Final Panel -

Eric Hermes, MD, Veterans Health Administration • Caroline Huang, PhD, U.S. Food and Drug Administration • Michelle Kim Leff, MD, MBA, Substance Abuse and Mental Health Services Administration • Lisa Robin, Federation of State Medical Boards • Gerard Sanacora, MD, PhD, Yale University

Hermes: Ketamine for mental health in the community - ketamine that VA delivers, over half, is from community providers. Limited by law for amount of data that can be asked of community providers. Dark spot in quality of care delivered to Veterans.

Leff: SAMHSA has been following policy and is not considered an allowable expense for SAMSHA funds. Not collecting ketamine clinical data currently. Access and affordability important.

Gelfand- DOD - ketamine is very much an orphan drug with evolving indications that will have impact to large segments of the population.

No fiscal incentive to pursue possibilities with this generic drug.

5 indications including acute pain - at least 40 years of evidence demonstrating the safety and efficacy in a trauma environment, echoed in at least half dozen other societies in trauma care. Ketamine as preferred trauma drug for moderate to severe pain in potentially unstable patients. Because of narrow FDA classification for ketamine, DOD has been unable to develop delivery systems that can be used in trauma and down range environment. Found even when given at higher doses, side effects are virtually non-existent. Hemodynamic stability maintained. Only FDA analgesic auto-injector is morphine. We are locked in a difficult situation. All the evidence would have us use ketamine as medicine of choice, but no way to safely administer it in pre-hospital environment. What evidence from 50 years of work is sufficient for the FDA for reclassification for analgesic use? That is goal of DOD, and has been using in trauma pain management in 2012 guidelines, but unable to implement delivery system. Low-dose analgesic use for trauma environment.

Emcee- ketamine is a repurposed drug - part of practice of medicine is to work with off-label, repurposed drugs - FDA indications are not required for every single repurposed medication.

Huang - FDA - gap in accessibility and acceptability and effectiveness for approved medications from provider and patient populations. Not surprising clients want to use ketamine. Want to be sure we can stand behind safety and efficacy if we have approved it. Looking at modernization of clinical trials - clinical trial innovation. Guidance on real world data and evidence. There is a recognition of FDA on the need for better at better data collection. Hopefully the start of collaboration. There is a lot of need. Important to address responsibly.

Robin - need guidance from FDA, otherwise patchwork of regulations will come from each state. There must be a policy framework that can support good care. Loopholes about off-label use, are people being exploited? Disparity in access.

Sanacora - most struck by knowledge gap, even from the speakers. Inaccuracies even in today’s presentation. COming soon - head to head study of Spravato vs iv ketamine. (Note: This has been done already) - Disconnect between what’s being done in the community, what is considered safe by FDA standards, and how to study, since what is happening in the real world is considered unsafe.

Emcee- Could we use real world data to inform and justify the dose used in studies or be used to structure the studies better?

Sanacora- Need more controlled clinical trials. Need both types to be informed by what is safe and efficacious. Studies should reflect what is being used in the real world.

Gelfand- Joint Trauma Registry tracks patients- often gaps in data - as they go through evacuation system.

Most analysis comes from trauma registry, what it has shown is more ketamine used in special forces. Indigenous populations got more ketamine (in Iraq, Afghanitsan) than military personnel. Higher doses didn’t present any significant side effects, or need for advanced airway support. Higer doses than prescribed by TCCC guidelines. Suggests they were titrating to effect. Each patient titrates differently, titrated up to 60 mg per hour.

Literature supports what we’re doing and what we’;re doing is based on the literature.

Emcee- Are there ways to gather info from legit medical practices online?

Sanacora- Some type of registration is necessary. REMS forces the data to be collected.

Refers to online study of 12000 people where only 3000 respond (most likely Mathai, et al, 2024). What happened to the other 9000 they could have died and we don’t know?

Average dose is above 1 mg/ kg well above what most FDA guidance is safe. Most guidance says no more than 60 mg per day. WHat people are getting much above that in the community.

Emcee- Benefit in navigating the FDA process for a repurposed drug like ketamine

Leff- SAMSHA interested in what’s going on illicit and licit use and trying to get a sense of what’s going on, harm reduction strategies, looking at national data trends

Emcee - Why being used? Areas of unmet need.

Gelfand- what you might need for mental health uses is not the same as the acute pain or chronic pain uses. There may be some relationships and safety data, you can pool populations to get combined safety information. In some cases some mental health indications may not be supported, however in pain management there is over 40 years of use.

Sanacora - (a propos nothing) - How dangerous is this use? It’s being used more widely every day, but we don’t lnow if its safe or efficacious.

Gelfand - animal studies not necessarily helpful. Generations of experience and literature.

