Tag: FDA

07/18/23

Repeating Past Mistakes with Esketamine

image by Owensart from Pixabay

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 In a new study that has not yet been peer-reviewed, Lii et al gave volunteers with mild to moderate depression ketamine while they were preparing to go under general anesthesia, essentially blinding them to the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.

12/31/19

Keeping ALKS 5461 Out of the Spotlight?

© Daniil Peshkov | 123rf.com

Alkermes has been stubbornly attempting to gain FDA approval for ALKS 5461 as an adjunctive treatment for major depression. After the FDA informed Alkermes it was refusing to review the NDA (New Drug Application) for ALKS 5461 on March 30, 2018, it rescinded its refuse-to-file letter, and said it would review an NDA for ALKS 5461. The target action date was set for January 31, 2019. The Chief Medical Officer at Alkermes noted there have been no new pharmacological treatment approaches for depression in 30 years and said, “FDA’s filing of the ALKS 5461 application is a positive step forward for patients suffering from major depressive disorder.”

Strategically, at the end of October 2018 Molecular Psychiatry published an article that indicated buprenorphine/samidorphan (ALKS 5461) was “a promising potential adjunctive treatment for patients with MDD.” In one clinical trial, FORWARD-5, adjunctive ALKS 5461 (BUP/SAM 2mg/2mg) consistently reduced depression symptoms compared to placebo across multiple timepoints in patients continuing their current antidepressant therapy (ADT). And it met the primary endpoints of reducing core and overall depression symptoms. In the previous FORWARD-4 clinical trial the primary endpoint of change was not statistically significant; it failed to meet its primary endpoint of change. But in post hoc analysis it did demonstrate greater reduction in MADRS-10 scores than placebo at all timepoints in both stages. “Reductions in symptom scores at multiple timepoints are consistent with the observed efficacy in FORWARD-5.”

This post hoc-analysis was bit like cheating, in that it reanalyzed the data from FORWARD-4 after the fact, and found one aspect of the trial with a significant result. Alkermes used the finding to “update” their methodology for FORWARD-5 to match the post-hoc analysis. It then attempted to argue that despite failing to meet its primary endpoints in the two previous phase III clinical trials, the FDA should approve ALKS 5461. See “The ‘Hotel California’ Effect” and “Nearsighted Drug Development” for more on the problems with this process.

Then on November 1, 2018 the results of the meeting of two combined FDA committees, the Psychopharmacologic Drugs Advisory Committee and the Drug Safety and Risk Management Advisory Committee was released. The Committee voted unfavorably for ALKS 5461. There were three core questions. Has there been substantial evidence presented to support the effectiveness of ALKS for adjunctive treatment of major depression? The vote was against the first question, 20 to 3. The second question was: Has Alkermes adequately characterized the safety profile of ALKS 5461 for adjunctive treatment of major depression? The vote was for the question, 13-10. The third question was also answered negatively, Do the data show a favorable benefit-risk profile of ALKS 5461 to support approval? The vote was against, 21 to 2.

Healio Psychiatry went on to note several concerns of the Committee. The FDA did not agree with Alkermes that the studies met the standard for substantial evidence for effectiveness. Three of the studies used a novel study design: a 2-stage, sequential parallel comparison meant to reduce the higher placebo response often seen in antidepressant studies. This was the first time a sequential parallel comparison design was submitted to the FDA to provide evidence of efficacy for a new drug. “This design has not yet been determined to be statistically acceptable to the FDA.”

Usually studies for antidepressant treatments examine an efficacy endpoint at a specific time point following several weeks of therapy, according to the FDA. These trials achieved primary endpoint because researchers averaged patients’ depression symptoms over multiple weeks, which is not standard for antidepressant trials. Although averaging scores from multiple weeks can reduce the symptom changes that often vary over time throughout treatment, scores at the final time point carry less weight.Although one of the phase 3 studies met its primary endpoint, the committees expressed worry because the trial investigators used an abridged 6-item version of the Montgomery Asberg Depression Rating Scale-10 for the primary endpoint of this principal study. The FDA’s Clinical Outcomes Assessment staff believe MADRS-6 cannot replace the MADRS-10 because it excludes concepts important in major depression, like reduced sleep, reduced appetite, concentration difficulties and suicidal thoughts, according to the review.

So MADRS-6 would not include data on the excluded depressive symptoms such as reduced sleep, and appetite, concentration problems, and significantly, suicidal ideation. Averaging scores would hide a pattern of progressively lower scores throughout the trial, suggesting the antidepressant effect of ALKS 5461 gets weaker over time and will eventually be no better than placebo—not the efficacy pattern to demonstrate when trying to have a NME approved by the FDA. Given the novelty of the methodology used in these clinical trials and the significance of the excluded depression symptoms, the FDA made it clear to Alkermes that any studies using the MADRS-6 would be “considered exploratory.”

The use of an opioid, buprenorphine, was also a concern of the committee. Given the growing opioid epidemic, there were concerns about use, misuse and abuse of buprenorphine. Predicting what might happen in patients being treated for depression is challenging due to the high-risk nature of the populations being treated. “It is not known whether similar misuse and abuse patterns will be seen.”

Finally on February 1, 2019, the FDA said it was not able to approve ALKS 5461 in its present form and requested additional clinical data (likely another clinical trial) to provide substantial evidence for its effectiveness. A review of the Alkermes website on October 12, 2019 failed to see ALKS 5461 listed in its Pipeline under Research and Development. But that doesn’t mean Alkermes has given up on it. There are two active clinical trials for ALKS 5461 listed on Clinical Trials.gov; one of which is recruiting. Its primary outcome measure is a change from baseline in the MADRS scores; the time frame is 11 weeks. The other trial is by invitation, and is a long-term study. The time frame is up to 68 weeks. Both are projected to be completed in 2021 and both have been updated after the FDA sent its complete response letter on February 1st.

It could be that Alkermes terminated these clinical trials after the FDA response letter, but why update the information on ClinicalTrials.gov? If Alkermes is still working on the studies, why does it not have ALKS 5461 listed in its Pipeline? It does not seem that ALKS 5461 is dead yet. One of the studies (clinical trial NCT03188185) apparently plans to use the same parallel assignment method used in FORWARD-4, which the FDA said it had not yet determined was statistically acceptable. The MADRS will be used for its primary and secondary outcome measures, but does not specify whether it will be MADRS-6 or MADRS-10. One of the listed outcome measures is the Columbia Suicide Severity Rating Scale, for suicidal ideation and behavior, but that isn’t necessarily suggestive Alkermes plans to use the MADRS-6.

It is possible that Alkermes is going ahead with a final attempt to gain FDA approval for ALKS 5461, but is trying to keep its efforts quiet and out of the media spotlight. We’ll have to wait and see.

