness and action from scientists and citizens.” Researchers believing that psychedelics are important and useful need to recognize how that faith is a double-edged sword “and we must remain truly willing to reconsider beliefs in light of new evidence, or it will be impossible to convince the broader public to do the same.”

Researchers have the opportunity and responsibility to properly communicate their findings and recommendations to the public. He thought this was vital if psychedelics were to be integrated into medical use within the wider culture. Meaningfully, he then said: “It is important to remember psychedelics are not the ultimate panacea for treating mental health concerns.” With time and reams of further research, they may become invaluable components of the medical and mental health toolkit. If the research is carefully and systematically done, I’d cautiously agree.

Let’s not repeat the mistake made with marijuana—failing to reschedule it so research into its risks and benefits is easier to do. The science—not the rhetoric—should be the deciding factor in the medicalization and the legalization of psychedelic substances. Rescheduling psychedelics as suggested by Rick Strassman seems reasonable and would permit the researchers holding back from doing psychedelic research to forge ahead. Some psychedelics, like psilocybin, appear to have potential while ketamine and the ketamine knockoff Spravato increasingly ring alarm bells for me because of their abuse potential and the quickness with which their effects seem to fade. For more information on ketamine and esketamine, see: “Hype and Concern with Esketamine” and “Is Ketamine Really Safe & Non-Toxic?”

03/12/19

Hype and Concern with Esketamine

Just before Valentine’s Day in 2019 an FDA advisory panel voted in favor (14 yes, 2 no, 1 abstain) of approving esketamine for the treatment of adult patients with treatment resistant depression (TRD). Psychiatry Advisor reported the decision was based on 5 Phase 3 studies. Patients in the studies had a diagnosis of Major Depression and a history of inadequate response to at least two previous antidepressants, the FDA criteria for TRD. Two of the five studies “showed that esketamine nasal spray plus a newly initiated oral antidepressant was associated with a statistically significant, clinically meaningful, rapid, and sustained improvement of depression symptoms.” So why are some experts concerned and hesitant?

In a STAT News article, Dr. Wendy Marsh said overall, esketamine is definitely of value. Dr. Eric Turner, a psychiatrist who serves on the FDA advisory committee, but couldn’t attend the recent meeting, said: “There’s sort of a split in academia. Some are cheering for something new and others are more skeptical.” Part of the concern is what the label “Treatment Resistant Depression” allows. Writing for Mad in America in “Nasal Spray for Depression? Not So Fast,” Kim Witczak said TRD is the new buzzword that allows drug companies to obtain FDA fast tracking or designation as a “breakthrough therapy.”

Such designation gives the pharmaceutical company the ability to present smaller, fewer clinical trials in order to get their drug to market quicker. While most approved antidepressants currently on the market had to show effectiveness data from at least two positive short-term trials, Janssen only presented one positive short-term trial and the second is an incomplete picture as it is from a withdrawal trial. Janssen’s other trials failed to meet their primary endpoints for efficacy.

Janssen, a subsidiary of Johnson & Johnson, submitted five Phase 3 studies: three short-term, one maintenance and one long-term safety study. One of the positive studies was a randomized trial in adults under the age of 65 with TRD who were started on an oral antidepressant and esketamine. After one month, around 70% of patients taking esketamine responded, where just over 50% in the placebo group had. The second positive study was a maintenance-of-effect study, where participants who responded to esketamine in one of the short-term studies are randomly assigned to either continue with the drug or be switched to a placebo. The FDA typically wants two successful studies, “but historically, withdrawal studies haven’t counted towards the total.”

Eric Turner said: “The threshold has been two adequate and well-controlled trials. In this case, they only got one.” Based on that, he would have voted no had he been at the meeting. Julie Zito was at the meeting and was one of the two advisory committee members who did vote “no,” thinking the risks if esketamine outweighed the benefits. If the drug was approved, she would like to see providers, patients and the families of patients keep tabs on possible side effects and how well the drug is working.

Dr. Gerard Sanacora, a psychiatrist who has been involved in several esketamine trials and has also served as a consultant to Janssen, said: “This is gonna be the big question: How do we use this in the clinic?” Current treatment protocol calls for esketamine to be given twice a week for the first month, then reduced to once a week or once every two weeks during the maintenance phase. But there are still questions about long-term treatment with esketamine, including how long to keep a patient on the medication and what the risks of long-term use might be.