Sanacora - would be nice to have that data to look at it. (Note- We HAVE the data. He has not looked at it.)

Ah ha moments for panelists-

Haung- Need more and better data to make better regulatory decisions. Room for innovation in study.

Gelfand - ketamine- has it shown non-inferiority to an existing medication like an opiate? Opiate may be superior inc ertain cases, but include much more risk. Common sense approach.

Leff - considering various bioavailability- hope is route of administration can be used in least restrictive setting considered safe so more available to everyone.

People canrt go to iv clinics 2-3 times a week.

Emcee- in product development, will it reach the populations

Sanacora - almost all work done in this field is NOT represnetative of the US population. Studies cost money, and its difficult to get fundng. Mechanism of funding essential. (Note - are his studies for Spravato not representative and generalizable?)

Who’s going to fund it?

These treatments are part of a treatment system, and there are huge contextual effects, like in all of medicine. The data doesn’t support thaat the experience matters. If told it matters, it will matter/. If told it won’t matter, then it won’t matter as much. Need to be generalizable to braod popualtion of the US.

Note- again - Sanacora studied Spravato for Johnson & Johnson, the pharmaceutical company who funded the research.

Robin - proliferation of clinics not doing good medicine. Fear of bad outcomes. Links to IV hydration clinics, some of which offering ketamine. “It’s kind of the “wild west” (note - Second mention of “Wild West”— will do a thread on that to follow)

Recording, transcript and slides posted later this week. Will link here, remove contemporaneous notes and do a post-meeting summary within the week.

Panel, continued -

FTC uses different analysis in different types of cases

Competent, reliable scientific evience required

DiStefano - biggest surprise is for how many indications ketamine is being advertised- 30 different uses being advertised beyond reasonable uses - lyme’s asthma, dementia, false claims

How to be a discerning consumer - can’t edxpect a lay person to be able to sift through an evidence based medicine analysis for any given purported use of ketamine.

(But again, Spravato plus antidepressant IS being advertised directly to consumers - Direct to consumer advertising started with Reagan.)

Berstein -

in study of telehealth and nline pharmacy - as result of pandemic move ytowards telehealth, 69% said they would be comfortable receiving a contolled substance exlcusively through tel;ehealth. How do you know if youc an trust them?

WHat are best practices?

There are some -

1. Are you talking to a real person? A real clinician? Or an ai computer?
2. Verifiy credentials
3. Platform hipaa complaint?
4. Are claims too good to be true?
5. what does your health provider say?

Don’t just find an online provider on google and just assume what they are offering is legal.

Around 50% believed if search shows up first, then that is legal and okay. And that is scary.

FTC: opportunity to make money - parallel to stem cell clinics - hundreds of clinics - inherent danger in going online and looking for therapy rather than through the normal course of consultation with physician. People will be drawn to believe misleading claims

Emcee- Some people searching online have an unmet need and are looking for a solution.

Berstein - similar to medspas, stem cells, botox and wieghtloss drugs.

There are real needs and this can be a real treatment.

Emcee- drug developers also called out as making claims on their drugs options

Policy and Regulatory Challenges for the Medical Use of Ketamine

Federal & State legal landscape

Examining restrictive definitions of sedation, anesthesia, state by state - some of the most restrictive states:

Utah-

Florida-

Oregon-

(More on this in future edit)

Policy and Regulatory Challenges for the Medical Use of Ketamine

Day -

on FDA risk alert on compounded pharmacy ketamine - a breakdown of what the alerts did and did not say. Confusion of clinicians in the industry.

Ketamine at 40 mg per kg, something like a 3000mg dose for a 70kg human, started to show neurotoxicity in rates, something the FDA cites in risk alert

Day mentions Hull study on at home, that has been used for over 30 years.

A number of studies, which clinicians use to evaluate the appropriateness of clinical use.

How do we achieve and maintain compliance?

Alliance for Pharmacy Compounding releases best practices for preparing and dispensing compounded ketamine by pharmacies in April 2024

Lacking DEA perspective

Pharmacist Legal Obligations & Diversion Concerns

Telehealth - verified patient-prescriber relationship, considering prescriber scope of practice, monitoring staff diversions Dosing limits- refers to clinical literature and other best practice guidelines Dosing forms - consider dispensing in child-resistant container.

In compounding the primary routes are via mouth and intranasal Documentation, Patient Education, written, verbal patient education - not multi-months worth of supply, emphasizing side effects, no driving or combo drug use.

Cannot dispense to practitioner, DEA says must send to patient. (Constructive transfer)

503A vs B - B’s outside the scope of traditional pharmacy practice - B could outsource to any licensed state pharmacy at wholesale

Ketamine is not esketamine. Distinct molecules. WHile esketamine is right for some patients, it’s not for everyone. ACcess to the right therapy is key.

