02/6/24

Psychedelics as the Newest Psychiatric Craze, Part 1

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In October California Governor Gavin Newsom vetoed a bill that would have decriminalized the possession and personal use of several plant-based hallucinogens, including psilocybin, mescaline and dimethyltryptamine (DMT), saying more work needed to be done on treatment guidelines. The legislation would have decriminalized possession before setting up regulatory treatment guidelines, with the California Health and Human Services Agency supposed to make recommendations to lawmakers after the consequences of decriminalization. The bill would not have arrested or prosecuted individuals who possessed limited amounts of plant-based hallucinogens. Also, the bill did not legalize the sale of these psychedelics. They are still illegal under federal law.

Public opinion was said to have shifted on using psychedelics to treat trauma and other disorders such as depression, and alcohol use disorder. There has been a significant amount of interest in the potential of psychedelics for mental health that includes encouragement and discouragement of treating psychiatric conditions with them. Sandy Cohen opened her article “Do psychedelics have a role in psychiatric treatment?” for UCLA Health, with the provocative question, “What if there was a medication that could significantly reduce symptoms of treatment-resistant depression in a single dose?” A UCLA Health psychiatrist, Walter Dunn, described two studies where psilocybin was found to have a significant reduction in symptoms of treatment-resistant depression. He said these results were unprecedented: “We have nothing that works this well.”

Dunn said the coverage in mainstream media and books aimed at lay audiences (such as Michael Pollan’s book, How to Change Your Mind) have raised interest and curiosity in psychedelics. He said when he goes to dinner parties and people discover his work is with psychedelic drugs, “I’m talking about them for the rest of the evening.” According to a UC Berkeley Psychedelics Survey, 61% of registered American voters support legalizing regulated therapeutic access to psychedelics. Thirty-five percent of those supporters said they strongly support such action. But there were 35% who opposed it and 69% did not see it as something “for people like me.”

We are in a historic moment in the space for psychedelic science, research and also mental health in general. . . There hasn’t been any time in modern psychiatry where there has been so much interest, awareness and discussion around a potential mental health treatment.

Dunn acknowledged the drugs come with risks, which was one of the reasons the FDA has been cautious about the trials being run. “These are not benign medicines. Anything that can help you can harm you.” He discussed how the FDA was set to consider MDMA-assisted therapy for PTSD in 2024. It’s still unclear whether or not the FDA will want a Risk Evaluation and Mitigation Strategy (REMS), if these treatments are approved. A REMS could require psychedelic-assisted therapy to included two specially trained and certified clinicians during the psychedelic experience. If a REMS is required by the FDA for MDMA-assisted therapy, it would reduce the pool of therapists who could administer the treatment and decrease access even as it enhances safety.

Joanna Moncrieff, a British psychiatrist, noted in “Psychedelics—The New Psychiatric Craze” where they were viewed as an increasingly fashionable medical treatment. But she wondered if they had any objective health benefits and were they safe. She noted where psilocybin, LSD, MDMA and ketamine were some of the psychedelics being recommended for an ever-lengthening list of problems that include depression, anxiety, addiction, and PTSD. She acknowledged some people might learn important about themselves through the effects of psychedelic drugs.

But these benefits are not medical or health effects. They are akin to the personal development people achieve through other sorts of activities and life experiences. . . And although the concept of drug-assisted psychotherapy acknowledges that it is the way the psychoactive effects of the drugs are used to promote a process of personal learning that is relevant, why not employ other, safer and cheaper methods? Why not nature-assisted psychotherapy (a walk in the park), for example?

Yet, the use of these drugs is portrayed as if they work by targeting underlying dysfunctional brain processes. Moncrieff is concerned that when psychedelics get a medical license, psychotherapy will be dropped or minimized. “As with ketamine, the tendency of all psychedelic treatment will be towards the provision of the drug in the cheapest possible way, which means the minimum of supervision and therapy.” Presciently, Moncrieff wrote her article two years ago, before the accidental death of Matthew Perry from the acute effects of unsupervised ketamine use.

She said most psychedelic research ignores the way the immediate psychoactive effects of the drugs impact people’s feelings and behavior in a way that will influence mood symptom ratings and may produce the impression of improvement.  She singled out the American Psychiatric Association’s report on ketamine treatment, which said there was compelling evidence the antidepressant effects of ketamine infusion are rapid and robust. While the APA acknowledged the antidepressant effects were transitory, they did not explain how they could be distinguished from the euphoria and other mental alterations associated with acute ketamine intoxication. “If ketamine’s effects are ‘antidepressant’ then so are the effects of all the other drugs that produce short-term euphoria including alcohol, cocaine, heroin, amphetamines, etc.”

Any powerful mind-altering drug will likely have ‘placebo’ effects. Drug-induced experience will lead people to expect they will improve or think they have improved. Psychedelic research also neglects the hours of medical supervision and professional attention associated with psychedelic treatment. Clinical contact improves people’s outcomes in depression, as was seen in esketamine trials, where a high level of professional contact seems to have exerted a powerful effect on some people.

The current craze for psychedelics also means the adverse effects are being minimised or overlooked. The ‘bad trip’ is a well-recognised phenomenon, and may not be that uncommon. Psychiatrist Rick Strassman, author of DMT: the Spirit Molecule, described how half of the 60 volunteers he injected with the powerful hallucinogen, DMT (N,N-dimethyltryptamine), experienced terrifying hallucinations and anxiety, and he discontinued his research, in part because of these effects. Science journalist John Horgan describes months of depression and flashbacks following a ‘bad trip’, and also reminds us that Albert Hofmann, who first synthesised LSD, also had doubts about it, calling his 1981 memoir LSD: My problem child.

Moncrieff ended her article by noting that while one or two doses of any drug is unlikely to do much harm, the tendency for treating mental health concerns is for long-term use. And repeated use of psychedelics is unlikely to be completely harmless. “As with so many other medical treatments, they have become popular through the potent mixture of financial interests and desperation.” There are many safer routes to promote personal development through an unusual experience. But we will be faced with a decision to legalize psychedelic-assisted treatment sooner rather than later, as MDMA-assisted therapy is expected to be submitted to the FDA for review for approval in early 2024. See Part 2 of this article for more information on the approval process for MDMA-assisted therapy.

01/16/24

Doubling Down on STAR*D Outcomes

Image by 2541163 from Pixabay

In January of 2006, the NIMH announced the results of Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study, the largest and longest study ever done to evaluate depression treatment. Its purpose was to determine the effectiveness of different treatments for people with Major Depression Disorder (MDD) who did not respond initial treatment with an antidepressant. The startling STAR*D results reported that almost 70 percent of those who did not withdraw from the study became symptom-free. “For the first time, doctors and people with depression now have extensive data on antidepressant treatments from a federally funded, large-scale, long-term study directly comparing treatment strategies.” However, the true remission rate turned out to be 35%, around half of what was reported.

In August of 2023 Ed Pigott and other researchers reanalyzed and published the patient-level data set from the STAR*D study in the British Medical Journal (BMJ), keeping their analysis to the original research protocol. They discovered the STAR*D investigators did not use did not use the STAR*D protocol-stipulated HRSD (Hamilton Rating Scale for Depression), but instead used a non-blinded clinic-administrated assessment, known as the QIDS-C, the Quick Inventory of Depressive Symptomatology. They also included 99 patients who scored as remitted on the HRSD at the outset of the study as well as 125 who scored as remitted when initiating their next-level treatment. “This inflated their report of outcomes.”

Unfortunately, the STAR*D investigators’ assertion of a 67% cumulative remission rate had already become accepted clinical wisdom. The NIMH’s director at the time, Thomas Insel, and an editorial in the American Journal of Psychiatry both claimed STAR*D participants achieved a 70% remission rate. “Our reanalysis found that in step 1, STAR*D’s remission and extent of improvement rates were substantially less than those reported in other open-label antidepressant comparator trials and then grew worse in steps 2-4.” The remission rate in step 1 was 25.5%; by step 4, it was only 10.4%.

Robert Whitaker further reported that Pigott and others discovered only 3% of the participants who entered the trial remitted and stayed well in the trial to its end in one year. One of the STAR*D investigators thought Pigott’s analysis was “reasonable and not incompatible with what we had reported.” That was 13 years ago and as of yet, there hasn’t been a public acknowledgement that these protocol violations were a form of scientific misconduct.

Yet, there has been no public acknowledgement by the American Psychiatric Association (APA) of this scientific misconduct. There has been no call by the APA—or academic psychiatrists in the United States—to retract the studies that reported the inflated remission rates. There has been no censure of the STAR*D investigators for their scientific misconduct. Instead, they have, for the most part, retained their status as leaders in the field.

Thus, given the documented record of scientific misconduct, in the largest and most important trial of antidepressants ever conducted, there is only one conclusion to draw: In American psychiatry, scientific misconduct is an accepted practice.

Whitaker said this presented a challenge to American citizens. If the American Psychiatric Association would not police its own research, it was up to the public to demand the STAR*D paper be withdrawn from the American Journal of Psychiatry. “As STAR*D was designed to guide clinical care, it is of great public health importance that this be done.”

He persuasively argued that there had been an intent to deceive. He said once Pigott and colleagues identified the deviations from the STAR*D protocol (which they did initially in 2010), “the STAR*D investigators’ ‘intent to deceive’ was evident.” After Pigott made the protocol and other key documents available in 2011 on two blogs for the Mad in America website, the scientific community could see the deception.

Their recent RIAT publication [in August of 2023] makes it possible to put together a precise numerical accounting of how the STAR*D investigators’ research misconduct, which unfolded step by step as they published three articles in 2006, served to inflate the reported remission rate. This MIA Report lays out that chronology of deceit. Indeed, readers might think of this MIA Report as a presentation to a jury. Does the evidence show that the STAR*D’s summary finding of a 67% cumulative remission rate was a fabrication, with this research misconduct born from a desire to preserve societal belief in the effectiveness of antidepressants?