Kim Witzcak also noted there were successful suicides that occurred during the clinical trials that were glossed over or presented as unrelated to esketamine. The FDA “Briefing Document” for the committee indicated there were three successful suicides; all were esketamine-treated subjects. After parsing the differences between all three cases, the Briefing Document said: “Given the small number of cases, the severity of the patients’ underlying illness, and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug-related.” Witzcak said: “In my opinion, we need more information on the potential link to suicide before an assumption can be made that it’s safe.”

The adverse events identified in the Briefing Document as of the greatest concern were sedation, dissociation, and increased blood pressure; most of which occurred within the first two hours of administration. In order to minimize the risk of misuse and abuse of esketamine, the committee has proposed the following Risk Evaluation Mitigation Strategies (REMS). The FDA can require REMS for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. “REMS are not designed to mitigate adverse events of a medication, rather, it focuses on preventing, monitoring and/or managing a specific serious risk by informing, educating and/or reinforcing actions to reduce the frequency and/or severity of the event.”

First, they would ensure esketamine is only dispensed to hospitals, certified outpatient pharmacies, and certified outpatient sites of care. A healthcare professional would monitor patients when they self-administer esketamine and then watch for transient dissociative and blood pressure changes until the patient is stable to leave the healthcare setting.

Second, pharmacies, practitioners and healthcare settings that dispense the drug would be specially certified to be sure esketamine is not dispensed directly to patients. They would be educated about the risks of esketamine and the importance of monitoring patients after the dose is self-administered.

Third, prescribers would register patients in the REMS program. “As part of the enrollment process, patients would be informed of the risks and the need for patients to report adverse events to their provider between patient visits.”

But Witzcak said she thinks most of the FDA Advisory Committee members vote for these controversial drugs and assume the REMS program will address any of their potential safety concerns. “What they fail to realize is that the REMS program is not enforceable and the drug companies are responsible for managing and reporting to the FDA.” She does not trust the drug companies and the FDA to do what they said they would do.

Eric Turner was also concerned with the hype around esketamine. He’s worried that although there is evidence that esketamine works, it will be seen and hyped as superior to other drugs for treatment-resistant depression or as a therapy that can produce rapid results—”two points he says studies don’t yet support.” Gerard Sanacora said patients will often wonder why they can’t just try the drug before seeing whether they respond to standard oral antidepressants. He is concerned the excitement over esketamine will lead patients to want it as a first-line treatment; or even a cure. “The danger is having it so positively portrayed. . . . I’ve been around enough to know this is not necessarily a condition [depression] that responds to miracle drugs.”

The drug is a chemical mirror of ketamine, used as an anesthetic and abused recreationally as “Special K.” For several decades ketamine has been known to be a drug of abuse. And in 1999 it was designated as a Schedule III controlled substance. Ketamine is abused for its dissociative and hallucinogenic effects. It also exists as a popular “club drug” used at nightclubs and raves. Like ketamine, esketamine would be a Schedule III controlled substance. Hopefully the hype over esketamine will not overshadow the potential dangers and adverse events.

On March 4, 2019 the NPR show, All Things Considered, said the FDA was expected to approve esketamine. Courtney Billington, the president of Janessen Neuroscience said if approved, it would be marketed under the brand name Spravato. While he confirmed it will only be available in approved and certified treatment centers and limited to patients who have unsuccessfully tried at least two other antidepressants, it was predicted that doctors already comfortable prescribing ketamine will continue to do so. A psychiatrist or physician can prescribe ketamine without the restrictions that will be applied to esketamine. “The generic form is cheap and can be taken at home in a nasal spray once patients know the right dose.”

Then on March 5, 2019 the FDA approved esketamine (Spravato). Johnson & Johnson, the parent company for Janessen, said the wholesale cost of each esketamine treatment will be in the $590 to $885 range, depending on the dose. As an aside, there will likely be a tolerance built with Spravato over time, requiring increased doses for the same antidepressant effect. The projected J&J price means that the recommended twice-weekly treatments during the first month will cost at least $4,720 to $6,785. Treatments afterwards will cost about half as much. A ketamine infusion directory stated the costs for ketamine infusion range from $400 to $2,000.