Operational protocols - physician, pharmacy

Panel:

Gail Bormel, RPh, JD, U.S. Food and Drug Administration • A.J. Day, PharmD, RPh, National Community Pharmacists Association • Lisa Harding, MD, Yale University • Seth Mailhot, JD, Husch Blackwell • Lisa Robin, Federation of State Medical Boards • Jenni Wai, RPh, MBA, Ohio Board of Pharmacy

More regulation to come, greater accountability for practitioners, further limitations on the practice - potential for bad actors to come in and take advantage of a lax approach - only appropriate treatment is administered.

Corporate practice of medicine -

Lisa Harding - Regulation is not necessary restriction. Regulation can be synonymous with safety.

Money - proliferation of ketamine clinics is questionable - access to care - why do compounding pharmacies even exist? Is it a way to circumvent the process?

People can want what they want, but regulations made by the adults in the room know what is best for people. Alleging - not enough evidence in the prescription of ketamine.

Day - why do compounded pharmacies exist?

Practitioners writing for ketamine assisted therapy are physicians with valid medical licenses who are licensed, trained, and make the determination of what to prescribe to their patients.

Off label is still legal and meets regulatory requirements. This is a valid prescription written by a physician.

Emcee- Is there a way to get approved products that may help where there is not coverage for products.

Harding - regulations keep people safe. Not evidence exists.

Bormel - FDA risk alerts are meant to provide information about what FDA is seeing. Compounding ketamine is legal if done within applicable sections of the Act. Seeing more adverse reports in more compounded ketamine by mouth and intranasal. Released statements To make everyone aware of using ketamine in a safe manner. FDA released statement so physicians could take better care of their patients.

Emcee- risk alerts led to industry improving care with ketamine

Wai - Ohio Board of Pharmacy - prescription monitoring program exists when ketamine is prescribed and sold.

Decrease in wholesale and increase in patient-prescriptions, which is where compounding pharmacies step in - with patient access at home and telehealth medicine these sessions, some of them do a good job, some may be lacking, there needs to be a standard of care to incorporate telehealth and create a set of standards. Are patients being counseled appropriately?

CLinics popping up - equates to weightloss clinics and botox clinics

Harding - ketamine is not a panacea in psychiatry - regardless of setting, they have ti have the appropriate indication for treatment. That’s where online is lacking. Does that person have an appropriate psychiatric provider?

Psychiatrist plus psychotherapist are basic team

Biggest risk - completed suicide - models of care must keep people safe and patients must meet appropriate diagnostic threshhold. Why is it all these non-psychiatrists are clamoring to treat psychiatric patients but not clamoring to take insurance and use established treatment options. Refers to Sanacara (also a psychiatrist)

Robin - State licensing boards - medical and pharmacy board communication - concerns on pill mills, proliferation of practices, especially with telemedicine practice. Refers again to physician telehealth practice that was shut down for prescribing thousands of prescriptions.

Wai - in Ohio Pharmacy and medical boards are communicating. Points out even compoudning pharmacies can make the medicine inappropriately

Mailhot - seeing focus on telemedicine as a concern and potential source of increased regulation. Advisory opinions - work within scope of practice

Day - what are we doing to build a system of care?

Whether compounded or not, ketamine is used in a variety of indications - how do we put guardrails but not over restrict.

Emcee- is the prescription monitoring program a data-source?

Wai - Possibly - looking for trends in data - out-of-state pharmacy in Ohio has been increasing. There is a need for compoudning pharmacies, but there are shifts in data

DiStefano - Online Promotion and Access to Ketamine —

Survey of Maryland ketamine clinics - Fraud, Misleading Advertising

Industry Standard drug website - example spravato website - Top - FDA approval, side effects, safety information

Most Advertised and Associated Costs

• Infusion 360-2500
• Ketamine Assisted psychotherapy - 150-500
• Consultation - 0-390
• Esketamine - 250-300
• IM- 450
• Oral - 89
• Intransal 300 (not esketamine)

(Note- Are costs included on the spravato website?)

Claims- ALL ketamine therpaist success rate over 90%

Minimize side effects, addiction, risk

takes some quotes out of context. The sample website said with medical sueprvision there is less risk**

5 sites minimize risk of abvuse

3 sites claimed ketamine non-addictive 7 sites did not disclose adverse effects

Advertisements for off label with lack of high quality data supporting use

10 sites did not disclose mental health conditions not FDA approved

Takeaway - Maryland consumers are misled, data suggest at least 800 clinics available nationwide

Heifets- Setting expectations about ketamine therapy for mental health indications

works with journey clinical and osmind

1. Patient expectations shape measured efficacy?
2. What kind of info do patients get about safety and efficacy?
3. Real world evidence- hard to collect data on safety

Potent therapy carries risk. Still an unmet public health need. Access to care is a big, severe issue. This does require a powerful approach. RIsk must be acknowledged.