In Psychiatry Under the Influence Whitaker and his coauthor Lisa Cosgrove wrote about how the STAR*D trial was an example of institutional corruption. They said there were two forms of institutional corruption, or economies of influence, driving that corruption: psychiatry’s guild interests and the extensive financial ties the STAR*D investigators had with the pharmaceutical industry. They said:

Although this was a NIMH-funded trial, industry influence was indirectly present during the trial. Rush and at least seven other STAR*D investigators had financial ties to Forest Laboratories, the manufacturer of Celexa. The investigators’ collective disclosure statement revealed hundreds of ties to pharmaceutical companies, with many investigators reporting that they had served as both consultants and speakers. Yet, given that this was a NIMH-funded trial, STAR*D couldn’t be blamed on the drug companies, and it could be argued that the “corruption” seen here far outstripped anything seen in a commercial trial of the SSRI antidepressants. (p. 129)

Whitaker said the American Psychiatric Association is best understood as a trade association that promotes the financial and professional interests of its members. The APA has long touted antidepressants as effective and safe treatment. He thought if the STAR*D results has been accurately reported, they would have derailed society’s belief in the safety and efficacy of antidepressants. The STAR*D investigators were, in a business sense, protecting one of their primary “products.” And they were safeguarding the public image of their profession.

This research misconduct has done extraordinary harm to the American public, and, it can be argued, to the global public. As this was the study designed to assess outcomes in real-world patients and guide future clinical care, if the outcomes had been honestly reported, consistent with accepted scientific standards, the public would have had reason to question the effectiveness of antidepressants and thus, at the very least, been cautious about their use. But the fraud created a soundbite—a 67% remission rate in real-world patients—that provided reason for the public to believe in their effectiveness, and a soundbite for media to trot out when new questions were raised about this class of drugs.

This, of course, is fraud that violates informed consent principles in medicine. The NIMH and the STAR*D investigators, with their promotion of a false remission rate, were committing an act that, if a doctor knowingly misled his or her patient in this way, would constitute medical battery.

This cataloging of harm done extends to those who prescribe antidepressants. Primary care physicians, psychiatrists, and others in the mental health field who want to do right by their patients have been misled about their effectiveness in real-world patients by this fraud.

The harm also extends to psychiatry’s reputation with the public. The STAR*D scandal, as it becomes known, fuels the public criticism of psychiatry that the field so resents.

Believing this to be a matter of great importance to public health, Mad in America put up a petition on change.org urging the American Journal of Psychiatry to retract the November 2006 article on the STAR*D results. Their hope is that the petition will circulate widely on social media and produce a public call for retraction that will grow too loud for the American Journal of Psychiatry to ignore. Whitaker hoped the publication of the August 2023 article by Pigott and others linked above in the prestigious journal British Medical Journal will lead the American Journal of Psychiatry to retract a paper that told a fabricated story about the outcome of the STAR*D study.

On December 1, 2023 the American Journal of Psychiatry published a letter from John Rush and four other STAR*D researchers, “The STAR*D Data Remain Strong: Reply to Pigott et al.” The researchers claimed the analytic approach by Pigott et al. had significant methodological flaws and stood by their results and methodology in STAR*D. They further said the effectiveness trials of their study were designed “to be more inclusive and representative of the real world than efficacy trials.” Pigott et al failed to recognize this rationale for the inclusion of the 941 patients in the original analyses that were eliminated from their reanalyses by Pigott et al.

The rationale for removing these participants from the longitudinal analysis appears to reflect a studious misunderstanding of the aims of the Rush et al. paper, with the resulting large difference in remission rates most likely the result of exclusion by Pigott et al. of hundreds of patients with low symptoms scores at the time of study exit.

Robert Whitaker responded to the letter in “After MIA Calls for Retraction of STAR*D Article, Study Authors Double Down.” He said the STAR*D investigators had inflated the “cumulative remission rate” in four principal ways. First by including ineligible patients in their tally of remitted patients. Second, by switching outcome measures. Third, by categorizing early dropouts as non-evaluable patients. Fourth, by calculating a “theoretical” remission rate.

By the end of their letter, they again affirmed the 67% cumulative remission rate. Whitaker thought they had “doubled-down on the fraud they committed in their 2006 summary report of STAR*D outcomes.”

Now that the STAR*D authors have “defended” their work, all the public really needs to know is this: The STAR*D investigators, by including 931 patients who weren’t eligible for the study in their final tally of cumulative remissions, greatly inflated that bottom-line outcome. That is research fraud, and in their letter to the editor, rather than admit that these patients weren’t eligible for the study, they instead falsely accused Pigott and colleagues of “creating” their own “post-hoc” criteria to remove those with “large improvements” in symptom scores from their re-analysis.

Whitaker said the STAR*D scandal evolved into a litmus test for psychiatry. Would they acknowledge the research misconduct and inform the public of how the STAR*S study had been compromised? Was it okay to deceive the public in this way? “And now, with this letter to the editor, we know the answer to that litmus test.”

12/26/23

The Sackler Cartel Goes Before the Supreme Court

Photo by Sigmund on Unsplash

The Sackler family’s legal maneuverings to avoid financial consequences from their privately-owned company, Purdue Pharma, just had another development. In August of 2023 the U.S. Supreme Court temporarily blocked the bankruptcy deal for Purdue Pharma that would have shielded members of the Sackler family from additional lawsuits and cap the Sacklers’ personal liability at $6 billion. This was in response to a Justice Department objection that said the settlement would allow the Sackler family to take advantage of legal protections meant for debtors in financial distress, while the Sackler family is reportedly worth $11 billion. The New York Times and SCOTUSblog reported on the Supreme Court arguments on Monday, December 4th over the bankruptcy deal.

The case could have far-reaching implications for similar lawsuits. If the court approves the deal, it would affirm a litigation tactic that has become popular in resolving lawsuits where people claim similar injuries from the same entity, whether that is a drug or a consumer product. “By turning to the bankruptcy courts as a tool to resolve those claims, businesses aim to free themselves from civil liability and prevent future lawsuits.” If the Supreme Court were to block the use of such a mechanism in this case, the Sackler family would no longer be shielded from civil lawsuits. Additionally, the Purdue Pharma bankruptcy settlement deal would be in jeopardy as the Sackler family previously threatened to walk away from the settlement if the bankruptcy protections were not included in the agreement. See “Carrot-and Stick Tactics of Purdue and the Sacklers” and “Supreme Court considers $6bn deal that shields Sacklers.”

The NYT said it was rare for the Supreme Court to hear a bankruptcy dispute, but this one was precipitated when a watchdog office of the Justice Department, the U.S. Trustee Program, petitioned the court to review the deal. Additionally, the opioid crisis is a nationally important issue. Allowing third parties to be shielded without declaring bankruptcy themselves has become an increasingly popular tactic for avoiding liability. And these rulings have divided lower courts.  The objection by the U.S. Trustee Program was, if approved, the Sacklers would get the benefits of bankruptcy without its costs.

Individuals who may want to sue individual Sackler family members—the ones actively involved in decisions made by Purdue Pharma—in civil court would be prevented from doing so. “The U.S. trustee argued that their constitutional due process rights would be summarily extinguished.” While the Justice Department and a few other plaintiffs are challenging the settlement, most others are concerned about the potential loss of funds to initiatives intended to address the opioid crisis.

Under the deal, Purdue would pay $1.2 billion toward the settlement immediately upon emerging from bankruptcy, with millions more expected in the years to come. The Sacklers would pay up to $6 billion over 18 years, with almost $4.5 billion due in the first nine years.

According to an agreement with tribal plaintiffs, all 574 federally recognized Native American tribes are eligible for payouts from a trust worth about $161 million.

Each state has devised a formula with its local governments for distributing the Purdue money. But all must follow the guidance for using it: that it be largely applied to initiatives intended to ease the opioid crisis, including addiction treatment and prevention.

If the agreement is upheld, about 138,000 plaintiffs, individuals and family members of victims who died from overdoses, would be able to file claims to a trust that would hold $700 to $750 million. Payments are expected to range from $3,500 to $48,000. “Though the payouts are small, the Purdue plan is one of only very few opioid settlements across the nation that set aside money for individuals.”

Purdue Pharma would cease to exist. A new company, Knoa Pharma, would receive the assets from Purdue. Knoa would be owned by creditors, and would manufacture addiction treatment and opioid reversal medicines at no profit. See “The Bondage of Buprenorphine” for a potential new product already developed by a Sackler. Knoa would continue to make opioids like OxyContin as well as nonopioid drugs, with the profits going towards the settlement funds. The Sacklers have been off the Purdue board since 2018, so why it there such resistance to members of the Sackler family avoiding further financial liability?

CNN reported members of the Sackler family withdrew more than $10 billion from Purdue Pharma and placed the money in family trusts and holding companies as pressure built over the nation’s opioid epidemic. An audit of Purdue related to its filing for bankruptcy in September 2020 showed that from 2008 to 2018 the family withdrew more than eight times as much money from the company as the previous 13 years. “From 1995 through 2007, the Sacklers received $1.3 billion from Purdue; but from 2008 through 2018, those payments amounted to $10.7 billion.” The larger withdrawals came after Purdue’s 2007 plea deal with the Justice Department to pay a $600 million penalty on a felony charge of misleading and defrauding physicians and consumers over OxyContin.

The withdrawals came during a time when Purdue Pharma was accused of fueling the nation’s opioid epidemic and amid growing concerns from many states that a significant amount of the family’s wealth may be held overseas; therefore unavailable to plaintiffs seeking relief through the courts.