11/12/19

Kratom Has Benefits and Risks

© AndreyPopov | stockfresh.com

The State of Ohio Board of Pharmacy (BOP) voted to classify kratom as a Schedule I controlled substance alongside heroin, LSD and other substances. “The board concluded kratom has a high potential for abuse, has no accepted medical use, isn’t safe to use in medical treatment and poses a public health risk.” This led to efforts from pro-kratom organizations, such as the American Kratom Association (AKA), to oppose the scheduling. Instead of a ban, it recommended regulation that would make it illegal for minors, require product labeling, and regulate for quality and purity. Then on August 9, 2019, after a public hearing, the state Board delayed that action in order to review testimony presented

Hundreds of people showed up to give testimony at the public hearing on August 5th. One man, in constant pain after three open heart surgeries, said the pain caused him to miss time with his family. “Being a part of my kid’s life is important to me so I mean, it killed me not to be able to attend stuff.” He said his life was changed when he found kratom as he was once again able to attend his son’s football games, pain free. “Honestly it’s sad and pretty pathetic that our government, or the pharmacy board would be pushing so hard to ban it and it doesn’t make any sense.”

The AKA held a press conference with a John Hopkins University professor, A Utah State Senator, an Arizona State Representative and a Georgia State Representative all urging the Ohio BOP to withdraw its proposed ban on kratom.  The Board decided “to put the kratom ban in a To Be Refiled (TBR) status and it will not be the subject of a Hearing before the Joint Committee on Agency Rule Review (JCARR) on Monday.” When the BOP announced the delay before baning kratom, the American Kratom released the following statement:

The American Kratom Association is deeply grateful to the Ohio Board of Pharmacy for listening to the pleas of the hundreds of Ohioans who provided testimony at the Public Hearing today, and responding to the thousands of email testimony provided by those who could not attend the Hearing in person. The decision to put this proposed ban on kratom in the “To Be Refiled” status will provide the opportunity for the Ohio Legislature to consider the Kratom Consumer Protection Act that Representative Gary Scherer intends to file in the coming week.  That legislation protects consumers and provides an appropriate regulatory framework to ban adulterated and mislabeled kratom products that are responsible for the deaths and adverse health impacts from using kratom laced with dangerous chemicals and opioids.  The AKA will work closely with the Board of Pharmacy and the Ohio Legislature to enact these regulatory schemes to protect consumers.  Utah, Arizona, Georgia, and Nevada have already enacted the Kratom Consumer Protection Act, and it is being considered in another dozen states currently. Our deepest appreciation to policy makers in Ohio who listened, understood, and stood with Ohio residents to allow consumers to use this plant for their health and well-being.

The BOP has been working on the process to make kratom a Schedule I controlled substance since September of 2018. Now that final stage in the scheduling process will have to wait until after the board’s September meeting. The delay could potentially allow Ohio lawmakers to regulate, rather than ban kratom. Rep. Gary Scherer said he’s filing a bill to regulate kratom based on regulations passed in Utah. “This will give the Board time to review all testimony at its September meeting and assess potential new legislation that was introduced on the matter.” Kratom advocacy groups can look on the delay by the Ohio Board of Pharmacy as a temporary victory, but despite the many positive testimonials at the hearing, there are serious legitimate concerns with kratom.

If you are worried about the risks of unscheduled or unregulated kratom, placing it as a Schedule I controlled substance may ultimately backfire by creating too many bureaucratic hurdles for sound, reliable kratom research to get over. Given the accumulating evidence of the potential risks with kratom, the above-proposed legislative regulation also seems to be too loose. The monitoring of kratom use and sales could be tightened through legislation, but let’s be sure to do the research and not make a decision based upon the political pressure of advocacy groups. Henry Spiller, the director of the Central Ohio Poison Control Center, said: “There’s a general feeling, I think, that this is a natural substance, so it is safe. But we need to get across there are risks with this.”

Within its rationale to schedule kratom, the BOP cited studies suggesting that kratom users can develop a dependency on the drug and asserted it had “no acceptable medical use in treatment,” another requirement for Schedule I classification. This claim is based on an FDA report that underscored kratom’s potential for abuse. Using the Public Health Assessment via Structural Evaluation (PHASE) methodology, the FDA concluded that the 25 most prevalent compounds in kratom “have the most structural similarities with controlled opioid analgesics, such as morphine derivatives;” 22 (including mitragynine) of the 25 compounds in kratom bind to mu opioid receptors. “This model, together with previously available experimental data, confirmed that two of the top five most prevalent compounds (including mitragynine) are known to activate opioid receptors (“opioid agonists”).” The FDA Commissioner Scott Gottlieb said he was concerned with the use of kratom to treat opioid withdrawal, saying there was no reliable evidence to support it.

We have been especially concerned about the use of kratom to treat opioid withdrawal symptoms, as there is no reliable evidence to support the use of kratom as a treatment for opioid use disorder and significant safety issues exist. We recognize the need and desire for alternative treatments for both the treatment of opioid addiction, as well as the treatment of chronic pain. The FDA stands ready to evaluate evidence that could demonstrate a medicinal purpose for kratom. However, to date, we have received no such submissions and are not aware of any evidence that would meet the agency’s standard for approval.

Commissioner Gottlieb went on to say the FDA has been monitoring the use of kratom for several years and placed kratom products on an import alert to prevent them from entering the country illegally. He said these actions were taken on a body of academic research that suggested there could be harm associated with its use. “And we are not alone in our evaluation and our public health concerns. Numerous countries, states and cities have banned kratom from entering their jurisdictions.” Dismissing FDA concerns as disinformation and accusing it of using bad science to justify scheduling kratom seems to be itself disinformation.

There was a paper published in the July 2019 issue of the journal Pharmacotherapy, “Kratom Use and Toxicities in the United States.” It was a retrospective study of data reported to the National Poison Data System. The review was conducted to determine toxicities associated with kratom use in the United States “in order to provide insight into its safety as a dietary supplement.” The authors concluded kratom use was associated with significant toxicities. They said their findings suggested kratom could not reasonably be expected to be safe and it posed a public health threat due to its availability as an herbal supplement. The results of the study were:

A total of 2312 kratom exposures were reported, with 935 cases involving kratom as the only substance. Kratom most commonly caused agitation (18.6%), tachycardia (16.9%), drowsiness (13.6%), vomiting (11.2%), and confusion (8.1%). Serious effects of seizure (6.1%), withdrawal (6.1%), hallucinations (4.8%), respiratory depression (2.8%), coma (2.3%), and cardiac or respiratory arrest (0.6%) were also reported. Kratom was listed as a cause or contributing factor in the death of four decedents identified by the county medical examiner’s office.

The lead author of the study, William Eggleston, said although kratom was not as strong as some prescription opioids, it still acted as an opioid in the body. “In larger doses, it can cause slowed breathing and sedation, meaning that patients can develop the same toxicity they would if using another opioid product. It is also reported to cause seizures and liver toxicity.” While kratom may have a role in treating pain and opioid use disorder, but more research was needed on its safety and efficacy. Eggleston and his team are working to better assess how many people are actually using kratom and if the risk for toxicity changes contingent with the dose of kratom taken.

Making kratom a Schedule I controlled substance will obstruct research into its potential medical uses. If “Kratom Saves Lives,” as the t shirts worn by AKA supporters at the press conference claimed, then it should be regulated it in a way to restrict indiscriminate availability because of adverse effects like those described above. Kratom regulation is needed for more than just to protect consumers from “adulterated and mislabeled kratom products that are responsible for the deaths and adverse health impacts from using kratom laced with dangerous chemicals and opioids.” There are legitimate safety concerns with kratom and the FDA’s ability to regulate it are currently limited because as a dietary, supplement, it is not subject to the same safety regulations as FDA-approved drugs.