It’s hard to blind ketamine studies. Is it the drug? The trip? Non-drug factors like preparation and what happens afterwards (integration into ongoing change in life) .

Small trial - minus the trip - approximated single-infusion studies- found - no separation between ketamine and placebo. Patient expectations affect outcome.

Patient expectations - what kind of media are patients being exposed to?

Psychedelic Media Exposure Questionnaire -

Almost half of patients identified ketamine as a psychedelic.

How is advertising impacting patient perceptions (Note - patients are advertised to for psychiatric drugs beyond ketamine)

There is a signal for efficacy - How do you quantify risk? Are safety claims reliable?

Medical news coverage in China - ketamine misuse increasing, suggest rescheduling schedule 1.

Ilisa Bernstein, PharmD, JD, Bernstein Rx Solutions • Michael DiStefano, PhD, MBE, Colorado University Anschutz, Skaggs School of Pharmacy and Pharmaceutical Sciences • Boris Heifets, MD, Stanford University School of Medicine • Richard Quaresima, Federal Trade Commission

FTC approach? - Truth in advertising - claims must be adequately substantiated- each claim and case has to be analyzed individually - what is competent in reliable scientific evidence is going to vary. A properly conducted rigorous clinical evidence. It has to be truthful, not misleading.

Emcee- Online promotion and chatter may complicate our ability to study them?

Heifets- Absolutely. Hype gets peoples hopes up. WHat happens when it doesn’t work?

EMcee- Ketamine is an anesthetic with dissociative properites- regulatory agencies don’t use the word psychedelic.

Berstein- this is why I stay away from Reddit. It’s not just one box about concern for online promotion and access. There are iv clinics that are brick and mortar. Then you have telemedicine and telehealth advertising online offering the drug. Then you have ketamine pharmacies selling medicine online. Online pharmacy type that takes your money and you dn’t see the drug. Compounding pharmacies are a different level.

Direct to consumer promotion is the problem. Compounding pharmacies don’t sell directly to consumers.

There are different risk for different types of practices.

Emcee “online drug sellers”

Quaresima - the truth is required/

Identifying Safety Concerns and Potential Risks Associated with the Use of Ketamine Products Discussion: • Francesca Cunningham, PharmD, U.S. Department of Veterans Affairs • Megan Ehret, PharmD, MS, BCPP, University of Maryland Baltimore School of Pharmacy • Joseph Palamar, PhD, MPH, New York University Langone Health • Mark Rogge, PhD, University of Florida School of Pharmacy • Eric Schwenk, MD, Thomas Jefferson University

Cunningham - K hole = dissociative anesthesia — used when you didn’t want a patient’s BP to catapult

Esketamine— Safety - tracking spontaneous reporting, looking at databases, medication evals, chart review, ask providers for live data

esketamine- mandatory tracking - real-time data-capture - collect safety info for REMS as well as for Veterans - Veterans more susceptible to adverse effects that the general population is not

20 minute monitoring

Typical - dissocaiton 80%, mild hypertensdion, tachycardia, treatable hypertension less than 10% - peak hypertension effects at 20 minutes, return to normal at 2 hours.

This is safe. Continuing to track. Looking at subjective information to be able to track. Standardize subjective info to make quantifiable

Why did you stop? What were longer term side effects? Just now starting to look at this info.

Ketamine - Difficult to track the safety? Difficult to capture data in our system.

Used more frequently in IM and in ER departments- what’s happening to the patient? Drug-drug interactions?

Medical Use Eval coming soon to be able to capture more data.

Schwenk — abuse - discrepancy between toxicity in medical use vs recreational use - in clinical settings, toxicity is not seen as much as recreational use.

Cystitis - small study of 4000 partients, within 90 days of infusions - 116 topic of focus, but only 2 patients were posisbly related to ketamine, and even those, it was probably the cathetet.

1000 mg of ketamine over series of weeks - no signal

Not rising to level of clinical concern

Neurotoxicity in rodents - in 20 plus years, we are not seeing patients with memory deficits. MOCA 5 day ketamine infuisions continuious, .7 or .8 mg per hour — on average cognitive assessments did not worsen - some improved out to 12 months after treatment. - upcoming published research

The rat studies are not consistent in what we see in humans

Rogge-

worked on products on market for decades, and realized a lot mopre we don’t know about these products than what we doknow. Drugs on market - we don’t understand them.