According to StatNews, political appointees at the Justice Department refused to approve felony charges for Purdue executives, letting the company off with a $600 million fine. Richard Sackler admitted he never bothered to read the entire 2007 plea deal document where prosecutors gave guidelines for Purdue’s future behavior. Instead, they doubled down on marketing OxyContin. The important result of the ruling was there was no trial. “A trial would have exposed the company’s OxyContin profits to forfeiture or prompted one of the executives to expose the magnitude of OxyContin scion Richard Sackler’s participation in the admitted crimes.”

An attorney for the Raymond Sackler family said the amount the family withdrew was publicly known. ““These distribution numbers were known at the time the proposed settlement was agreed to by two dozen attorneys general and thousands of local governments.” But Letitia James, the New York Attorney General said the audit showed the need for even more information:

The fact that the Sackler family removed more than $10 billion when Purdue’s OxyContin was directly causing countless addictions, hundreds of thousands of deaths, and tearing apart millions of families is further reason that we must see detailed financial records showing how much the Sacklers profited from the nation’s deadly opioid epidemic.

CNN said a spokesperson for the Sackler family defended the withdrawals, saying: “Members of the Sackler family who served on Purdue’s board of directors acted ethically and lawfully, and the upcoming release of company documents will prove that fact in detail.” The statement of the Purdue audit said the family’s ownership interest of Purdue Pharma had been valued at between $10 billion to $12 billion.

In his testimony for federal bankruptcy court, Dr. Richard Sackler, a former president and co-chairman of the bord of directors of Purdue Pharma said he, the Sackler family and Purdue Pharma did not have any responsibility for the opioid crisis in the United States. Yet during his tenure, Purdue pleaded guilty twice to federal criminal charges related to marketing and sales of OxyContin. In an email he wrote in 2001, he said “We have to hammer on abusers in every way possible… They are the culprits and the problem. They are reckless criminals.”

A congressional committee investigating the Sacklers, released a statement saying the Sackler family, who owned a controlling interest in Purdue Pharma since 1952, were collectively worth $11 billion. See the statement for a listing of the Sackler family’s assets. The chairperson of the committee said the family built its enormous fortune in large part through sales of OxyContin:

Members of the Sackler family pushed Purdue to use deceptive marketing practices to flood communities with this dangerous painkiller, and now the Sackler family is attempting to use Purdue’s bankruptcy proceedings to evade individual responsibility for their role in fueling the opioid epidemic.

Untangling the contributions of the Sackler family from executives for Purdue Pharma in order to get a clear picture of exactly what individual family members were responsible for may be an impossible task. But looking at how family members contributed to the opioid epidemic and Purdue Pharma’s facilitation of the opioid epidemic is easily done.

Arthur Sackler’s marketing strategies were applied to OxyContin after his death, and Mortimer Sackler transferred millions of dollars from trust companies to himself as early as 2009. Records show approximately $1 billion in wire transfers between the Sacklers, entities they control, and different financial institutions—including funds placed in Swiss bank accounts.

According to StatNews, the evidence of callous greed by Purdue was chilling. The privately-held company fired employees who tried to blow the whistle on its activities and maneuvered to have reporters working on the story of fraud at Purdue fired or removed from their beats. Sales reps were encouraged to allow doctors to believe morphine was stronger than OxyContin; it wasn’t. Executives at Purdue knew the opposite was true.

The 2007 plea deal document discussed above didn’t slow them down. It allowed Purdue Pharma to continue marketing and selling OxyContin. Now with the assistance of consultants at McKinsey & Co., they “turbocharged” their sales, concentrating on known pill mill operators, pushing the highest-dosage pills, “and banning together with other opioid makers to pull end-runs around FDA regulators.”

For more information on the Sacklers and OxyContin, read Pain Killer, by Barry Meier, which “exposes the roots of the opioid epidemic at the hands of Purdue Pharma and Raymond and Mortimer Sackler.”  Also see: “What Purdue and the Sackler Family Treasure,” “It’s Strictly Business,” and “Giving an Opioid Devil Its Due.” Read “The Tale of the OxyContin Lie” and watch PainKiller on Netflix if you think the Sackler family should get a pass by the Supreme Court.

12/5/23

Xanax Is Not the Way Out of Anxiety

Image by Pete Linforth from Pixabay

In November of 2022 Maria Shriver and her daughter Christina Schwarzenegger released a documentary on Netflix titled, Take Your Pills: Xanax. Their film looked at both the cure and curse Xanax has become for so many people. In their interview Maria said we are in the midst of widespread anxiety for which people want a quick fix. Now individuals are asking, “What is the effect of taking this pill on my brain, or on my body?” What impact might this have if I want to stop taking Xanax down the road?

Xanax was originally approved by the FDA as in 1981 to treat anxiety associated with depression. The patent expired in September of 1993. On January 17, 2003 the FDA approved Xanax XR, an extended-release form, to treat panic disorder, with or without agoraphobia. The patent for Xanax XR will expire on April 8, 2028. FDA Approved Labeling for Xanax-XR says its longer-term efficacy has not been systematically evaluated. “Thus, the physician who elects to use this drug for periods longer than 8 weeks should periodically reassess the usefulness of the drug for the individual patient.”

Xanax, alprazolam, is the most widely prescribed benzodiazepine on the market today. PsychCentral said it was the nineth most prescribed psychiatric medication with 16.78 million prescriptions in 2020. “A Review of Alprazolam Use, Misuse, and Withdrawal” said its clinical use has become a point of contention as addiction specialists consider it to be highly addictive, while primary care doctors prescribe it for much longer time periods than recommended. And it has been shown to have a more severe withdrawal syndrome than other benzodiazepines, “even when tapered according to manufacturer guidelines.” Data on national emergency department (ED) visits indicated alprazolam is the 2nd most common prescription medication and the most common benzodiazepine involved in ED visits related to drug misuse.

Alprazolam has a high misuse liability, particularly when prescribed to individuals with a history of some type of substance use disorder. Individuals with a history of alcohol or opiate use seem to prefer it to other benzodiazepines like Serax (oxazepam) because they found it to be more rewarding. CDC prescription death rate data indicated alprazolam was used with another drug over 96% of the time, usually with fentanyl. Heroin was the second most frequent concomitant drug. See Table D taken from the CDC report.

The above cited review of alprazolam said, “All benzodiazepines carry a risk of misuse, diversion tolerance and physical dependence.” Withdrawal symptoms seem to be more severe with Xanax because of its shorter half-life and high potency causing severe rebound anxiety. Alprazolam is also more toxic than other benzodiazepines in cases of overdose, and should not be prescribed to patients at increased risk of suicide, or who use alcohol, opioids, or other sedating drugs. The use of benzodiazepines with opioids doubles the risk of death and respiratory depression, and should be avoided. “Alprazolam should be prescribed primarily in its extended-release formulation for a short duration to minimize misuse liability and only to those with no prior substance use history.”

Well-designed human studies addressing alprazolam’s reinforcing effects and the discontinuation syndrome [withdrawal] are needed, and must consider important issues such as selection of appropriate comparison drug, dose, formulation, and population. Future research should also further investigate the misuse liability of alprazolam XR, and should attempt to clarify the role of carbamazepine, clonidine, other anticonvulsant drugs, and related compounds in the treatment of the alprazolam withdrawal syndrome.

A new study published online on October 19, 2023 examined both the published and unpublished data from five FDA-reviewed trials for Xanax XR. Only three of the five trials were ever published, and all published trials claimed the results of their respective studies were positive. The researchers compared the overall trial results according to the FDA, to the corresponding published literature of the 3 published trials and found only one of the trials was positive. “Publication bias substantially inflates the apparent efficacy of alprazolam XR.”

We found that alprazolam XR may be less effective than the published literature would suggest. According to the published literature, every trial of alprazolam XR found it to be effective. By contrast, according to the FDA, only one of five trials was positive.

The researchers noted where selective reporting of clinical trials undermines the integrity of the evidence base “and deprives clinicians, patients, researchers, and policymakers of accurate data critical for decision-making.” Their study highlighted the value of regulatory data for public health. It brought to light unpublished trial data and provided a more balanced and realistic view of the efficacy of alprazolam XR, compared to what was previously reported. Neuroscience News indicated that publication bias inflated alprazolam’s effectiveness by over 40%!

The senior author of the study, Eric Turner, who is a former FDA reviewer, said clinicians were well aware of the safety issues with alprazolam, but didn’t question its effectiveness. “Our study throws some cold water on the efficacy of this drug. It shows it may be less effective than people have assumed.” He concluded how the study reinforced caution before starting a prescription for alprazolam.

The documentary Take Your Pills: Xanax said after 9/11, prescriptions for antianxiety drugs increased 23% in New York City and 8% nationally. Even before COVID-19, anxiety had overtaken depression as the “diagnosis du jour.” One of the psychiatrists in the documentary said drugs like Xanax were meant to taken short-term—no longer than about a month. But the fact is many people who begin taking a benzodiazepine “will continue to take that for years or even decades.” This is despite that the medication guide for Xanax says it is not known if Xanax is safe and effective to treat anxiety for longer than 4 months or to treat panic disorder for longer than 10 weeks. And it warns you to not stop benzodiazepines suddenly, or you may have “symptoms that can last several weeks to more than 12 months.”

Since direct-to-consumer advertising was approved for prescription drugs and medical devices, patients have come to their doctors telling them what medications they want. And doctors write the prescriptions to avoid a poor evaluation when the patient doesn’t get the drug they were told to “ask your doctor” about. “Medicine has become industrialized to the point where doctors kind of function like workers on an assembly line.” There is also a problem when training doctors about prescribing and using these medications “is not always as robust as one would hope.” Additionally, the typical consumer who asks their doctor for a certain medication is changing.