Spravato contains a boxed warning that cautions “patients are at risk for sedation and difficulty with attention and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.” Stop a minute and think about this. Spravato has been approved for treatment-resistant depression, and the noted side effects include misuse/abuse of the drug itself and suicidal thoughts and behaviors! And the work around coming at some point will be the development of a nasal spray device that can be used with ketamine without the restrictions applied to Spravato. In pursuit of the newest possible “treatment” for depression, FDA has crossed a boundary into territory that apparently sets aside the maxim to “First do no harm” when approving drugs. Are the risks of Spravato really worth it?

I’ve written several articles here addressing concerns with ketamine or esketamine. This is the twelfth one. See: “Falling Down the K-Hole,” “Esketamine Craze” and “Is Ketamine Really Safe & Non-Toxic?” for more information; or just search for ketamine or esketamine. You can read “Bait and Switch: the Great Ketamine ‘Breakthrough’” for a personal story about someone who almost enrolled in one of the failed clinical trials.

06/12/18

Esketamine Craze

U.S. Department of Justice photo; in the public domain

I’ve been following the research on treating depression with ketamine and its analogue, esketamine, for over three and a half years. Since I wrote “Falling Down the K-Hole,” that research has progressed—as has the hype and unbridled enthusiasm for ketamine and esketamine as fast-acting antidepressant treatments. It seems there was also a recent media blitz extolling esketamine as “a promising new depression treatment.” Not-so-coincidentally, Janssen researchers (and others) recently published the latest results of their ongoing research with esketamine in The American Journal of Psychiatry.

The American Journal of Psychiatry study by Canuso et al. reported the results of a completed Janssen clinical trial (ClinicalTrials.gov Identifier: NCT02133001). It follows another Janssen study by Daly et al. published in JAMA Psychiatry on the efficacy and safety of intranasal esketamine. The Daly et al. study reported the results of another completed Janssen clinical trial (ClinicalTrials.gov Identifier: NCT01998958).

The Daly et al. study was published in February of 2018, while the Canuso et al. study was published on April 16, 2018. The Fix published an article on the “new study” (Canuso et al.) on April 20^th, as did The Washington Post, where it was said to be a potential “major advance in the treatment of suicidal depression.” WebMD discussed the study in an article published on April 17^th, and Medical News Today published its “announcement” on April 18^th. Additional articles include ones by Business Insider, Newsweek and BBC News—all on April 16^th—to name just a few news organizations.

Janssen Pharmaceutical Companies of Johnson & Johnson is ahead in the “race” to bring its esketamine nasal spray to market as the first of a new class of psychiatric medications known as “glutamate receptor modulators,” which are also being investigated as treatments for bipolar disorder and schizophrenia. The FDA awarded esketamine “breakthrough” status in 2016, meaning it is fast-tracking the drug through the approval process. The above two linked articles report the results of Phase 2 clinical trials, while a Phase 3 trial in underway (ClinicalTrials.gov Identifier: NCT02782104).

On May 5, 2018 Janssen and J&J announced the completion of two Phase 3 Clinical Trial studies. FierceBiotech noted J&J’s intention to present the results from the studies at the American Psychiatric Association’s annual meeting the weekend of May 5^th-6^th. The study of adults with treatment resistant depression met its primary endpoint, demonstrating a statistically significant improvement in patients’ depressive symptoms. Three secondary endpoints were not met. The study of elderly patients with treatment resistant depression “narrowly missed” its primary endpoint. FierceBiotech reported J&J said the elderly patient group often has lower response rates to antidepressants, which could explain the result.

A review of the two studies by Health News Review suggested Janssen had highlighted insignificant findings alongside modest results with its esketamine nasal spray. They noted where the press release gave a good deal of information about trial protocols and specific differences in the depression scale that was used, but didn’t address cost. “While there may be promising results to report, the findings are reported in a way that makes it difficult to understand the advances — or even to tell the advances from the things that were inconclusive.”