Unpredictability with ketamine -

matobolism - metabolized by 3a, 2b, 2c pathways - a lot of variability n those pathways. Why do some people end up with higher bp and others won’t at the same dose? Changes in metab?

Rate of increase in bp in the dissociative range —

How does ketamine get into the brain? Passive? Active transporters moving in and out of brain?

More research needed.

Potential opioid situation. How can we avoid? Could ketamine be a gateway drug? What can we do to make sure people getting it under proper conditions don’t go on to use illegal.

Poisonings— due to purity? Higher doses? Route of admin?

Boundaries - outpatient? Are there safe means? More advanced devices to prevent overdose? Opportunity there, but better to manage now than to have to fix it later

Emcee- where is the data? It’s not in health records. It’s not in usual sources of real world data and evidence? How do we bridge data gaps?

Palomar- hard to harmonize data

Comparing trends in prescribing — compare patient and physician response

How easy was it to get ketamine? Did you lie? Do you sell the ketamine? Night club people, college students

Emcee- when people are stigmatized in the medical system, they may go on to seek medicine in illegal settings

Schwenk -

back to COhen’s comment on need for RCT- registry pluys RCT, requires effort and funding

FDA should lower the bar to study.

Used as anesthetic, ketamine is not used as much as in pain and psychiatric use.

Cunningham - pragmatic clinical trials then follow over the long term

Emcee- conversations with the patient-

Patient screening, accessibility, insurance, patient preference - can they come in 2x weekly for esketamine? Can they come in for ECT? Patient level is important - talk about risks and what we don’t know. Accessibility is important.

Hour break

Identifying Safety Concerns and Potential Risks Associated with the Use of Ketamine Products Megan Ehret, PharmD, MS, BCPP University of Maryland Baltimore School of Pharmacy

Tolerability & Safety

Psychiatric Side Effects Dissociation- some literature shows decrease of disocciation over subsequent administrations, peaks within 40 minutes, resolves in 1-2 hours CLinical Rating scales (CADSS) too challenging to adminsiter Psycotomimetic - pre-existing vulnerability - (aka psychedelic) Dizziness, drowsiness, light-headedness - fall risks Long term exposure? Cellular or lolecular evidence of neurotoxicity - DOn’t know if we have the evidence yet

Hemodynmaic - increase in BP 10-50%, observed in 20-50 minutes of treatment Resolve in 2-4 hours

with esketamine, we have the REMS that dictate when and what to measure 20-30% have increased BP

Genitourinary - 20-40% of recreatinal users - nocturita, painful hematuria, dysuria, urinary urgency, incontinence - dose-dependent relationsip

Abuse Liability Increased liking, (cites 2017 and 2008 research)

Esketamine vs ketamine REMS?

Esketamine required to reduce occuraence of severity esketamine- increased risk of seadation, discoiation, repiratory dewpression after admin

Many providers see REMS as a barrier to esketamine prescription

Ketamine does not have a REMS

Identifying Safety Concerns and Potential Risks Associated with the Use of Ketamine Products Joseph Palamar, PhD, MPH New York University Langone Health

History of abuse possibly as far back as 1967, law enforcement seizures of medicine, 99% of which is in powder form, produced by clandestine labs in southeast asia and smuggling through Mexico— this is not medicine-grade ketamine being diverted.

In US — Ketamine use over time as decreased since 2000, hovering around 1% use in adolescents. In adult use, some increase, but well below 1% of the full US population of adults.

In UK - 3-4% use in 16-24 year olds in the UK.

In Nightclub scene, close to a third of night-club goers in NYC have used ketamine in the last year. Ketamine is coming back. Past month use, close to 15%, with 8% having used in the last 24 hours going into clubs.

Effects - why in a nightclub? quotes murderer, James St. James

Numbness, passiveness, that world is not real, changed perception of body consistence, arms feel like wood, weightlessness, floating, absence/distortion of time. Even small doses lead to hallucination/disccoiation. Larger doses lead to a “k hole” out of body / near death experience.

Ketamine artwork — Almost creepy, not beautiful like psychedelic artwork

Effects can be pleasurable but “a lot of people find effects are horrific”

So uise increasing, but peopole find it creepy and horrific?

59% asked for help, 7 % went to ER.

Majority of ketamine hospializations involved alcohol use. Do not mix ketamine with alcohol.

Adverse effects - impaired consicousness 45 % hypertention 40% tachycardia 39%

second mention of Matthew Perry - what if bad things happoen to you while on the medicines? Mugged? Beat up? Raped? You wouldn’t remember what happened. Use disorder.

K cramps, bladder issues seem pretty common

Ketamine posionings - 1 in a million report to poison conrtrol - 5% of cases were child exposures.

2019-2023- number of poisions have doubled to 400 in the last year.