That typical profile of a patient who might be prescribed benzodiazepine is widening. So, whereas it might have been, typically, you know 30 years ago, a middle-aged woman, now we’re seeing younger and younger age groups. We’re seeing very old people are not only being prescribed benzodiazepines, but being kept on them for much longer periods of time.

I’ve written about concerns with the use of benzodiazepine for a while and was pleased to see the Ashton Method for benzodiazepine withdrawal mentioned in Take Your Pills: Xanax. There is a World Benzodiazepine Awareness Day (W-BAD) on July 11th that seeks to raise awareness about iatrogenic, medically caused, benzodiazepine dependence and adverse effects of benzo withdrawal. There is another documentary by Holly Hardman, As Prescribed, which also promotes awareness of benzodiazepine harm: “People don’t realize when they’re given benzodiazepines what’s going to come of it in the end.” Also see, “It Takes Away Your Soul” and Are Benzos Worth it?”

One person in Take Your Pills: Xanax said the only way out of anxiety is to go through it. “What’s going to get you on the other side of the anxiety is to actually go through it and experience it and understand it and make some sort of peace with it.” Another person thought that benzodiazepines like Xanax “erode the resilience that we must rely upon at some point in our lives to manage distress, anxiety, difficult situations.” What is so seductive about benzodiazepines like Xanax is how well they work. We need to remember, “the only way out is through” the anxiety.

11/14/23

Voyages on the Starship Ketamine

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

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

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

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

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

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

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

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

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

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

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

A Cunning Methodology

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

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

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

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

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

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

10/24/23

Is Adult ADHD the Latest Fad Diagnosis? Part 2

Photo by Tara Winstead: www.pexels.com

Dramatic increases in ADHD diagnoses and prescriptions for ADHD medication noted in Part 1 are not just happening in the U.S. BBC Scotland claimed, “The number of adults receiving an NHS prescription for ADHD had increased seven-fold over the last 10 years.” Data obtained from Public Health Scotland indicated 26,000 patients were prescribed ADHD medications in 2022/23. Almost half were adults. The number of adult prescriptions rose steadily from 1,603 in 2013/14, to 5,920 in 2019/20, and then doubled to 12,182 by 2022/23.

Although ADHD content on social media platforms like TikTok contributes to the current problem of over diagnosis, it didn’t create it. In Saving Normal, Allen Frances, who was the chair for the DSM-IV, said until the mid 1990s ADHD medications had been off patent for decades and could be purchased generically for pennies a pill. There was no advertising to patients or marketing to doctors. Then several newly patented—and expensive—medications ADHD medications came to market. And then drug companies were given the right to advertise to consumers.

The blaring propaganda message was the usual—ADHD is extremely common, often missed, and accounts for why Johnny is a behavioral problem and isn’t learning in school. “Ask your doctor.” Armies of eager sales reps filled the offices of pediatricians, family doctors, and psychiatrists peddling a pill that would magically prevent classroom disruptions and solve home meltdowns. Parents, teachers, and physicians were recruited in an all-out effort to identify and aggressively treat ADHD.

PsychCentral listed the top 25 psychiatric medications in 2020. The top three most expensive medications, making the most money for their manufacturers, were all ADHD medications: methylphenidate (Concerta, $3.28 billion), lisdexamfetamine (Vyvanse, $3.01 billion), and amphetamine/dextroamphetamine (Adderall, $2.35 billion). Adderall had the fourth most prescriptions written with 26.24 million, Concerta was 10th with 18.55 million prescriptions, and Vyvanse was 20th with 8.64 million prescriptions.

Dr. Frances Levin of Columbia University, an internationally recognized expert in adult ADHD, said: “It’s difficult to get a clear picture of how many individuals in this country fit a clinical definition for ADHD, when there are no U.S. guidelines for diagnosis and evaluation of ADHD in adults.” Practice guidelines currently exist only for childhood ADHD. She thought both underdiagnosis and overdiagnosis of ADHD are happening. The American Society of ADHD and Related Disorders (APSARD) recently appointed a special committee to write guidelines for adult ADHD in the U.S. Dr. Levin co-chairs the committee. Her understanding of the rise in overdiagnosis is dramatically different than Dr. Frances.

She said in the early 1990s, there was a belief that ADHD diminished with age as well as concern in the scientific community about the validity of diagnosing ADHD in adults. “Then in the 1990s, the increase in diagnoses of childhood ADHD led to greater public awareness.” More adults recognized and reported symptoms in themselves and adult ADHD was added to the DSM-IV in 1994. Older psychiatrists, she said, weren’t schooled in evaluating and treating adults with ADHD; and now younger clinicians don’t get much training or experience with this population. The creation of uniform standards will address a critical need for healthcare providers and patients.

In Saving Normal, Dr. Frances there was no real reason to think that the prevalence of attentional and hyperactivity problems has actually increased. “We now diagnose as mental disorder attentional and behavioral problems that used to be seen as part of life and of normal individual variation.” He suggested six contributing factors to the increase of diagnosing childhood ADHD. There were: wording changes in DSM-IV; heavy drug company marketing to doctors and advertising to the public; extensive media coverage; pressure from parents and teachers to control unruly children; extra time on tests and extra school services if a child had an ADHD diagnosis. “And finally, the widespread misuse of prescription stimulants for general performance enhancement and recreation.”

Unchastened by the false “epidemic” of ADHD already running rampant among kids, DSM-5 has set the stage for creating a new epidemic of ADHD in adults. As usual, the experts worry so much about missed cases, they fail to consider the much greater risk of overdiagnosis. Attentional problems and restlessness are nonspecific and extremely common among normal adults and in those suffering from any of the other mental disorders. The easy path to adult ADHD suggested by DSM-5 will mislabel many normal people who are dissatisfied with their ability to concentrate and get their work done, especially when they feel bored and don’t like the work they’re doing. It will also misdiagnose those whose problem in concentrating is really caused by something else—e.g., substance abuse, bipolar disorder, depression, all the anxiety disorders, psychotic disorders, and many others. No one should ever get diagnosed or treated for adult ADHD until all of these are first ruled out as the primary cause—lest inappropriate stimulant treatment may worsen their already existing psychiatric problems.

He went on to say adult ADHD was already too easily diagnosed. Symptoms are mostly subjective and based on self-perceptions of poor concentration and task performance. “The DSM-5 lowering of requirements will capture many adults who want to be sharper but don’t have specific or serious enough problems to qualify for a mental disorder.” He said fake adult ADHD would be common in college students, in people with demanding jobs, and in those who struggle to stay awake, like long-haul truck drivers. Remember that Allen Frances was the chair for the DSM-IV.

An article by Allen Frances on Psychtherapy.net thought the numbers given for the prevalence of current adult ADHD were absurdly high. In the general population, the current rate for adult ADHD is reported to be 4.4% (5.4% for males and 3.2% for females). He thought the best guide was that by Keith Conners, considered to be the father of the ADHD diagnosis. Conners thought the rate of childhood ADHD was around 2-3% and about half that number in adults. Frances then gave the following as reasons for the overdiagnosis of adult ADHD.

Almost all mental disorders and almost all substance addictions can perfectly mimic ADHD since they can cause its two classic symptoms — hyperactivity and trouble focusing attention.

  1. Real or imagined attention problems are a very common complaint among perfectly normal people.
  2. Getting an ADHD diagnosis is a gateway to legal speed — desired for performance enhancement, all-nighters for school tests or work assignments, recreational purposes, or for sale into the extensive secondary ADHD pill market.
  3. Careless diagnosis and prescribing by MDs.
  4. An inevitable consequence of overdiagnosing ADHD in kids is overdiagnosing ADHD in adults.
  5. Promotion via drug companies and social networking.

Frances said the risks of overdiagnosing ADHD in adults were:

  1. Meds used for ADHD are usually quite harmful if the person’s symptoms are due to another psychiatric disorder that has been missed — especially bipolar disorder, depression, schizophrenia, eating disorders, or anxiety disorder.
  2. Overdiagnosis of ADHD results in over-medication with drugs that cause harmful side effects and can lead to or worsen addiction.
  3. There is now a huge secondary market for ADHD meds, especially on college campuses.
  4. There is also a nationwide shortage of ADHD meds for patients who really need them — because the meds are so often prescribed for those who don’t or diverted to the illegal market.

His bottom line was that most of what looks like adult ADHD is not adult ADHD. Most of it is normal behavior, sometimes caused by another psychiatric or medical problem or substance use. ADHD drugs are not safe unless carefully used for accurately diagnosed ADHD. Frances thought it was past the time to stop the adult ADHD fad before it gained more traction.

Easy access to legal “speed” has created a large illegal secondary market of diverted pills. ADHD drugs have become the campus recreational drug of choice at parties and the performance-enhancement drug of choice for all-nighters during finals week. Legal speed can cause many medical and psychiatric adverse effects, and emergency room visits for complications are skyrocketing. The Drug Enforcement Agency and the FDA are now trying to contain the epidemic — but their efforts are too little/too late. The adult ADHD fad will be stopped only if clinicians and patients fight against its seduction and insist on more careful diagnosis and cautious treatment.

Writing for Psychiatric Times, Mark Ruffalo and Nassir Ghaemi noted in “The Making of Adult ADHD” that twenty years ago, the consensus view in American academic psychiatry was that ADHD rarely persisted into adulthood. Now, adult ADHD is the “diagnosis du jour.” The rates of diagnosis and the prescriptions for the psychostimulant drugs that treat them are skyrocketing. They thought adult ADHD was a case of disease mongering, rather than psychopathologists and psychiatric nosologists missing the disorder for more than a century. Along with Allen Frances, they also associated the rise in diagnosis of adult ADHD to marketing by the pharmaceutical industry.