This release is, frankly, confusing. Hundreds of words are spent describing a trial for which there were no statistically significant findings, with the pharmaceutical manufacturer arguing that the findings should be considered anyway. The release also refers repeatedly to the “newly initiated oral antidepressant” used in both the control and placebo groups for both studies, without any information about which antidepressants were used. The release does refer to two pages on ClinicalTrials.gov, which contain relevant information on the first trial and on a second trial focused on older adults. But honestly, that’s not good enough. And the failure to address cost, even in general terms, is deeply problematic. What’s more, the primary efficacy endpoint (i.e., how they could tell whether the drug worked) is described in technical terms that are difficult to parse for many readers.

Nevertheless, as FierceBiotech noted: “J&J remains confident it is on course to file the nasal spray formulation for approval in treatment-resistant depression in the second half of the year.”

The Daly et al. study in JAMA Psychiatry reported that intranasal esketamine appeared to have a rapid antidepressant effect for more than 2 months with continued, but reduced frequency dosing. The Canuso et al. study in The American Journal of Psychiatry supported the conclusion of a rapid improvement in depressive symptoms, adding there was also evidence of improvement with some measures of suicidal ideation among patients at imminent risk for suicide.

However I’m concerned the media hype on the benefits of esketamine may sometimes be running ahead of the results. You have to carefully read the above articles in order to get through the praise for the “fast-acting benefits” of esketamine nasal spray before getting to get to the limitations of the research and the concerns with using ketamine and esketamine to treat depression. One of the first limitations to realize with both Daly et al. and Canuso et al. is that all participants in those studies were still taking their prescribed antidepressants in addition to intranasal esketamine. And as with previous ketamine studies, the beneficial effects of esketamine were temporary.

There were significant improvements noted in depressive symptoms at four and twenty-four hours, but at the 3-day mark, the initial dramatic improvement had flattened out, according to The Washington Post. “And by the end of the trial, at four weeks, there was no difference between the esketamine group and the control group.” Medical News Today added that there was a significant improvement in measures of suicidal thoughts after 4 hours, “but not after 24 hours” or the end point of the study at 25 days.

BBC News reported where the Royal College of Psychiatrists said the Canuso et al. study was significant, bringing esketamine “a step closer to being prescribed in the NHS.” It also pointed out how the effects had leveled out by 25 days. WebMD said psychiatrists “were cautiously optimistic” about the potential for ketamine in treating depression. Again the limited effects were noted. They added the potential for ketamine (and esketamine) to be misused. The most common side effects among participants taking esketamine included nausea, dizziness, dissociation (a sense of detachment from reality), headache and an unpleasant taste.

There was a rare editorial signed by the majority of the board of the American Journal of Psychiatry, the journal that published the Canuso et al study. They noted how the effects of intranasal esketamine were similar to those found with intravenous ketamine. If positive, longer-duration results emerged for intranasal esketamine, “it is possible that this treatment will help a significant number of patients who do not respond adequately to existing antidepressant therapies.” After reviewing the history of what “led to a national epidemic of opioid-caused deaths,” they noted how preventing abuse was seldom raised as a concern in the rise of prescription opioid use.

Ketamine drug-seeking behavior has already appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation. Some patients use the intravenous formulation intranasally repeatedly without supervision. Diversion of ketamine intended for pediatric and veterinary anesthesia, its current approved use, is occurring already.Canuso et al. observed an attenuation of ketamine-specific clinical response over time; the failure to demonstrate longer-term benefits raises questions about the risk versus the benefit of long-term use.

The authors of the editorial referred to “A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders,” published online on March 1, 2017 by the American Psychiatric Association. The Consensus Statement only has intravenous ketamine in mind, but many of the expressed concerns also apply to intranasal esketamine. The report said its main intent was to highlight the current state of the field and the critical issues to be considered when contemplating the use of ketamine for treatment-resistant depression. The following excerpts are from the APA Consensus Statement:

Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder. Close clinical follow-up with intermittent urine toxicology screening for drugs of abuse and inquiries about attempts to receive additional ketamine treatments at other treatment centers should be implemented when clinical suspicion of ketamine abuse is present. Moreover, the number and frequency of treatments should be limited to the minimum necessary to achieve clinical response. Considering the evidence suggesting that the mechanism of action requires some delayed physiological effect to the treatment and does not appear to require sustained blood concentrations of the drug to be present, there is no evidence to support the practice of frequent ketamine administration. At this point of early clinical development, we strongly advise against the prescription of at-home self-administration of ketamine; it remains prudent to have all doses administered with medical supervision until more safety information obtained under controlled situations can be collected. Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment. The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected. The rapid onset of robust, transient antidepressant effects associated with ketamine infusions has generated much excitement and hope for patients with refractory mood disorders and the clinicians who treat them. However, it is necessary to recognize the major gaps that remain in our knowledge about the longer-term efficacy and safety of ketamine infusions. Future research is needed to address these unanswered questions and concerns.