Most cases of poisonings are moderate - 20% major events, couple of deaths (least likley) 41% reports co-drug use, mostly alcohol. Do not mix ketamine with alcohol.

Ingestion - liquid, powder, lozenges, injecting has decreaswed

Most using liquid, then powder, — solid 15% and lozenge use least misused.

At home psychiatric treatment - big concern -

reference to Smith Family MD prescribed to over 3000 patients - clinic shut down

What ifs -

anxiety, panic, dysphoria self harm, harm to others left stove on? Kids? Operate a car/heavy machinery?

You don’t know what’s going to happen

Diversion - a month’s supply of ketamine - who’;s to say they’re not selling it, diverting, anything could happen if you give someone a large supply

Stockpiling large doses

routes of administration - lozenges at home - people are trying to break them up and sniff them - I’ve googled it, and looked on reddit

Swallowing it instead of spitting it out

Ketamine use disorder — it is not classically addicting

What stops people from buying it on the street? Seeking illegal supply after introduced to medicine

More research needed, surveillance, is off-label ketamine making its way to black market? (not according to the info he presented)

Panel Discussion -

Cohen, Hermes, Kogan, O’Brian, Poole, Prashad

O’Brian “We’ve done a lot of research, but have a long way to go, more research needed** (how many studies have been cited?) - Dose Response Curve, Maintenance Treatment “ - follow up study showed majority of providers starting .5 mg/kg then titrating up throughout course of treatment to optimize patient response - no trials that are testing repeating doses that are titrating above .5 yet community clinics are going above this. No RCT trials — large gap remains between studies and real-world use.

Psychedelic-assisted psychotherapy - hopeful more studies integrating psychotherapy in ketamine treatment to enhance effects and extend benefits, more important to focus on maintenance doses.

Poole “ Revisit evidence and update the guidelines - Certified Nurse Anesth. — Need for alternative treatment paths for psychiatric and pain disorders, but no foundation or language in regulations or statutes that would guide.

Pennsylvania guidelines on safe practices focus on appropriate multidisciplinary members available, address prescribing, diagnosis, appropriate patient selection.

Prashad “American Society of Ketamine Physicians” (rebranded as ASKP3) — with oral antidepressants, only a 3rd will be treated. Why ketamine? Focus on TRD in private practice

**Kogan - we have seen ketamine due to the failure of standard of care for at least a half dozen conditions - pain, depression, long covid, chronic lymes, POTS, Parkinsons - some signal of benefit. We only used the word psychedelic once - that’s not right. We have to be open, yes, it’s scare to say, but it is a classic psychedelic, best with IM/IV, weakest with oral and nasal, but youc an get there, afrter thousands of treatments, the psychedelic effect is where the magic happens here. COming out of tripm patients have “ah ha” “I se eit differently now”. Gifted THERAPIST will flush it out so you know where you’re going next with therapeutic journey”. Report on long covid (30% cure — research coming) —

Are we studying psychedelic experiences like Hopkins did with psilocybin? Where are we with that?**

Cohen - for all psychiatric treatments, the psychiatric doses are always higher, and it takes longer — for ketamine, people use higher doses for higher pain than for psychiatric indications. Everything that works for depression works for pain. Are we underdosing for psychiatric and overdosing for pain? Anesthesiologists give 4.5 mg/kg no problem giving boluses.

Hermes— Dose- VA .5 mg/kg — most facilities staying with that dose, Maintenance Treatment - Single most important factor - Not a lot of data Psychedelics- VA is moving forward in sponsoring psychedelic research and psychedelic medicine. Developed workgroup for clinical implementation of psychedelic medicine if approved in future

Prashad- “depression" is many different things, there is an art to dosing - sweet spot, nuanced - some patients do better with different doses

Settings-

Kogan - 90% will not peak with nasal, bias towards iv/im

Coach - yoga therapist 2000 hours of psychedelic training / sitting - not a therapist officially , also ketamine-assisted psychotherapy doing counseling (with a therapist) - ketamine administered without that would have no benefit - the benefit is in the counseling, not in the actual drug., The drug induces the state that aids counseling”

Evidence- use a lot of counseling - psychologist, social worker there as a therapist - followed by multiple after-session continuous counseling Fertile ground to continue counseling “Like 10 years of psychotherapy in 2 hours” we hear this repetively. If it’s not guided, the effect is fractionally as good. Dramatically enhanced by having a therapist

O’Brian - Psychologist / psychotherapist - evidence speaks for itself, plenty of trials with no psychotherapy component and patients are getting better. Cites ASKP3 conference where private practice provider presents data compared with and without therapy - outcomes were identical. Having psychotherapy support can take a bad experience and produce a good outcome. No one sized fits all approach. There are different settings. Screening patients for best setting.