The rise in diagnosis of adult ADHD fully coincides with marketing by the pharmaceutical industry when Eli Lilly and Company got the first US Food and Drug Administration indication for this label with atomoxetine (Strattera) in 1996. Since that date, many academics have been promoting the concept of adult ADHD. The adult ADHD market has become a multibillion-dollar industry, with the rise of digital companies specializing in online diagnosis and treatment—some of which have come under legal scrutiny.

They noted retrospective studies, (that look backwards to determine if cases of childhood ADHD continue into adulthood), commonly find 50% to 60% of childhood ADHD persists into adulthood. “However, these data are disproven by prospective studies, which repeatedly show that about 80% of children with ADHD do not continue to have that diagnosable condition, followed prospectively either into young adulthood or even for 33 years into their fourth decade of life.” Ruffalo and Ghaemi don’t think that adult ADHD is a scientifically valid diagnosis. They don’t mean that the symptoms don’t exist. Adults do have problems with attention, concentration, focus, memory and other related abilities. However:

What we mean is that these symptoms have not been shown to be the result of a scientifically valid disease (adult ADHD) and are better explained by more classic and scientifically validated psychiatric conditions, namely diseases or abnormalities of mood, anxiety, and mood temperament.

They concluded the history of psychiatry shows the field has been vulnerable to a host of diagnostic fads. “Adult ADHD is the latest of such fads, and a careful review of the scientific literature reveals that the range of ADHD-like symptoms in adults is more accurately explained by other empirically validated psychiatric disorders.”

10/17/23

Is Adult ADHD the Latest Fad Diagnosis? Part 1

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WebMD has an article on statistics and facts about Adult ADHD, where it estimated adult ADHD affects more than 8 million Americans, with many of them not knowing it. “Several studies suggest less than 20% of adults with ADHD are aware they have it. And only about a fourth of those who do know are getting treatment for it.” Supposedly, every adult with ADHD had symptoms during childhood; and more than 60% of children with ADHD will still have it as adults. This begs the question, why don’t more adults realize they have it?

WebMD said adult ADHD can affect careers, relationships and other aspects of daily life, costing the U.S. economy up to $138 billion a year in lost income and productivity. It tends to occur with other mental health issues, like anxiety, depression or bipolar disorder. “Symptoms of adult ADHD can be mistaken for those conditions.” WebMD seems to presume ADHD is the primary disorder or cause. But what if it is the reverse? Psychiatrist Allen Frances thinks adult ADHD should not be diagnosed until these and other psychiatric problems are first ruled out (see Part 2).

Although researchers don’t know what causes ADHD, it runs in families. Forty percent of children with ADHD have at least one parent with symptoms. “If you have relatives with ADHD, you’re four to six times more likely to have it yourself.” This article ends with a link to the next article, “Do You Have ADHD?”, which then links to, “ADHD Medications and Side Effects.” If you’ve persisted in following the tidbits on adult ADHD, to this point, you’ll read how “Medication is an important part of your ADHD treatment.”

Another source, saying many of the same things, is the CDC, which in “Research on ADHD,” referred to ADHD as a serious public health problem that effects a large number of children and adults. The reader will learn that the criteria used to diagnose ADHD have changed over time. “This has led to different estimates for the number, characteristics, and outcomes of children with the disorder.” Although the exact causes of ADHD are not known, research show that genes play a role, with other factors contributing or making symptoms worse.

This led to the conclusion that there are many unanswered questions about ADHD and how it affects people throughout their life. In “Data and Statistics About ADHD” the CDC used datasets from parent surveys and healthcare claims to understand diagnosis and treatment patterns for ADHD. Concentrating on children, the CDC reported there were 6 million children between 3 and 17 (9.8%) ever diagnosed with ADHD. Many children with ADHD (64%) had at least one other mental, emotional or behavioral disorder. About half had a behavior or conduct problem (52%).

A national parent survey in 2016 reported 62% of children currently with ADHD were taking ADHD medication and 47% received behavior treatment. About 30% were treated with medication alone; 15% received behavior treatment alone. Around 32% received both medication and behavior treatment. And about 23% with ADHD received neither medication treatment nor behavior treatment. Not surprisingly, the American Psychiatric Association reported in November of 2019 that a study, Chung et al, found adult ADHD diagnosis increased 123% between 2007 and 2016.

Chung and colleagues suggest the increase in ADHD among adults may partly reflect an increasing awareness among health care professionals and the public of ADHD in adults. The study authors also address the misuse of ADHD medications particularly among adult-aged students to boost academic performance, noting that “diagnosis seeking to obtain stimulant medication for nonmedical use may be more common among white vs nonwhite patients.” The study found adults who identified as students were at highest risk of ADHD diagnosis.

Chung et al speculated that this increased risk of diagnosis in students could be due to some individuals seeking diagnosis and treatment for the purposes of “cognitive enhancement” with ADHD medications. They said pharmacological cognitive enhancement with prescription and illegal stimulants among individuals not diagnosed with ADHD has been increasing. There has been to be an concern about cognitive enhancement with ADHD medications among college students for some time. See, “Academic Steroids.”

In a related, but nonacademic article, the Guardian described how some tele-health startups have received criticism for their aggressive and misleading advertising campaigns. “These companies offer evaluations in as little as 30 min with no wait lists and prescribe medication, sometimes including controlled stimulant medications like Adderall and Ritalin.” The startups took advantage of an emergency provision established during the pandemic that permitted healthcare providers to prescribe controlled substances (like ADHD medications) via tele-health. While there are guidelines for diagnosing and treating ADHD in children, “There are no guidelines in the US about how to diagnose adult ADHD.”

The CDC reported that while the prevalence of adult ADHD did increase in recent decades and continued during the COVID-19 pandemic, there was a notable upturn during 2020-2021. Improved access to ADHD care through tele-health during the pandemic “introduced the potential for inadequate ADHD evaluations and inappropriate stimulant prescribing.” The significant increase in adults receiving prescription stimulants during the COVID-19 pandemic “draws attention to the need for clinical practice guidelines for ADHD in adults.”

The Guardian noted that the US medical system can’t serve all the people seeking diagnosis and treatment for ADHD, “and social media is filling in those gaps.” This increased demand contributed to an Adderall shortage that began in October of 2022. See, “Bad Things Could Happen with ADHD and the Adderall Shortage.”

A psychologist in Seattle who conducts adult ADHD evaluations said she thought TikTok accounted for at least 50% of her current requests for intakes. Supporting her estimation, a study in the Canadian Journal of Psychiatry, “TikTok and Attention-Deficit/Hyperactivity Disorder,” found that 52% of the most popular TikTok videos about ADHD were misleading if used to determine if you have ADHD.

TikTok videos with titles like “5 signs you have ADHD” and “5 things ADHDers hate,” are driving a lot of interest around adult ADHD. They list symptoms like daydreaming, swaying to avoid things while walking or picking skin for hours. Some videos have disclaimers, informing viewers that they should not replace medical advice, some are from users who list medical credentials, or are from people who have been diagnosed – but it’s not clear how credible each video is.

According to a psychiatrist who specializes in diagnosing and treating ADHD, the average, normal adult has two or three of these so-called “symptoms.” The DSM-5 diagnosis for ADHD requires at least five ADHD diagnostic criteria or symptoms, and those must cause “significant impairment” in at least two settings, like work and home.

TikTok videos facilitating people getting diagnosed for adult HDHD is an alarming trend. The psychologist in Seattle said she was frustrated when patients come to her because they’ve seen some TikTok videos and are hoping to “understand themselves better.” Some of these patients complain she is “invalidating” their experience when they don’t get the ADHD diagnosis they expect. She’s fearful these “patients” are putting pressure on an already overloaded medical system. The trend raises the question if these TikTok videos have led to more people believing they have adult ADHD, how valid of a diagnosis can it be? More on this in Part 2.

 

09/26/23

Don’t Roll the Dice with MDMA, Part 2

Photo by Guillermo Velarde on Unsplash

The psychedelics industry is booming, as companies plan out their patent strategies in order to stake out their future share of the market. In the early days of the industry, nonprofits like MAPS and smalltime startups dominated the psychedelics space. Then the FDA granted breakthrough status to MAPS for MDMA-assisted therapy to treat PTSD in 2017. And in 2018 psilocybin-assisted therapy was approved as a breakthrough therapy for treatment-resistant depression. According to Insider, venture capitalists have now invested $139.8 million into startup psychedelic companies in a few short years.

The Hill noted California was on its way to be the third state to decriminalize psychedelics after its Assembly passed Senate Bill 58 by a 42-11 vote. In addition to decriminalizing personal possession and cultivation, the bill would allow “community-based healing” practices to promote the therapeutic use of psychedelics. Interestingly, the specified substances included psilocybin, psilocin, dimethyltryptamine (DMT) and mescaline, but did not mention MDMA. However, ecstasy or MDMA has been progressively moving through the FDA’s clinical trial gauntlet for approval in MDMA-assisted therapy and MAPS recently published the results of its second Phase 3 clinical trial.

MAPS, the Multidisciplinary Association for Psychedelic Studies, has been advocating for MDMA-assisted therapy to treat PTSD since 1986. In 1985 the DEA classified MDMA as a Schedule I drug, meaning the agency thought it to have no medical use and a high potential for abuse. Rick Doblin, the founder of MAPS said, “The big tragedy to point out is that it was pretty clear in the late 1970s and early 1980s that MDMA had incredible therapeutic potential.” But there is more to know about the history of MDMA and Rick Doblin, who chose PTSD as the disorder to target in his quest to end the government ban on psychedelics.

Doblin said MAPS wanted to help a population that would automatically win public sympathy. “No one’s going to argue against the need to help them [veterans].” When the DEA moved to criminalize MDMA in 1984, Doblin created MAPS and sued the agency, but failed to stop the DEA from permanently classifying it as a Schedule I controlled substance. He realized then psychedelics were seen as too fringe to win public support and decided that both he and the issue needed to go mainstream. So, he applied to the public policy program at Harvard, shaved off his mustache, cut his hair and began to dress more conventionally.