A CDC report from 2016 said kratom was “an emerging drug of concern.” Published case reports associated kratom with psychosis, seizures, and deaths. The report study said 24.5% of the reports on adverse events were for minor complications; 41.7% required some treatment and were considered to be moderate complications. There were major complications—meaning life-threatening signs or symptoms, with some residual disability—for 7.4% of the kratom exposures. The adverse effects included: tachycardia [abnormally rapid heartbeat] in 25% of the reported cases, agitation or irritability in 23.8%, drowsiness in 19.4%, nausea in 14.7% and hypertension in 11.7%. There are also reports of liver damage and withdrawal. The science confirming adverse effects and supporting the scheduling of kratom as a controlled substance is not as weak as claimed. Allow research to be done that demonstrates and confirms its medical benefits and its adverse effects.

See also “The Secret of Kratom,” and “Noose Tightening on Kratom” on this website for more information on kratom and its regulation.

10/1/19

Doublespeak with Abilify MyCite

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Abilify MyCite was approved by the FDA in November of 2017, but it isn’t being used much. At least one expert said that was because the antipsychotic pill contains a tracking chip the size of a grain of sand that confirms whether or not an individual actually takes the medication. A psychiatrist from Columbia University said people with psychotic disorders often struggle with some degree of paranoia, believing that outside forces are trying to monitor and control them. “The idea that we’re giving this group of patients a pill that, in fact, transmits info about them from inside their body to the people that are involved in their treatment almost seems like a confirmation of the worst paranoias of the worst patients.”

The Daily Mail reported medication nonadherence is a particular problem for doctors treating schizophrenic patients. Otsuka Pharmaceuticals replied that people who are afraid of their medicine, are not likely to be given Abilify MyCite. The medication is supposedly designed for people who ask for it as a way of improving their mental health. A spokesperson for Otsuka said, “It’s really about patients who want to improve their treatment goals. If they have any concerns, it’s probably not the right solution for them.”

Really? A medication that tracks when you have taken your medication is for motivated clients who want to improve their treatment goals, meaning to be more compliant with taking Abilify MyCite? What about patients who seek to minimize or eliminate the adverse side effects from the medication, including weight gain, agitation, unusual urges, akathisia (a feeling of inner restlessness), and more, including thoughts about suicide?

An individual who participated in the clinical trial for Abilify MyCite and who was compliant with his medication hasn’t had paranoid thoughts in a long time. He said that if he had an opportunity to take ‘digital Abilify,’ “I wouldn’t take it.” See, “Biomedical ‘Big Brother’” for more on the adverse side effects of Abilify and other antipsychotics.

The metallic tracking chip contains copper, magnesium and silicon sends a signal to a patch worn on the patient’s arm. It is activated when it becomes immersed in stomach juices, completes a circuit and generates a small electric charge. “The patch then synchronises with a mobile app on the patient’s smartphone or tablet, and sends data to their doctor over the internet to show whether the pill has been taken.” Ingestion is recorded between 30 and 120 minutes after the patient swallows the drug.

The BMJ Evidence-Based Medicine journal published research by Lisa Cosgrove and others that analyzed evidence submitted to the FDA for approval of digital arpiprazole (Abilify MyCite). This was the first such drug-device combination to receive FDA approval, and it “sets a precedent for how technology-enhanced products will be evaluated before marketing.” The authors also said it was important to examine how the clinical trial evidence supporting this approval was represented in news stories and reports. Recent research had documented the presence of ‘spin’ (distorted interpretation of trial evidence) when the results of clinical trials are reported in journals and news reports. This spin gives the impression of there being a greater benefit to the drug than is warranted by the data in both media reports and the scientific literature.

Their review of the clinical trial data submitted to the FDA for the approval of Abilify MyCite revealed the data were limited to trials that “simple assessed whether patients could use the product as intended.” There was no evidence of superiority or non-inferiority compared with non-digital versions of arpiprazole, other antipsychotics or placebo. In the FDA’s clinical review letter, one simulated trial (where the participants did not ingest the drug, but simply placed it in a container to simulate ingestion) provided no additional data about adherence or regarding transmission times. “Considering these limitations, the most accurate statement regarding Abilify Mycite’s capabilities is that ‘Abilify MyCite successfully tracks ingestion of aripiprazole with embedded sensor.’” The lack of even a single comparative trial was said to mean “there is no way to know whether digital aripiprazole improves treatment adherence, quality of life, psychiatric symptoms or remission.”

Patients with serious psychiatric illnesses often suffer from paranoia. An ingestible drug with a sensor brings surveillance to a new level, and the potential negative effects on this patient population merit careful consideration. The potential harm of the surveillance aspect of this technology to the therapeutic alliance and to patients has not been adequately assessed. Thus, it is reasonable to ask if there was a financial rather than a scientific impetus for choosing aripiprazole as the first-ever digital drug.

Before it went off patent in 2015, Abilify made over $7.5 billion. It was the best-selling drug in the US for 2014 with an average cost of $800 for a month’s supply. After the patent expired, sales of arpiprazole dropped to $600 million in 2015, which was when Otsuka and Proteus first submitted an application for market approval for digital arpiprazole. The cost for a month’s supply of the Abilify MyCite is $1,650. In comparison, the generic oral version of arpiprazole costs less than $20 per month. In order to avoid this dramatic loss in revenue, pharmaceutical companies have developed several different schemes.

Drug manufacturers have developed a number of strategies to extend market monopoly after a blockbuster drug (defined as over US $1 billion in yearly revenue) goes off-patent. These are known as ‘evergreening’ strategies, with highly questionable benefit to patients. Evergreening involves the patenting of a slight modification (eg, subtle changes to the medicine’s structure) of an existing drug as a new invention. For the manufacturer, the result is that their product is considered as a new chemical entity that qualifies for market exclusivity (ie, no generic version is available). The possibilities afforded by sensor-based technology make room for a new dimension of practice, an evergreening 2.0. That is, ‘digital evergreening’ may develop as a means whereby manufacturers can gain market exclusivity for a generically available medicine (such as aripiprazole) by combining it with a monitoring technology.

Cosgrove et al added to the growing body of literature documenting the extent and effects of spin in the scientific literature and in media reports by noting the affiliation of authors with the parent pharmaceutical company, Otsuka. Researchers searched the Web of Science to identify all publications in English citing the clinical trials for arpiprazole. Then they reviewed the database NexisUni for all news stories and press releases about the approval of Ability MyCite from January 1, 2015 to January 23, 2018. The researchers defined spin as ‘a specific way of reporting, intentional or not, to highlight that the beneficial effect of the experimental treatment [digital arpiprazole] in terms of efficacy or safety is greater than that shown by the results.’ They identified 70 articles and two press releases which met their inclusion criteria for their study.

Of these, 57% (40/70) did not acknowledge the lack of efficacy data from RCTs [randomly controlled trials], 93% (65/70) did not report on the scarcity of safety data, and no story reported on the absence of a non-digital comparator in clinical trials. Three-fourths (52/70) conveyed an impression of benefit without mentioning the lack of research to support that impression. Most of the news stories (77%, 54/70) cited an expert, and of those 39% (21/54) cited experts who had financial ties to either Otsuka or Proteus.