Cohen - in pain clinics- iv works better, doses are higher, often 100’s of mg, 2 patients 1 nurse, sometimes 1 nurse 1 patient,

Tolerance possible, but not like opiods - behavioral tolerance, changes of sensitization, lots of ways for tolerance — there should be some flexibility. At Johns Hopkins, ketamine infusions don’t have CPT codes for ketamine

Neuropathic itch vs nociplastic itch or nociplastic pain — some signal that it helps

Kogan- - chronic pain IM shots, 2 shots 20-30 minutes apart, sitter there to observe. Several patients at once. Physician available, theoretically a billable model if physician on staff

Home setting administration -

Speaker notes a clinic “in a strip mall” linking home use with “stip mall”

Home use - O’Brian — CPT codes for home visit, how to bill for sitter? From patient’s perspective, really good- patients in home environment. Practitioner goes to patient’s home.

Psychologist - unsupervised at home - as safe as it is, it still is a medicine that requires some supervision. Doing that at home makes it more complicated. Safety & Efficacy in home use

Prashad- no home use in her clinic. ASKP3 thoughts are- few situations where it may be appropriate. Strong provider alliance required. Increased likelihood of misuse.

O’Brian - almost always it’s only after it’s been done in office and safety has been established.

Cohen - other medicines in pain medicine are used at home. There is a contradiction with ketamine — there should be some consistency.

Hermes- how to provide maintenance treatment -

Pool - goal in guidelines - clinics opening with no guidance from the State — safety protocols emphasized, but no guidelines on prescribing — side effects and adverse effects - quite minimal, but can still occur. Recommend ACLS certified, other advanced medical practitioner if medical complications — what types of providers physically present— how many patients safe to treat at one time? At least 2 providers required to monitor throughout infusion.

Prashad- data for longer term safety - what is the safety for repeat dosing? I don’t know that we have enough data.

O’Brian - developing a registry would be helpful. Trials lasting more than 5 years - hard to do. Partnering with real-world practices to critically evaluate the data.

Prashad - what do we need to be tracking?

Cohen - I do clinical trials. The placebo effect is higher than the intrinsic effect for almost everything. Some psychiatric conditions have even higher placebo effect. Placebo effect in pain in a procedural intervention is greater than the medication. Ethical question - you can’t blind these studies for pain. Registries are important, but limitations at looking at this data. People on opioids fail at everything. If you’re on opiods, you fail on everything. Registries needed, but also high-quality randomized trials.

Eric Hermes, MD - VA — disclosure — has a ketamine clinic

Scope of Ketamine Use Clinical Practice

Rollout of esketamine and ketamine at the VA

National Protocol Guidance for VA for infusions (July 2022) and Esketamine (Feb 2022) — providers see these guidelines, then make their own decisions at the facility and provider/patient level

Rollout strategies- Email group, monthly meetings, ketamine/esketamine special interest group, national training program for ketamine / esketamine clinical teams, info hub, technical support for implementation, program eval

These programs rolled out without funding. Each facility’s clinical teams decide whether to implement or not

IV ketamine infusions are more available than esketamine, and referral to community facilities outside the VA are common

As of June - 39 facilities provide one or other at facility, 13 facilities provide both - large areas of the country are unserved.

IV ketamine - Depression outcomes of IV ketamine treatment for depression in the VA health system (Pfeiffer 2024) — n- 215 patients, mean of 18 infusions (about 3 months) , 50% improved significantly, 26% reached response

Comorbidity of PTSD and Treatment Resistant Depression

Increasing availability and utilization by veterans despite resources, coordination of care Challenges - rich facilities get richer — difficult getting programs into facilities that don’t have any treatments Persistant undertreatment — we’re only treationg 2% of veterans who may havbe TRD

Note- TRD is NOT a diagnosis, you can’t code it.

Next steps- Improve standardization of delivery & data capture, explore utilization of care, identify barriers, prepare for psychedelic-assisted psychotherapy — ***NINE VA FACILITIES “formally” integrate psychotherapy as part of ketamine or esketamine delivery ***

*** First mention of psychotherapy and first mention of “psychedelic"

Stephen Cohen - Ketamine for pain

Guidelines on pain medicine - USPSTF Guidelines allow for more flexibility.

Best indications, Contraindications, Risk Mitigation, Dosage

Labs not needed for healthy people in most surgeries. Low dose ketamine, labs unnecessary.

Higher doses used for chronic pain.

Role for oral ketamine - claims “most studies not positive”, “ a lot of risks with oral ketamine”, a hospital had a huge lawsuit because of it. Intranasal has higher bioavailability.