“I used to laugh about how simple it was,” he said. “You put on a suit, and suddenly everyone thinks you’re fine.” Doblin’s dream is to see psychedelic treatment centers in every city, but not simply to treat PTSD. These centers would be where people could go for spiritual experiences, enhanced couples therapy and personal growth. He believes psychedelics can even help homelessness, global warming and world peace: “These drugs are a tool that can make people more compassionate, tolerant, more connected with other humans and the planet itself.”

But this kind of rhetoric makes others nervous. A psychology professor at Swansea University in Wales thinks MDMA’s a dangerous substance. He’s worried FDA approval for the treatment of PTSD will lead many in the public to believe MDMA is safe for recreational use, despite its problematic side effects. See “Give MDMA a Chance?” and “MDMA-Not!” for more information on the history of MAPS and concerns with adverse side effects with MDMA.

Nevertheless, MAPS plans to submit a new drug application (NDA) for MDMA-assisted therapy to the FDA by the end of the year, which brings us to the question posed towards the end of Part 1 of this article: Should the FDA approve MDMA-assisted therapy?

The New York Times described the second Phase 3 clinical trial for MDMA-assisted therapy in “MDMA Therapy [was] Inches Closer to Approval” and said it seemed to be effective in reducing symptoms of PTSD. After giving a brief history of MAPS and Doblin’s efforts towards FDA approval of MDMA-assisted therapy, they gave a summary of MAPP2, the second Phase 3 clinical trial: “MDMA-assisted therapy for moderate to severe PTSD,” published in Nature Medicine. The findings were similar to the results of MAPP1, the first Phase 3 study of MDMA-assisted therapy for PTSD. See Part 1 for a discussion of those findings.

As in previous studies of MDMA-assisted therapy, the treatment was generally well-tolerated, according to the data presented about adverse events. Common side effects, primarily for those in the MDMA group, included muscle tightness, nausea, decreased appetite and sweating.

Two participants in the MDMA group and one in the placebo group experienced serious suicidal ideation during the study, but no suicide attempts were reported.

Allen Frances, a professor emeritus of psychiatry at Duke University and the chair of the DSM-IV, didn’t think the study’s results would meet the FDA’s criteria. He said the benefits in the active group were not much greater than the benefits in the placebo group. The cost of the treatment process would also put it out of the reach of many, if not most, potential patients. “MDMA treatment would add huge costs to the treatment system while providing only a small, specific benefit — and thus result in a massive misallocation of already very scarce resources.”

There is the cost of training therapists for psychedelic-assisted therapy as part of that expense. MAPS already oversees its own therapist education program. But the standards and requirements from the FDA are still not specified for MDMA-assisted therapy. “Drug-assisted therapy hasn’t been approved before, so there’s not a lot of precedent.” Then there is the variability of the price for assisted therapy. MAPS “will not manage how much the therapy component will cost.”

In a Nature news article, “Psychedelic drug MDMA moves closer to US approval,” Eric Turner, a psychiatrist at Oregon Health & Science University (and a former reviewer of psych drugs for the FDA), said while the reported difference between the MDMA and placebo groups was impressive, he doubted it was as big as it seems because it wasn’t a blinded study. “Around 94% of people who received the drug and 75% of those who didn’t correctly guessed which group they were in.” He added that even if MDMA was a safe substance, the study didn’t meet the FDA’s usual criteria for a well-controlled study. Jennifer Mitchell, the lead author for “MDMA-assisted therapy for moderate to severe PTSD,” worried about people trying MDMA on their own, where it could be harmful for those with heart conditions or with a family history of schizophrenia, which could be triggered by the drug.

I’ve been following the MAPS progress with MDMA-assisted therapy since 2016. And I’ve also wondered about the associated proliferation of psychedelic start-ups in “Psychedelics Are Not a Magic Bullet.” With the examination of the rhetoric and published spin on the two studies of the clinical trials for MDMA-assisted therapy, I think it almost appears to be a “con job” of rhetoric instead of the steady, progressive march towards the approval of a novel treatment for PTSD. And it seems I am not alone.

Psychologist James C. Coyne was critical of what he saw as a well-orchestrated publicity campaign by the funders of the MDMA research done by MAPS in “The MDMA-Assisted Therapy for PTSD Study: What You’ll Get Wrong.” He focused his critique initially on an older New York Times article, which he accused of “shilling for the promoters of psychedelics.” He likened the clinics dispensing psychedelics for mental health treatment to “expensive spas where customers can go without a diagnosis of mental disorder and have a guided psychedelic experience.” He said:

Readers, including even experts, are falling for a hard sell job by venture capitalists who launder their funding of the study through a nonprofit foundation [i.e., MAPS] and seek not legalization of psychedelics and related illegal drugs but lucrative control over their use for therapeutic and recreational use.

The potential dangers with MDMA are real and even acknowledged by researchers like Jennifer Mitchell, the lead author of “MDMA-assisted therapy for severe PTSD.” She conceded the expense and time intensity of MDMA-assisted therapy and the concern of addiction. In Psychiatrist.com, she said: “Just like all the other amphetamines, you want to be very careful with them, to not over-administer, and to make sure that somebody doesn’t have an addictive tendency to the amphetamine.” You wouldn’t send it home with people to do in their own living room. “You do it in a good, trained treatment facility and that way, you don’t have to worry as much.”

But people will try it at home in their own living room unless its only dispensed in a treatment setting with trained therapists. But this adds to the expense and time intensity of MDMA-assisted therapy. And also leads to Coyne’s expectation of expensive, spa-like treatment centers.

Mitchell thinks younger generations and the prevalence of psychostimulant use among millennials and Gen Zers with ADHD will make them more accepting of psychedelic, MDMA therapies. She also looks to how MDMA has completely transformed some patients. “That’s typically the kind of change that takes years to occur in psychotherapy.”

But this does not change the fact that there is a lack of research on the impact of MDMA on the entire brain and its long-term effects Psychedelic researchers, including MAPS, don’t allow participants in their studies who suffer with comorbidities. The participants are PTSD without co-occurring like the ones noted previously—substance use disorder, eating disorders, depression, autism, compulsive disorders, schizophrenia and anxiety. Mitchell herself said, “We don’t yet know what these compounds in general—but MDMA in particular—do to those people who have these other disorders.” Could it make the depression worse, increase anxiety, or compound the substance use diagnosis in some participants?

Let’s not roll the dice with MDMA and PTSD. And let’s be sure the research studies are done in a way that clearly demonstrates its potential to heal an individual and not just give them a substance use problem or an intensified mental health disorder. Let’s insist that Phase 3 clinical trials for MDM and other psychedelics have at least the recommended 300 participants and a more credibly double-blinded methodology.

09/19/23

Don’t Roll the Dice with MDMA, Part 1

Photo by lil artsy: pexels.com

Rick Doblin, the founder and Executive Director of MAPS, the Multidisciplinary Association for Psychedelic Studies, was interviewed on Fox Business in January of 2023. He announced that the MAPP2 clinical trial study was completed in November of 2022 and had achieved its objectives. With two confirmatory Phase 3 Trials now completed, Doblin thought it “quite likely” the FDA will approve MDMA-assisted therapy by May of 2024. He predicted the significance FDA approval of MDMA-assisted therapy would be for the “whole field of psychedelic-assisted therapy” (i.e., for psilocybin, ibogaine, ayahuasca, mescaline and others). He added that MDMA was a therapy drug in the 1970s before it became the party and “rave” drug, ecstasy.

In the interview, Doblin emphasized that it was therapy that was main change agent. “It’s not the drug itself; it’s the therapy that is the primary act of treatment. And the MDMA makes the therapy more effective.” Don’t miss what he is saying—the therapeutic process is the primary treatment and the MDMA facilitated the therapy. Nevertheless, the results reported in the MAPS studies were dramatic.

In Mapp1, 67% of the participants in the MDMA-assisted group “no longer qualified for a PTSD diagnosis” after three treatment sessions. Another 21% had a clinically meaningful response, adding up to 88% of participants in the MDMA-assisted therapy group experienced a clinically meaningful reduction in symptoms. These participants also had statistically significant reductions in functional impairment relative to the placebo group with therapy. However, 32% of the placebo with therapy group also no longer met the criteria for PTSD. This percentage of change in the placebo group underscores the importance of the therapy as the primary change agent emphasized by Doblin. See the following graphic.

The results of the MAPP1 clinical trial were published in Nature Medicine, “MDMA-assisted therapy for severe PTSD” and provide a more detailed examination of the data underlying the Phase 3 trail results reported in the above graphic.

The study abstract reported the standard methodology used in the study as “randomized, double-blind, placebo-controlled” and that the placebo itself was inactive. The small number of participants in the study groups was also noted. There were 42 individuals in the MDMA-assisted group and 37 individuals in the placebo group. Turning to the celebrated primary endpoint of the study being met by 67% of the study participants, there were only 28 participants who no longer met the diagnostic criteria for PTSD. The researchers acknowledged that the participant population was smaller than originally planned, which they attributed to the pandemic. They then pointed to the results, saying “given the power noted in the study, it is unlikely that population size was an impediment.” Really?

The FDA described how researchers should design clinical trials to answer specific research questions for a medical product here, saying “Clinical trials follow a typical series from early, small-scale, Phase 1 studies to late-stage, large scale, Phase 3 studies.” Phase 3 clinical studies, like MAPP1 And MAPP2 were recommended to contain 300 to 3,000 participants who have the condition; and the length of study to be 1 to 4 years. The MAPP1 study only had 79 participants; and the length of the study was only 18 weeks. The Procedural timeline in “MDMA-assisted therapy for severe PTSD” said: “Following the screening procedures and medication taper, participants attended a total of three preparatory sessions, three experimental sessions, nine integration sessions and four endpoint assessments (T1–4) over 18 weeks, concluding with a final study-termination visit.”