Not only were some authors of the published studies Otsuka employees, there was evidence of ghost writing in the dissemination of the trial data: “’Editorial assistance was provided by the medical communications company C4 MedSolutions LLC (Yardley, PA, USA), a CHC Group company’, with Otsuka funding.” Both of the positive clinical trial studies were published in the journal Neuropsychiatric Disease and Treatment, whose editor is described as an ‘independent pharma consultant [who] advises and consults worldwide to several pharmaceutical and venture capital organizations’.

Our case study reveals that the approval of this digital drug for marketing in the USA was granted on very limited data. Both the scientific literature and the popular news reports conveyed an unsupported impression of benefit. As a result, the general public and healthcare professionals may be making medical decisions based on industry-friendly, but not necessarily scientifically accurate, information about the efficacy and safety of this new product. Also, if patients are incentivised to take the digital version (eg, by being offered lower copayments or by being offered outpatient treatment—rather than forced inpatient treatment), the line between incentivising and coercion will be blurred. We recommend that other regulatory bodies (eg, the European Medicines Agency) take note of the findings in the current study as well as the medicolegal issues that emerge with the use of digital drugs.

The authors suggested the general public and healthcare professionals may be making medical decisions based on industry-friendly, but scientifically inaccurate, information about the safety and efficacy of Abilify MyCite.

Please do not let the allure of a new pharmaceutical technology seduce you. This doublespeak about how digital arpiprazole will improve your treatment goals, is simple marketing rhetoric. Also do the math, one month of Abilify My Cite is $1,650 and a generic pill will cost you less than $20 per month. The savings leaves you enough to hire a skilled mental health coach and have an even better chance of improving your treatment goals.

09/3/19

Red Flags with Spravato

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Spravato (esketamine) was approved as a fast-acting antidepressant for treatment-resistant depression in March 2019. There were several problems with the FDA’s approval of the drug, including the price—nearly $900 per dose, the acceptance of a withdrawal study for the needed second positive clinical trial, and the fact that it carries a boxed warning that cautions patients are at risk of “suicidal thoughts and behaviors after administration of the drug.” And like ketamine, it is a Schedule III controlled substance, putting patients at risk for abuse and misuse. It seems Spravato needs some positive spin to win a patient population.

Dr. John Miller obliged, writing an article for Psychiatric Times, “Depression’s Journey From Monoamines to Glutamate.” He traced the history of ketamine as a racemic mixture, meaning it has an equal mixture of esketamine and arketamine. Janssen developed its intranasal spray with esketamine and named this new molecular entity Spravato. The so-called “paradigm shift” of depression treatment with ketamine acting on the NMDA glutamate receptor, and appearing to reduce depressive symptoms within 72 hours, was contrasted with the older, traditional monamine hypothesis of depression that would take weeks. All other FDA-approved antidepressants before Spravato act on the monoamine system.

Dr. Miller then guided his readers through a review of the two positive clinical trials submitted to the FDA for approval of Spravato. There were actually five phase 3 clinical trials, meaning Spravato failed to demonstrate statistical significance in three of the five clinical trials. Nevertheless, he saw Spravato as crossing into “a new paradigm of TRD [treatment resistant depression].” He hoped esketamine was the first of “a long list of non-monoamine-based treatments to help improve the lives and functioning of the many individuals suffering from TRD.” By the way, Dr. Miller is on Janssen’s Advisory Board as well as the Speaker’s Bureau for Spravato.

Another study by Daly et al, “Efficacy and Safety of intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression” found a “clinically meaningful treatment effect” versus placebo. The antidepressant response was rapid and dose related. It seemed to persist for more than 2 months with a lower dosing frequency. Jodi Rintelman reviewed the study for The Mental Elf, and said it gave hope for a fast-acting antidepressant. Depression scores showed statistical improvement in seven days. “That’s a huge improvement over SSRIs, which can take 4 to 8 weeks to show significant improvement in mood.”

CEP (Council for Evidence-Based Psychiatry) pointed out on Twitter how the Mental Elf article initially failed to note that eight of the study’s authors were Janssen employees. In the comments section to the blog, Andre Tomlin then cited two paragraphs quoted below that appeared in the blog article afterwards. The first was added to the Strengths and Limitations section and the second was in the Implications for Practice section.

The authors also may have a vested interest in Spravato’s commercial success. Renaissance Pharmaceuticals, LLC is manufacturing Spravato for Janssen Pharmaceuticals, Inc. Eight of the authors, including the lead author, work for Janssen Research & Development and hold stock in the company. As the U. S. Food and Drug Administration continues to provide less money for drug development, drug companies are picking up the slack. The impact of this funding trend on our patients is not yet known.

It’s important to note that while no deaths were reported in this trial, in the trials reported to the FDA for consideration, there were six deaths in the treatment arms. While none of the deaths were proven to be drug-related, three people died from suicide, one from a motorcycle accident, one had a heart attack, and the sixth person likely died as a result of complications from hypertension and obesity.

Then Bloomberg reported President Trump offered to help the Department of Veterans Affairs to negotiate the acquisition of Spravato, saying he had “really read quite a bit” about the drug and believed it could help reduce the suicide rates of veterans. He told the Veteran Affairs Secretary, Robert Wilkie, he thought Johnson & Johnson (the parent company of Janssen) would be very generous to the VA. The President said:

Give it to anybody that has the problem, because you have people calling and our folks do a great job on the phone — but it’s a telephone. . . . You have people calling for help and if those people had that, I’m hearing like instantaneously they’re in better shape.

Wilkie acknowledged the medicine was “very effective” and hoped Spravato would have the drug in all VA hospitals by the end of the year. But concern that the President’s remarks were contributing to a rushed approval by the VA, led Mark Takano, the Chairman of the House Committee on Veterans’ Affairs, to say:

I am incredibly alarmed by reporting today that suggests Spravato, a controversial new drug, is being rushed through critical reviews and may be prescribed to veterans before fully vetting the potential risks and benefits.

Already, many concerns have been raised about the drug’s safety and efficacy, its suspicious fast-track approval through FDA review, and VA’s contracting process. Today’s reporting raises additional concerns that VA’s own process for objective review is being undercut by undue influences.  Questions remain about the ultimate impact on the health and safety of veterans, who should not be made into a “test case” while the clinical community continues to gather data about this treatment.

We demand that VA provide documents and information about its review and contracting process to adequately address critical questions—including whether VA officials were pressured by the White House or the Mar-a-Lago “three” to prescribe this drug to veterans. Spravato should not be added to VA’s formulary until we have more answers about what this means for our nation’s veterans.

The VA announced that it would offer Spravato for treatment-resistant depression, but would not include it on the VA’s formulary, meaning doctors need prior approval before prescribing and buying the medication for patients. A VA spokesperson said VA psychiatrists could offer Spravato “when clinically indicated,” but would have to keep “with the FDA-approved indications for esketamine use and safety requirements.” Susan Carter, the VA’s director of media relations said the VA will closely monitor the drug’s use and effectiveness and compare it with other treatments. Mark Takano said he asked the VA to provide documents and information to ensure the VA was not “pressured by the White House” to prescribe Spravato to veterans. Takano said: “Spravato should not be added to VA’s formulary until we have more answers about what this means for our nation’s veterans.”