Clearly, the American Psychiatric Association is concerned with longer-term efficacy and safety concerns with ketamine, particularly its potential for misuse and abuse. But that isn’t the end of concerns for ketamine and esketamine.

Janssen said esketamine belonged to a new class of drugs in psychiatry known as “glutamate receptor modulators.” They speculated that esketamine could “help restore synaptic connections in brain cells in people with major depressive disorder.” Yet two Cochrane studies questioned the efficacy of ketamine and other glutamate receptor modulators for depression and bipolar depression. Cochrane is a global independent network of researchers, professionals, and others who “work together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest.” Their work is recognized as an international gold standard for high quality, trusted information.

“Ketamine and other glutamate receptor modulators for depression in adults,” by Caddy et al., sought to find out if ketamine and other glutamate receptor modulators were more effective than placebo or other antidepressants and whether they were more acceptable than placebo and other antidepressants. Only ketamine was more effective than placebo at reducing symptoms of depression. However, “These effects lasted no more than one week after treatment and clearly disappeared after two weeks.” Ketamine also caused more confusion and emotional blunting than placebo. “There was no evidence of a difference between the other nine glutamate receptor modulators included in this review and placebo or other medications.” The review concluded there was limited evidence that ketamine reduced symptoms of depression when compared to placebo.

“Ketamine and other glutamate receptor modulators for bipolar depression” sought to answer the same questions, namely if ketamine and other glutamate receptor modulators were more effective than placebo or other antidepressants and whether they were more acceptable. It was possible that ketamine could be an effective add-on medication to mood stabilizers for people with acute bipolar depression, “but due to the small amount of data usable for analysis we are unable to draw any firm or reliable conclusions.

Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression. Overall, we found limited evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did not show any better efficacy in terms of remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. Ketamine’s psychotomimetic effects could compromise study blinding; this is a particular issue for this review as no included study used an active comparator, and so we cannot rule out the potential bias introduced by inadequate blinding procedures.

A very small pilot study done by the Black Dog Institute in Sydney Australia was published March 15, 2018 in the Journal of Psychopharmacology. The study sought to investigate how repeated use of intranasal ketamine might work for patients with severe and treatment-resistant depression. All participants were trained to self-administer the ketamine nasal spray; the process was similar to other commonly used nasal spray medications. But the study participants could not get through the needed ten sprays to get the full dose.

As soon as the ketamine hit their bloodstreams, the subjects started losing motor coordination, which got so bad that none of them managed to do all the sprays without the help of research staff monitoring the treatment. When the researchers tried to space out the nasal sprays with a five-minute interval, things only got worse – the subjects’ blood pressure shot up, and they started experiencing psychotic-like effects as well.

The study had to be cut short because of the adverse side effects. The researchers pointed to an earlier ketamine nasal spray trial where the drug was well tolerated. They speculated the 2014 trial had better tolerance because of a lower dose (50mg instead of 100mg) and their study’s participants being trained to use the nasal spray, resulting in their subjects ending up with higher levels of the drug in their blood streams. “Our results suggest that absorption via the intranasal mucosa may be too rapid when careful attention is paid to the administration technique, resulting in the development of rapid and intense side effects.”

So despite the hype and unbridled enthusiasm for the potential of ketamine and its analogue esketamine as fast-acting antidepressant treatments, the existing evidence is not conclusive. And the safety and efficacy concerns, particularly with regard to long-term use and addiction, are not known. Existing evidence with intravenous ketamine suggests the real potential for abuse. And it doesn’t look like it will be a good idea for subjects to self-administer intranasal ketamine or esketamine in the privacy of their homes.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: ketamine