The double-blindedness of the study was also neutralized by using an inactive placebo, given the psychoactive properties of MDMA. Participants as well as the researchers and others who assisted in the study (i.e., the trained therapy team) would know in which study group the “blinded” participants were in by observing participant’s behavior after they ingested the supposedly unknown substance. This limitation was acknowledged by the researchers:

Given the subjective effects of MDMA, the blinding of participants was also challenging and possibly led to expectation effects. However, although blinding was not formally assessed during the study, when participants were contacted to be informed of their treatment assignment at the time of study unblinding it became apparent that at least 10% had inaccurately guessed their treatment arm. Although anecdotal, at least 7 of 44 participants in the placebo group (15.9%) inaccurately believed that they had received MDMA, and at least 2 of 46 participants in the MDMA group (4.3%) inaccurately believed that they had received placebo.

Anecdotally then, 95% of the MDMA-assisted group (44 of 46) and 84% of the placebo group (37 of 44) were able to accurately state which research group they were in. The double-blind methodology was clearly ineffective and the dramatic results reported by the study should be understood with this in mind. Emphasizing the differences between the MDMA-assisted group and the placebo group for the lost PTSD diagnosis and a clinically meaningful response draws the readers attention away from these damning limitations for a Phase 3 clinical trial study: the miniscule population size and the failure to use a legitimately double-blinded study methodology.

The MAPP2 Clinical trial was completed on November 2, 2022, and MAPS announced the results on November 17, 2022. The primary and secondary endpoints for the MAPP1 and MAPP2 studies were the same. However, MAPP2 enrolled participants with moderate and severe PTSD, where MAPP1 only enrolled participants with severe PTSD. It had 104 participants.

The results for MAPP2 are expected to be in a peer-reviewed journal sometime in 2023: “The full data from MAPP2, expected to be published in a peer-reviewed journal later this year [2023], will support MAPS PBC’s new drug application to be filed with the U.S. Food and Drug Administration (FDA).” MAPP2 treated its 104 participants “living with PTSD with either MDMA-assisted therapy or placebo with therapy.” The results were said to confirm the findings from MAPP1, with no serious adverse events observed among the participants. Rick Doblin was quoted as saying:

When I first articulated a plan to legitimize a psychedelic-assisted therapy through FDA approval, many people said it was impossible. Thirty-seven years later, we are on the precipice of bringing a novel therapy to the millions of Americans living with PTSD who haven’t found relief through current treatments. The impossible became possible through the bravery of clinical trial participants, the compassion of mental health practitioners, and the generosity of thousands of donors. Today, we can imagine that MDMA-assisted therapy for PTSD may soon be available and accessible to all who could benefit.

MAPS went on to give a brief history of where MDMA had been legally used in therapy for a decade before it was “criminalized” (i.e., classified as a Schedule 1 Controlled Substance) in 1985. MAPS was founded the next year “to fund and facilitate research into the potential of psychedelic-assisted therapies; educate the public about psychedelics for medicine, social, and spiritual use; and advocate for drug policy reform.” The publication of the MAPP1 clinical trial was said to be a major milestone. MDMA-assisted therapies are being planned or conducted to evaluate “conditions closely related to PTSD” such as substance use disorder and eating disorders. Trials of other therapies with couples and group therapy among Veterans are also being planned or conducted.

“These additional Phase 2 trials will determine if MDMA-assisted therapies may be effective for other conditions or with other treatment modalities commonly used to address PTSD.”

Psychiatrist.com echoed these expectations if the FDA approves MDMA-assisted therapy, adding that approval would enable the exploration of the drug’s benefit for depression, anxiety, substance-use disorders, autism spectrum disorder, and compulsive disorders. The lead author of “MDMA-assisted therapy for severe PTSD” described for Psychiatrist.com how MDMA acts on the amygdala, the part of the brain that processes fear-related memories and facilitates memory retrieval. When used in a clinical setting (i.e., with therapy), “they say it helps untangle, consolidate, and release deeply-ingrained memories that may have been suppressed.” MDMA also facilitates the release of oxytocin, a hormone that makes you feel self-compassion and connected to others. The end result is MDMA helps create an environment in which “participants take comfort in their therapy team, approach their memories from a different lens, and ultimately begin to heal.”

This description of MDMA and oxytocin needs to be nuanced, as it glosses over some of the not-so positive connections made with the release of oxytocin. In “The two faces of oxytocin,” the American Psychological Association said recent research has shown that oxytocin is part of a response to social separation and related stress. When it operates during times of low stress, oxytocin physiologically rewards people with good social bonds with feelings of well-being. However, it may “lead people to seek out more and better social contacts” during times of high social stress or pain. This two-faced context for MDMA facilitating the release of oxytocin again underscores the importance of the therapeutic aspect of MDMA-assisted therapy.

Should the FDA approve MDMA-assisted therapy? Should we roll the dice and see what happens? A recent survey noted Americans have mixed feelings. According to the UC Berkeley Psychedelics Survey, 61% of registered American voters support legalizing regulated therapeutic access to psychedelics. Thirty-five percent of those supporters said they strongly support such action.

And yet, there were 35% who opposed it, with 61% also saying they do not see psychedelics as “good for society” and 69% who don’t think psychedelics are something they would personally use. “The data suggested voters are open to policy change but also have significant reservations.”

A reliable answer to whether the FDA should approve MDMA-assisted therapy is hampered by the Schedule I classification of psychedelics, which creates multiple hurdles that researchers have to get over in order to investigate their therapeutic value. And further, it seems supporters of psychedelic-assisted therapies are following a strategy taken from the playbook of legalizing recreational marijuana—focus on the legalization of psychedelics one state at a time. More on this in Part 2.

09/12/23

Bad Things Could Happen with ADHD and the Adderall Shortage

In case you didn’t know, the U.S. has been in the midst of an Adderall shortage since October of 2022 when the FDA announced a shortage of the immediate release formulation. At the time, the FDA said some manufacturers having intermittent manufacturing delays, while others reported they could not meet the increased demand. The agency said it has posted information on the shortage and a list of current manufacturers that are still available, and will continue monitor supply and assist manufacturers “with anything needed to resolve the shortage.” But the shortage problem was still with us.

Kate Underwood reported in Green Matters that as of June 2023, the FDA’s Drug Shortages still listed Adderall as a current shortage. While manufacturing disruptions are the typical issues leading to drug shortages, other concerns such as increased demand for the drug, and shortages of the active ingredient or supplies can also occur. Additionally, drug manufacturers don’t usually make a single drug. So, increasing the production of a drug in short supply could negatively impact the availability of other drugs made in the same facility.

Writing for Vox, Dylan Scott added another factor to the Adderall shortage—it is a stimulant drug with the potential for misuse or addiction. The DEA lists Adderall and other stimulant-based ADHD medications as Schedule II drugs, meaning they are considered to have the same addictive potential as many opioids. “The fear is that Adderall would follow the same path as opioid painkillers: careless overprescribing would lead to an epidemic of drug addiction — this time, to stimulants.”

One of the active ingredients in Adderall is amphetamine, and therefore the drug is regulated as a controlled substance under federal law. Its potential for abuse has long been recognized, with the cliche example being college students taking the drug to help them study. A 2018 study by federal researchers found that about 5 million Americans misused a prescribed stimulant, of which Adderall is the most common, at least once in the past year; about 400,000 misused stimulant drugs frequently enough to be characterized as having a disorder. (About 2.7 million people in the US report they have an opioid use disorder.)

Medical News Today described the medical uses, side effects and misuse of amphetamines. The opening sentence on the page says, “Amphetamine is a powerful stimulator of the central nervous system. It is used to treat some medical conditions, but is also highly addictive, with a history of abuse.” Amphetamines are used today to treat ADHD. In the past it has been used to treat narcolepsy, but concerns with side effects have led to it being increasingly replaced by modafinil.

Physical side effects can include low or high blood pressure, erectile dysfunction, rapid heart rate, blurred vision, dry mouth, tics, nosebleed, and others. Psychological effects may include apprehension, anxiety, irritability and restlessness, mood swings, insomnia, obsessive behaviors and grandiosity, or an exaggerated sense of one’s own importance. “In rare cases, psychosis may occur.”

When used as a recreational drug it can speed up reaction times, increase muscle strength and reduce fatigue. A methamphetamine called Pervitin was used by Hitler’s forces for these benefits during WW II; see “Repeating Past Mistakes.”

The DEA Drug Fact Sheet said the following about amphetamines:

The effects of amphetamines are similar to cocaine, but their onset is slower and their duration is longer. In contrast to cocaine, which is quickly removed from the brain and is almost completely metabolized, methamphetamine remains in the central nervous system longer, and a larger percentage of the drug remains unchanged in the body, producing prolonged stimulant effects.

Chronic abuse produces a psychosis that resembles schizophrenia and is characterized by paranoia, picking at the skin, preoccupation with one’s own thoughts, and auditory and visual hallucinations. Violent and erratic behavior is frequently seen among chronic users of amphetamines.

In order to mitigate the potential for abuse, the DEA sets production limits for the manufacturers of Adderall and its generic competitors. In 2019 the DEA announced it was permitting more production of Adderall, but we still don’t know exactly how much production has been authorized or what limits have been set for individual companies. “We don’t know which company gets how much.” Some companies say they are short, but the DEA replies they haven’t used all their supply, so there’s back-and-forth finger-pointing going on. Listen to the On Point program, “What’s behind the ADHD drug shortage” to hear more discussion of this issue.