Three psychiatrists, including one who is a therapist for the MAPS Clinical Study of MDMA-Assisted Psychotherapy for PTSD, wrote an opinion article for Vice, “The New Ketamine-Based Antidepressant Is a Rip-Off.” They pointed out where esketamine was no better than placebo in two of the three short-term Phase III trials submitted to the FDA for approval. Yet they thought the problems with the drug weren’t the biggest concern. Spravato (esketamine) is just a way for “Johnson & Johnson to make a significant profit off gullible insurance companies and vulnerable patients.”

Ordinary ketamine is a racemic medication, meaning it is made up of two molecules that are mirror images of each other. Because ordinary ketamine is generic, Johnson & Johnson simply isolated one of the two molecules in regular ketamine so that it qualified as “new.” The reality is that we don’t know whether esketamine is more or less effective than regular ketamine because there have been no head-to-head trials between the two. Johnson & Johnson only tested esketamine against a placebo, likely because they feared esketamine might actually perform worse than the generic version.

Kaiser Health News described a series of red flags overlooked by the FDA with Spravato. There was only modest evidence of its effectiveness and then only in limited trials. Janssen provided no information on the safety of Spravato for long-term use beyond 60 weeks. And as noted above, there were three patients who died by suicide during clinical trials. Facing political pressure to rapidly bring drugs treating life-threatening conditions to market, the FDA endorsed it anyway.

Some deep misgivings were expressed by members of the FDA advisory board in its day-long review meeting. Dr. Jess Fiedorowicz, a member of the advisory committee and the director of the Mood Disorders Center at the University of Iowa, said Spravato’s benefit was “almost certainly exaggerated.” He was surprised by the vote, which was strongly in favor of the drug. The approval process for esketamine (Spravato) shows how drug makers take advantage of several steps in the FDA approval process to bring a potentially lucrative drug to market.

The first Step was taken in 2013 when Janssen was able to get the FDA to approve esketamine as a “breakthrough therapy” for it potential to rapidly reverse depression. This is a holy grail for suicidal patients, especially those found in emergency rooms. That potential was based upon a two-day study with 30 patients being given esketamine intravenously. This “breakthrough therapy’ status placed esketamine in a fast track for approval, with more frequent input from the FDA.

The second Step in the process occurred during discussions between FDA regulators and Janssen regarding the amount and quality of evidence required by the agency. With regard to Spravato, questions were raised about how many drugs must fail before a patient’s depression in considered “treatment-resistant”? And how many successful clinical trials are necessary for FDA approval of a potentially life-saving drug?

The third Step left the FDA’s expert advisory committee hamstrung in reaching a verdict before they met. With Spravato, the FDA had pre-approved Janssen’s study design. This caused Fiedorowicz to abstain from voting because he considered the study design to be flawed.

The expert panel cleared the drug according to the evidence that the agency and Janssen had determined was sufficient. Dr. Matthew Rudorfer, an associate director at the National Institute of Mental Health, concluded that the “benefits outweighed the risks.” Explaining his “yes” vote, he said: “I think we’re all agreeing on the very important, and sometimes life-or-death, risk of inadequately treated depression that factored into my equation.”

But others who also voted “yes” were more explicit in their qualms. “I don’t think that we really understand what happens when you take this week after week for weeks and months and years,” said Steven Meisel, the system director of medication safety for Fairview Health Services based in Minneapolis.

Although the drug received breakthrough status for its potential for results in 24 hours, the trials were not strong enough for the FDA to say it was “rapid-acting.” Janssen only provided one successful short-term trial when the FDA typically requires at least two. In order to reach the two-trial threshold, the FDA permitted the company to count a trial conducted for a different purpose: relapse and remission trends. And the single positive efficacy trial showed a mere 4-point improvement in depression symptoms compared to the placebo treatment on a 60-point scale used by some clinicians to measure depression severity. Some committee members pointed out how the study wasn’t really blind since participants could recognize they were getting the drug from side effects like a temporary out-of-body experience.

And finally, the FDA lowered the criteria bar for “treatment-resistant depression.” Initially, that meant trial participants had to have failed two classes of oral antidepressants. Less than two years later, the FDA loosened that definition to say a patient needed to have only failed with two different pills, no matter what the class. Forty-nine of the 227 participants in Janssen’s only successful efficacy trial had failed just one class of oral antidepressants. Dr. Erick Turner, a former FDA reviewer who serves on the committee but did not attend the meeting said “They weeded out the true treatment-resistant patients.”

Red flags were waving all around the approval of Spravato, but they seemed to be disregarded by the FDA. Is the pipeline of developing new antidepressants so bankrupt that the FDA has to turn the clinical trial process into a game of limbo by continually lowering the bar for approval of a new medication?

For more on the worries with ketamine and Spravato, see “Hype and Concern with Esketamine.”

07/16/19

Noose Tightening On Kratom

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The “Noose Tightens Around Kratom” as the DEA and FDA continues to underscore concerns with the herbal product. The FDA warned consumers not to use kratom, as it effects mu receptors, the same receptors as opioids, and seems to have properties “that expose users to the risks of addiction, abuse, and dependence.” The DEA listed kratom as a “drug of concern” several years ago, but it continues to be unregulated and sold as an herbal supplement after the agency backed away from Scheduling it and limiting its ability to police it. See “Kratom: Part of the Problem or a Solution?” The FDA’s ability to regulate herbal products is limited to concerns with the safety of kratom and preventing vendors from making overt, unapproved health claims.

As a dietary supplement kratom is not subject to the same safety regulations as other drugs. However, the FDA has persisted in doing what it can to monitor companies that sell this herbal product and so-called “dietary supplement.” The FDA ordered a recall of some kratom products because of Salmonella contamination in April of 2018. In May of 2018 the agency accused three sellers of kratom products of making unapproved health claims.

The FDA continues to warn consumers not to use Mitragyna speciosa, commonly known as kratom, a plant which grows naturally in Thailand, Malaysia, Indonesia and Papua New Guinea. The FDA is concerned that kratom, which affects the same opioid brain receptors as morphine, appears to have properties that expose users to the risks of addiction, abuse and dependence. There are no FDA-approved uses for kratom, and the agency has received concerning reports about the safety of kratom.The FDA is actively evaluating all available scientific information on this issue and continues to warn consumers not to use any products labeled as containing the botanical substance kratom or its psychoactive compounds, mitragynine and 7-hydroxymitragynine. The FDA encourages more research to better understand kratom’s safety profile, including the use of kratom combined with other drugs.

MedPage Today noted the FDA included kratom on “import alerts” in 2012 and 2014, which allowed it to seize kratom and kratom products worth over $5.5 million in 2014 and 2016. Several suppliers reported having tons of kratom seized during that time. There were no further seizures for a while, but they seem to be sporadically occurring again as kratom companies adjusted their marketing strategies. A Denver company, Kratom Café USA, reported recently that its order of kratom was seized by the FDA. When the FDA began tightening its restrictions, the company revised its website. Kratom Café USA now claimed it sold kratom for aromatherapy and making candles. Despite the benefits section of their website having the following disclaimer, the FDA detained 540 kilos of kratom on November 30, 2018:

We make no claims that kratom cures, prevents or treats any disease or ailment. Keep this product out of the reach of children. Kratom is not a dietary supplement, but a precise amount of an ingredient sold as a raw materials and/or bulk herbs. All information provided has not been evaluated by the FDA, and all kratom products on this site are sold for horticultural, educational and scientific use.

But what is the real story? Nicolas Moodley, the owner of Kratom Café USA, said he thought the FDA’s action was “government overreach” and a violation of his rights. Besides, he added, it was taking a toll on his business. Moodley himself became dependent on opioids as the result of chronic pain from his work as a roofer. He credited kratom with relieving his pain and helping him kick the opioid habit. Now take a look at some of the Testimonials on Kratom Café USA:

Gabe T. said: “I love to use kratom for working out and for chilling out. Your powder is off the hook! I don’t mind paying a little more to get 5 time the potency and nearly lasts twice as long.” Richard G. said: “I have been using kratom for a few years now for anxiety and mood swings. It has worked okay from some head shops I buy from. The first time I used your product I was amazed how much more effective & smooth it is. Your kratom is the best I have EVER used.” This does not sound like Moodley’s customers are using kratom bought from him for aromatherapy and candle making.

An article published in Clinical Toxicology analyzed exposures to kratom reported to poison control centers (PCCs) in the U.S. from 2011-2017. Kratom exposure increased over fifty-fold, from 13 exposures in 2011 to 682 exposures in 2017. “Almost two-thirds (65%) of these exposures occurred during 2016-2017.” Most exposures were with adults 20 years old and above (65%) and most were with males (70.8%). Exposure rates by state were highest in Idaho and Oregon and lowest in Delaware and Wisconsin. “There were seven neonatal exposures reported during the study period and five were attributed to kratom withdrawal.”

Clinical effects observed for single-substance kratom exposures among the neonates included agitation/irritability, diarrhea, and hyperventilation/tachypnea. These neonatal withdrawal cases suggest that transplacental transfer is possible and that healthcare providers should educate pregnant women on the risks of kratom use during pregnancy. Notably, although not in a neonate, one exposure was documented as having occurred through breast milk. Thus, the possibility of exposure via breast milk should also be communicated to new mothers who use kratom.

The authors said the clinical effects observed during the study highlighted the fact kratom can have serious physiologic effects. Common non-opioid effects included tachycardia (21.4%), agitation/irritability (22.9%), seizures, and hypertension. More than one-third of exposures resulted in admission to a health care facility and more than half resulted in a serious medical outcome. “These high percentages reflect the potential toxicity of the active compounds found in kratom leaves.” And they highlight the need for kratom regulation by the FDA “to ensure quality and safety.”

Despite the perception that kratom is safe because it is classified as an herbal supplement, a variety of serious medical outcomes following exposure to kratom have been documented, especially when kratom is used in combination with other substances. More research is needed to define the human response to kratom. At a minimum, kratom products should be free of potentially harmful contaminants, provide a uniform strength of active ingredients, and have appropriate labeling. Increased regulation of kratom products would help guarantee product quality and safety. Individuals who choose to use kratom should be educated about its potential risks, including the dangers of using it in combination with other substances.

While there is no federal ban yet for kratom, a number of states and some smaller jurisdictions have banned its use. Currently there are six states where kratom is a controlled substance and thus illegal to sell, possess, use and grow: Alabama, Arkansas, Indiana, Rhode Island, Vermont, and Wisconsin. Several additional states have banned kratom in certain counties or cities. Others like Illinois and New Hampshire have set a legal age limit for its use.

Then on June 25, 2019, the FDA again issued warning letters to two additional marketers and distributers of kratom products, Cali Botanical and Kratom NC for illegally selling unapproved and misbranded kratom products. The companies claimed their products could treat or cure opioid addiction, withdrawal symptoms, depression, anxiety and even cancer. The FDA has also found high levels of heavy metals in kratom products. The Acting FDA Commissioner said “Despite our warnings, companies continue to sell this dangerous product and make deceptive medical claims that are not backed by science or any reliable scientific evidence.” Some examples of the claims being made by these companies include:

Kratom is frequently used as a natural alternative to treat depression, anxiety, addiction, diabetes, chronic pain and fatigue…Kratom has been reported to have taken the place of brand name drugs like Hydrocodone or Oxycodone for individuals, all the way to weaning people off of Heroin.Some researchers have even claimed that kratom can protect you against cancer!Kratom is used for energy, to increase attention/focus, to relax, and also to treat pain and addiction. Here is just some of what our customers have used kratom to treat . . . Chronic Pain, Migraines, Opiate Addiction, ADHD/ADD, Anxiety, Depression, Arthritis, Insomnia and much more!

There is an ongoing dispute about kratom-positive overdose deaths, with kratom advocates pointing to how the herbal supplement was not the only substance found in most decedents. In the Morbidity and Mortality Weekly Report (MMWR) for April 12, 2019 the CDC analyzed data from the State Unintentional Drug Overdose Reporting System (SUDORS) for July 2016 through December 2017. SUDORS records all substances detected on postmortem toxicology testing. The CDC analyzed overdose death where kratom was detected on postmortem toxicology testing and deaths where the medical examiner or coroner determined kratom to be a cause of death.

Kratom-positive deaths occurred in only 152 of 27,338 overdose deaths (.56%) for the time period of the study. “Kratom was determined to be a cause of death (i.e., kratom-involved) by a medical examiner or coroner for 91 (59.9%) of the 152 kratom-positive decedents, including seven for whom kratom was the only substance to test positive on postmortem toxicology.” However, the presence of additional substances could not be ruled out. And here is the rub: “Postmortem toxicology testing detected multiple substances for almost all decedents.” About 80% of the decedents with a kratom-positive and kratom-involved death had a history of substance misuse.

Focusing attention on the kratom-positive decedents who only used kratom appears to be a misdirection tactic. The problem seems to be individuals with a history of substance misuse who miscalculated on the strength or influence of the kratom they used—along with the other substances they ingested—and overdosed as a result of their mistake. Remember that in the Clinical Toxicology article, Post et al. concluded: “Despite the perception that kratom is safe because it is classified as an herbal supplement, a variety of serious medical outcomes following exposure to kratom have been documented, especially when kratom is used in combination with other substances.” The noose of regulation needs to get tighter around kratom and needs to occur sooner rather than later.

05/7/19

Psychedelic Renaissance?

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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?”

04/9/19

Not JUULing Around

Wiki Commons

Under its Commissioner Scott Gottlieb, the FDA has taken several steps to address what it sees as an ‘epidemic’ of youth e-cigarette use. On September 12, 2018, it issued more than 1,300 warning letters and fines to retailers who illegally sold JUUL and other e-cigarette products to minors. This was part of its Youth Tobacco Prevention Plan. Twelve warning letters were also issued, as some retailers had ignored previous warning letters issued in May of 2018. One of the FDA’s potential actions was to remove some or all of their flavored products from the market and require a premarket authorization from the agency. It then announced a public hearing was to be held on December 5, 2018 “to discuss the agency’s efforts to eliminate youth e-cigarette use.”