However, there also seems to a problem that stems from the opioid crisis. In 2021 there was a settlement with the three largest drug distributors that “flag and sometimes block” pharmacies’ orders of controlled substances like Adderall when they exceed a certain threshold. Bloomberg reported that pharmacists said it restricts their ability to fill many different types of controlled substances in addition to opioids. The rules force some independent pharmacists to use creative workarounds. “Sometimes, they must send patients on frustrating journeys to find pharmacies that haven’t yet exceeded their caps in order to buy prescribed medicines.”

This was illustrated in an article for STAT, written by a “biopharma supply chain specialist” who can’t find the Adderall she’s prescribed. She said she’s been using Adderall for ten years to help her function. Then in February of 2023, she was unable to fill her prescription at the pharmacy down the street. She finally was able to fill it at the 20th pharmacy she called, although it meant a 50-minute drive. She recommended several steps to increase the transparency in the supply chain of Adderall. “This will foster efficiency, reliability, and the ability to identify potential risks before they spiral out of control, as has happened now with not just Adderall but other ADHD medications.”

Money making considerations are also involved in the Adderall shortage. Vox reported that after Adderall was approved in 1996, it quickly became the most commonly prescribed treatment for ADHD, although Ritalin and other drugs are still used. PsychCentral listed Adderall as the fourth most prescribed psychiatric medications, with 26.24 million prescriptions in 2020. Other medications prescribed to treat ADHD within the top 25 most prescribed drugs included: Concerta (10th), Vyvanse (20th), and Focalin (24th). Three of the most expensive medications, making the most money for their manufacturers were Concerta ($3.28 billion), Vyvanse ($3.01 billion), and Adderall ($2.35 billion). ADHD prescriptions accounted for over a third of the prescriptions in 2020.

Axios reported some different statistics for both generic and branded Adderall prescriptions, according to IQVIA, a health research firm. Since 2017, IQVIA reported Adderall prescriptions rose from 32.2 million to 41.4 million. This was up more than 10% from 2020. See the following graph taken from the Axios article.

Axios said prescriptions skyrocketed as it became significantly easier to get a diagnosis of ADHD and a prescription for Adderall during the pandemic. A wave of telemedicine startups emerged on TikTok and Instagram, suggesting people should look into ADHD medication if they felt distracted. The Wall Street Journal reported some startups diagnosed people with ADHD and prescribed stimulants after 30-minute video calls — “entirely remotely, and much faster than a typical diagnosis from an in-person psychiatrist.” The trouble with rapid diagnoses is it can be difficult to tell whether the problem is actually ADHD. “Anxiety can present as ADHD, and depression can present as ADHD.”

This spike in diagnoses raises questions about whether ADHD is being over-diagnosed, but that’s really a question that predates the pandemic. See (“The Tip of the ADHD Iceberg” and “National ADHD Epidemic”) for more information. If supply can’t keep up with demand, experts are warning we could have a public health crisis. Even worse, we could face another movement of people from the pharmaceutical market to the illicit drug market, as what happened with opioids. Leo Beletsky, an epidemiologist at Northwestern University said, “Lots of bad things can happen. … Conditions are very much ripe for that to happen here.”

Overdiagnosis of ADHD

In “Twenty-Year Trend in Diagnosed Attention-Deficit/Hyperactivity Disorder”, Xu et al estimated the prevalence of diagnosed ADHD among US children and adolescents from 1997 to 2016. They estimated the prevalence of diagnosed ADHD among US children and adolescents was 10.2% in 2016. There was a consistent upward trend across subgroups by age, sex, race/ethnicity, family income, and geographic regions. “These findings indicate a continuous increase in the prevalence of diagnosed ADHD among US children and adolescents.” They said the common perception that ADHD overdiagnosed in the US was not supported by the scientific evidence. But that is not the end of the matter.

A 2021 study by Kazda et al, “Overdiagnosis of Attention-Deficit/Hyperactivity Disorder in Children and Adolescents” said that questioning the appropriateness of ADHD diagnosis has grown along with the diagnosis rates. They acknowledged that disagreement continues about how much of the increased diagnoses can be attributed to true increases in frequency, improved detection or diagnostic inflation because of misdiagnosis and/or overdiagnosis. They systematically reviewed the research literature to identify and appraise any evidence of overdiagnosis of ADHD in children and adolescents. They found evidence of overdiagnosis and overtreatment of ADHD.

Of the 12,267 potentially relevant studies retrieved, 334 (2.7%) were included. Of the 334 studies, 61 (18.3%) were secondary and 273 (81.7%) were primary research articles. Substantial evidence of a reservoir of ADHD was found in 104 studies, providing a potential for diagnoses to increase (question 1). Evidence that actual ADHD diagnosis had increased was found in 45 studies (question 2). Twenty-five studies showed that these additional cases may be on the milder end of the ADHD spectrum (question 3), and 83 studies showed that pharmacological treatment of ADHD was increasing (question 4). A total of 151 studies reported on outcomes of diagnosis and pharmacological treatment (question 5). However, only 5 studies evaluated the critical issue of benefits and harms among the additional, milder cases. These studies supported a hypothesis of diminishing returns in which the harms may outweigh the benefits for youths with milder symptoms.

They recommended that practitioners, parents and teachers carefully weigh the potential benefits and harms that can go along with ADHD diagnosis and treatment, particularly when individuals with milder symptoms are identified. “For this group, the benefits of diagnosis and treatment may be considerably reduced or outweighed by harms.”

In his review of the study for Mad in America, Peter Simons said “Each [of the 334 included studies] provided data on at least one of the five conditions. They found that all five conditions were supported by the research.” There was also significant evidence of harm after diagnosis, including how a biomedical view of difficulties was associated with disempowerment. He said the researchers warned that diagnosis “can also deflect from other underlying individual, social, or systemic problems.”

Because there is no biological test for ADHD, and the diagnosis is applied subjectively across age, gender, race, and socioeconomic status, there is room for the diagnosis to expand. Additionally, as the diagnostic criteria are loosened, rates of ADHD have increased. The researchers confirmed that a large proportion of the new cases are on the “mild” end of the spectrum. Rates of stimulant treatment for ADHD have also increased, including those with “mild” or “subclinical” ADHD.

In his book, Saving Normal, Allen Frances, a psychiatrist and the former chair for the DSM-IV, said in retrospect, he wishes there had been cautions in the DSM-IV about overdiagnosis and tips to avoid it. He thought they missed the boat. “No one dreamed that drug company advertising would explode three years after the publication of the DSM-IV or that there would be the huge epidemics of ADHD, autism, and bipolar disorder—and therefore no one felt any urgency to prevent them.” For more on the DSM and overdiagnosis, see “Guild Interests Behind DSM Diagnosis.”

The Demedicalization of ADHD

Not only does it seem ADHD is overdiagnosed, there are some researchers who question whether the diagnosis of ADHD meets the criteria for a disorder set out in the manual used by the medical and psychiatric fields. Freedman and Honkasilta argued that the definition of ADHD relies on subjective cultural values to define “abnormal” behavior. Reviewing their study for Mad in America, Peter Simons said, “The diagnosis thus fails to meet the criteria, as stated in the DSM, that disorders must not be reducible to behavior that violates social norms.” The researchers argued that ADHD should be demedicalized and removed from the DSM, like homosexuality was in 1980.

The British Child and Adolescent Psychiatrist Sami Timimi said in his 2017 article, “Non-diagnostic based approaches to helping children who could be labeled ADHD and their families” that it required little intellectual effort to conclude that the concept and definition of ADHD “is replete with problems around reliability and validity.” The diagnostic guidelines note how ADHD behaviors may be minimal or absent in several settings. These include when the person in under close supervision, engaged in an activity that is particularly interesting to them or in a new, novel setting. Even if a genetic basis for ADHD were found, we’d still have to ask why such behaviors should be treated as disorder rather than differences. “Deciding where to draw the line between what we consider part of the “ordinary” spectrum of behaviours and what we decide is “pathological” is more dependent on cultural than scientific processes.”

He said if he asked the question, “what is ADHD?”, it is not possible for him to reply by referring to a particular known pathological abnormality. Instead, he would have to provide a description ADHD as the presence behaviors like of hyperactivity, impulsivity and poor attention. This was contrasted with answering the question, “what is diabetes?” “Diagnosis in that context sits in a “technical” explanatory framework. In psychiatry what we are calling diagnosis (such as ADHD) will only describe but is unable to explain.”

Timimi concluded that ADHD is then not a medical diagnosis, but rather a descriptive classification. And since it is not a medical diagnosis, “it is not surprising that there has been a failure to find any specific and/or characteristic biological abnormality such as characteristic neuroanatomical, genetic or neurotransmitter abnormalities.” He thought the idea of ADHD as a medical diagnosis was past its use-by date and should be discarded.

ADHD is a cultural construct. It is often argued that the use of categorical constructs like ADHD enables the study of aetiology, treatment and prognosis. Evidence outlined above demonstrates that far from enabling any advancement of knowledge or clinical practice, it has created an illusion of progress and resulted in exposure of possibly millions of children and young people to unnecessary and potentially harmful medications. It has spurred on liberal use of stimulant medication, despite the lack of evidence for improved long term outcomes resulting from this.

We are not at the cultural crossroads with ADHD today that we were with homosexuality in 1980. ADHD will likely continue to be a diagnosable disorder. Yet serious consideration of the above discussion of its overdiagnosis, its future demedicalization and removal from the DSM as a disorder and the lack of improvement in long-term outcomes of individuals taking ADHD prescribed stimulants should be done. In retrospect, the Adderall shortage may not truly be the serious public health crisis that is getting all the press coverage. But if it leads people from the pharmaceutical market to the illicit drug market in search of their amphetamines to help them function, like the person in the STAT article, “Lots of bad things can happen.”