In an embedded YouTube video, JUUL CEO Kevin Burns said their mission was to “improve the lives of the world’s one billion smokers and eliminate cigarettes.” Their intent was never to have youths use JUUL, “but they are.” The numbers tell them underage use of e-cigarette products is a problem they must solve. “For us to successfully fulfill our mission of helping adult smokers, we must be trusted – and we must earn that trust. That starts with action, not words.”

He then announced JUUL”S intent to stop selling flavored products  (Mango, Fruit, Crème and Cucumber) in retail stores and only make them available online. They also limited online customers to two devices and fifteen JUUL pod packages per month; and no more than ten devices per year. They planned to strengthen their retail compliance and shut down their social media accounts: “By deterring social media promotion of the JUUL system by exiting our accounts, we can better prevent teens and non-smokers from ever becoming interested in the device.”

We are implementing this plan starting today [November 13, 2018]. We will be a transparent, engaged, and committed partner in this effort with FDA, state Attorneys General, local municipalities, and community organizations. We thank Commissioner Gottlieb for his ongoing leadership on this critical issue. JUUL Labs hopes the components of our plan are implemented industry-wide. If implemented across the category, these actions will have the greatest impact in restricting access and ultimately decreasing underage use, along with 21+ laws on all tobacco products. On that point, JUUL Labs will not only continue to support Tobacco 21, we will actively pursue it by drafting legislation, funding advocacy campaigns, and engaging with lawmakers.

Sounds like JUUL Labs is trying to do the right thing, doesn’t it? Now see this August 10, 2018 video by Vox, “How Juul made nicotine use go viral.” It announced JUUL has taken over about 70% of the retail e-cigarette market. The technological simplicity of JUUL means it looks more like a “cool gadget and less like a drug delivery device.” The JUUL co-founders met at Stanford Design School and one of them worked as a design engineer at Apple. No wonder it’s called “the iPhone of E-cigs.”

The video said current marketing today for JUUL is focused on adult ex-smokers. “But when JUUL first launched, their marketing looked a lot different.” Those ads bear a striking similarity to old cigarette ads. “Both marketed relaxation, sharing, travel, freedom and sex appeal.” Now it is illegal for cigarette brands to use these suggestive advertising themes. But for e-cigarette manufacturers who had products on the market before 2016, “those strategies are still unregulated.” JUUL launched in 2015.

In “Juul’s Convenient Smoke Screen,” The New York Times reported that in 2015, a research and development engineer for JUUL said: “We don’t think a lot about addiction here because we’re not trying to design a cessation product at all. . . .  Anything about health in not on our mind.” James Monsees, JUUL’s co-founder and chief product officer said the company was forced to be careful about its marketing. Under federal regulations it is permitted to bill its device as a “switching product” for smokers, “but not as a smoking cessation or health device.” Although JUUL ran ads in the past it would not do today, he said, it always focused on eliminating cigarettes. “Since 2005, we have been focused on creating a product to help people switch away from smoking combustible cigarettes — the number one cause of preventable death in the world.”

But Juul’s public marketing told a different story. Few of the company’s early ads made any mention of cigarettes’ risks, or advocated for smokers to switch; most were focused on playing up vaping’s cool factor. As recently as 2017, the front page of the company’s website said nothing about switching from cigarettes at all, only that the Juul offered an “intensely satisfying vapor experience.”Recently, Juul — now equipped with an army of lobbyists and a slick communications team that includes a former White House spokesman — has studiously revamped its image. Glossy profiles have been written about the company’s “lifesaving mission” and Juul’s new chief executive, Kevin Burns, has gotten on message, emphasizing the company’s focus on adult smokers.

The president of the antismoking advocacy group Campaign for Tobacco-Free Kids, Matthew L. Myers, saw JUUL’s new ad campaign as a P.R. effort aimed at lawmakers and regulators. “”Juul has engaged in all the traditional tactics of a company that is trying to fend off meaningful regulation, rather than actually change their behavior,’ Mr. Myers said. ‘That is classic Big Tobacco.’”

Juul wants you to believe that it became a teenage sensation entirely by accident, that its products were only ever meant for adult smokers and that taking billions of dollars from Big Tobacco is consistent with the values of a company that has always put a priority on health over profits. The truth is much hazier than that.

There was a study published in JAMA Network Open on October 19, 2018 that said adolescent use of pod-based e-cigarettes was increasing rapidly, “and adolescents and young adults report corresponding misperceptions and lack of knowledge about these products.” The researchers reported that only 25% knew all JUULs contained nicotine. Adolescents and young adults were recruited from 10 high schools in California from July 13, 2014 through October 11, 2015. Only 2.5% reported exclusive use of JUULs; 25.2% reported using three products: pod-based e-cigarettes, other e-cigarettes and cigarettes.

The 3 most concerning insights from the data presented here are the high prevalence of co-use and polyuse of pod-based e-cigarettes with other e-cigarettes and traditional cigarettes and the higher proportion of participants who reported past 30-day use together with the much higher frequency of use reported for pod-based e-cigarettes vs other e-cigarettes. These findings point to the potential for greatly increased harm for adolescents and young adults associated with the use of pod-based e-cigarettes, as their still-forming brains are particularly vulnerable to the effects of nicotine, with increased earlier exposure to nicotine being associated in a dose-response manner with deleterious health effects.

Then there was the announcement on December 19, 2018 that Altria, the company that owns Marlboro and is the nation’s largest maker of traditional cigarettes, bought a 35% stake in JUUL Labs for $12.8 billion. Part of the deal was a $2 billion bonus, which will be split among JUUL’s 1,500 employees. According to The New York Times, JUUL Labs will now have access to Altria’s  “deep lobbying pockets” and its more experienced government relations team. Altria spent more than $7 million on lobbying in 2018, while JUUL Labs spent almost $900,000.

The New York Times reported how the “F.D.A Accuses Juul and Altria of Backing Off Plan to Stop Youth Vaping.” Scott Gottlieb drafted letters to both companies criticizing them for “publicly pledging to remove nicotine flavor pods from store shelves, “while secretly negotiating a financial partnership that seems to do the opposite.” In October Altria agreed to stop selling pod-based e-cigarettes until it received FDA permission “or until the youth problem was otherwise addressed.”

But the new deal commits the tobacco giant to dramatically expanding the reach of precisely those types of products, by giving Juul access to shelf space in 230,000 retail outlets where Marlboro cigarettes and other Altria tobacco products are sold. (Juul currently sells in 90,000 stores.)It is a development that startled the F.D.A., which in September had threatened to pull e-cigarettes off the market if companies could not prove within 60 days that they could keep the products away from minors. Altria, Juul and three tobacco companies sent the detailed plans spelling out how they would comply with the agency’s request. Now, those plans appear in jeopardy, Dr. Gottlieb said.

In an interview at the Brookings Institution, Gottlieb said the phenomenon of teen vaping was an “epidemic” and suggested Altria reneged on earlier promises to withdraw pod-based products from the market.  He said in October of 2018 he asked the e-cigarette industry for a plan to address teen vaping. Altria responded by giving the FDA a 15-16 page letter “saying that they would agree to withdraw their pod-based products voluntarily,” and further stating they would not put flavored products on the market until the FDA approved them. The company then withdrew some of its brands like MarkTen and Green Smoke, while at the same time investing in Juul Labs. Gottlieb said: “I continue to have concerns that some of the activities [Altria is] taking in the market are not necessarily consistent with what they’re telling us.” Then on March 5th, Scott Gottlieb resigned as the FDA commissioner. His last day was April 5th.

JUUL was looking more and more like Big Tobacco; and now it IS Big Tobacco!

03/19/19

Double Whammy of Teens Vaping Marijuana

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The FDA recently announced there is a “growing epidemic of youth e-cigarette use” and held a hearing on December 5th to discuss efforts to eliminate teen e-cigarette use. Since 2014, the most commonly used method of consuming tobacco products among teens has been vaping—“used by 1.73 million (11.7 percent) high school students and 390,000 (3.3 percent) middle school students in 2017.” FDA Commissioner Scott Gottlieb expressed concern that a large pool of nicotine users is being created among school-age children. But that isn’t the only substance teens are smoking more. In JAMA Pediatrics a research letter said nearly one-third of middle and high school students are vaping marijuana.

USA Today reported the researchers found 8.9% of those surveyed said they had smoked marijuana in e-cigarettes. “Among those who reported vaping, nearly 1 in 3 high school students and about 1 in 4 middle school students reported using cannabis in the devices.”  Unless the manufacturers can prove they are trying to stop children and teens from using e-cigarettes, the FDA will stop the sales of flavored ones. “We’re going to have to take action.”

Gallup also reported that vaping is more prevalent among Americans who were under 30. While 9% of all Americans said they regularly or occasionally vape, 20% of those who were between the ages of 18 to 29 do so. This compared to 8% among those who were 30 to 64 years of age; and less than 5% among those 65 and over. See the following table.

Young people were less likely than those over 30 to believe vaping was risky; somewhat parallel to their views on marijuana. Twenty-two percent of those under 30 believe vaping was “very harmful” to your health, compared to at least 40% for every other age group. Notice how at the same time young people’s views about the health effects of traditional smoking was no different than older age groups’ views. See the following table.

There are several things that make vaping marijuana appealing to teens, according to Bonnie Halpern-Fisher. Vaping has less of an odor than smoking. And marijuana is increasingly easier to obtain, as it is legal in ten states for adults. Helpern-Fisher also expressed concern over the number of youth vaping marijuana. “You’re basically using it in a very strong form.” Teens face a special risk because their brains are still developing: “Youth are at a very vulnerable time.” See “Priming Young Adults with Vaping” for more on marijuana use and vaping among teens.

A small study in JAMA Network Open found that vaporized cannabis resulted in “significantly greater subjective drug effects, cognitive and psychomotor impairments, higher blood THC concentrations than the same doses of smoked cannabis.” They speculated the procedures in former studies enabled users to titrate their THC dose, while the current study required participants to self-administer a fixed amount of cannabis. “Therefore, holding THC dose constant, vaporizers appear to be a more efficient cannabis and THC delivery method, likely because with traditional smoked preparations, more THC is lost as a result of pyrolysis (combustion) and/or sidestream smoke.” The researchers concluded:

In this study, participants experienced dose-orderly increases in subjective drug effects, cognitive and psychomotor impairment, acute cardiovascular effects, and blood THC concentrations following inhalation of smoked and vaporized cannabis. Notably, vaporized cannabis produced greater changes in study outcomes relative to smoked cannabis. As the legal cannabis marketplace continues to expand, future studies should further explore the effects of vaporizers and other novel methods for cannabis administration in users with different degrees of experience with cannabis, as the pharmacokinetic and pharmacodynamic profiles will likely differ substantially across products and users.

However, the effects on cognitive functioning could be temporary in some cases. A meta-analysis by Scott et al., published in JAMA Psychiatry, found there was a “small but significant overall effect size for reduced cognitive functioning in adolescents and young adults” reporting frequent cannabis use. The studies requiring abstinence longer than 72 hours had a small, nonsignificant effect size. The researchers speculated that reported deficits could reflect residual effects from acute use or withdrawal.

Nevertheless, Gruber et al. said in “The Grass Might be Greener” there is a large body of evidence suggesting marijuana use was related to cognitive decrements, including deficits in verbal memory, attention and executive function. And while these deficits were found in adult marijuana users, they were more prominent in adolescent users, who were in the midst of neurodevelopment.  The deficits have also been linked to changes in brain structure and function. “Similar to studies of cognitive performance and brain structure, fMRI studies have revealed that earlier onset of MJ use is related to altered patterns of brain activation during tasks requiring cognitive control and inhibition.”

It seems that this poorer cognitive performance was due to the effects of THC (Δ9-tetrahydrocannabinol), while CBD (cannabidiol) has been shown to improve cognitive function. “In general, studies suggest that THC and CBD have opposite effects on cognition-related brain activation.” So they hypothesized that after 3 months of medical marijuana treatment, patients would demonstrate improved task performance and these changes would coincide with changes in brain activation patterns measured by fMRI.

Following 3 months of MMJ treatment, patients exhibited improved task performance and related alterations in frontal brain activation patterns during the completion of the MSIT, a measure of executive function and cognitive control, relative to pre-MMJ treatment. Within the cingulate cortex (CC), patients did not exhibit any significant pre-treatment activation during the Interference condition of the MSIT; however, after 3 months of treatment, robust activation was noted within this region. In fact, the magnitude of activation significantly increased over the course of treatment such that post-treatment activation patterns appeared more similar to that of healthy controls observed in previous studies. Activation within the frontal ROI was also notably increased following 3 months of MMJ treatment relative to pre-MMJ treatment. Taken together, these changes may be reflective of a potential “normalization” of brain function following 3 months of MMJ use.

There was also improved task performance and self-reported improvements in mood and quality of life, as well as reduced sleep disturbance and lower motor impulsivity. “It is possible that improvements in symptomatology (i.e., relief of symptoms, improved mood/sleep) are directly related to observed improvements in cognitive function and alterations in brain activation.”

While findings in this study show improvements in cognitive task performance, previous studies entirely focused on recreational (THC) marijuana users have reported decrements in cognitive performance. Among the factors that may account for this difference, Gruber et al. noted the majority of prior studies of recreational marijuana use included adolescent and young adult populations. Studies have overwhelmingly demonstrated that early onset of recreational marijuana use was related to poorer task performance and changes in brain function. Given that participants in their study were well-beyond the critical stages of neurodevelopment (mean age=50.64), “They are less likely to be vulnerable to the adverse neural effects of THC.”

The dangers then seem to be from recreational marijuana use—in other words from strains with higher THC and lower CBD levels. Early onset of recreational marijuana use also increases the adverse effects of cognitive decrements. When these factors are added to the FDA’s concern with the “growing epidemic of youth e-cigarette use,” there seems to be a double whammy to finding that nearly 1 in 3 high school students are vaping marijuana. They are in danger from increased exposure to nicotine and marijuana.

03/12/19

Hype and Concern with Esketamine

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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.