Cites studies from 1999, 2007, 2010, 2013, 2014, 2017

“Now ketamine clinics all over the place”

Recommend dosing 8-12, higher doses, repeat infusions

Any evidence for dose-response curve Higher doses above .5mg/kg over 40 minutes were more effective than lower doses

Mentions “psychomimetic effects” (psychedelic effect) - psychomimetic effects correlated to anti-depressant effects

Positive Treatment Response - 30% decrease in pain is “clinically meaningful”

Cites data more than 20 years old, claims low-powered studies

Chronic pain associated with psychiatric disorder - higher doses work better, iv ketamine works better, psychomimetic effects are correlated to antidepressant effects (ie the psychedelic experience is importnat)

Growing rate of abuse, legal issues, Hong Kong - 50% of motor vehicle accidents related to ketamine, in US, there are legal issues as well

FDA - no difference in Cancer pain or other types of pain.

Cognitive-Evaluative component of pain - obese patients (in two studies) — strong affective component of pain - ketamine may act on the cognitive evaluation of pain — people report feeling better, even if they’re still feeling pain

Claims meta-analysis that includes 3 papers

consensus guidelines needed

WILD WEST (mention 1— we’ll do a whole thread of people who describe the ketamine space as “the wild west”

Dose response relationship for subanesthetic ketamine for chronic pain

growing evidence in acute pain

Intro speaker— Dr. Sokolowska

FDA does not regulate the practice of medicine.

Esketamine was approved in 2019 as a nasal spray for treatment resistant depression in conjunction with an oral antidepressant, and in 2020, was approved for suicidality.

The FDA has not approved ketamine for other mental health indications, nor pain conditions, and does not approve compounded medicines.

The FDA issued 2 risk alerts on compounded ketamine products.

In spite of this, the FDA recognizes the real-world use and ongoing study of ketamine in a variety of formulations.

Today’s meeting goals - expand knowledge, knowledge gaps, safety issues

Sanacora from Yale (affiliated with Johnson & Johnson and has several financial disclosures / conflict of interests as he profits from people being prescribed Jansen’s esketamine branded Spravato). History of ketamine - lists first study on antidepressant efficacy in 1990. (Inaccurate)

Mechanism of action - neural plasticity & NMDA receptors (circa 1990) - suggested depression was more of a cortical disorder

Found ketamine can have rapid, lasting antidepressant activity (notes small studies with small sample sizes) 2016 studies

Alleges very little clinical evidence, with evidence on neurotoxicity and brain lesions, unaware of the wealth of data at the time, yet was part of the American Psychiatric Association’s position statement on ketamine in psychiatric use in 2017.

Who will do multi-million dollar studies? Someone came up with the idea of using esketamine, half of what’s in normal racemic ketamine.

Esketamine, more potent at NMDA receptor. Jansen pharmaceucticals sponsored the studies required by the FDA, which approved the medicine in 2019. Data over 58,000 patients with 800,000 administrations of esketamine.

Compares to ketamine study of 195 people from 2019, does mention Osmind study, alleging community using higher doses

Rapidly shifting landscape, mentions recent oral and iv ketamine studies, alleging poor scientific rigor.

Make treatment available, but balancing with safety.

A more complete discussion on Sanacora later.

The Reagan-Udall Foundation for the FDA, in collaboration with the FDA, is hosting a hybrid public workshop on “Understanding Current Use of Ketamine for Emerging Areas of Therapeutic Interest.” Ketamine is a Schedule III controlled substance that is FDA-approved for induction and maintenance of general anesthesia. Although ketamine is not approved for the treatment of conditions such as depression or chronic pain, there has been increased interest in it’s use for these types of conditions. This public workshop will explore topics such as the scope of ketamine use, including approved products and compounded products, for these emerging areas of therapeutic interest; potential safety concerns; and online promotion of and access to ketamine.

Speakers will include clinicians, academic researchers, and federal partners. (No psychotherapists or psychedelic therapists are scheduled to speak.)

See the Full Agenda Review the Slides View Speaker Bios

“After assessing the semantic similarity between 15,000 reports linked to the use of 165 psychoactive substances with 625 NDE {Near Death Experience} narratives, we determined that the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine consistently resulted in reports most similar to those associated with NDEs. Ketamine was followed by Salvia divinorum and a series of serotonergic psychedelics, including the endogenous serotonin 2A receptor agonist N,N-Dimethyltryptamine (DMT). This similarity was driven by semantic concepts related to consciousness of the self and the environment, but also by those associated with the therapeutic, ceremonial and religious aspects of drug use. Our analysis sheds light on the long-standing link between certain drugs and the experience of “dying“, suggests that ketamine could be used as a safe and reversible experimental model for NDE phenomenology, and supports the speculation that endogenous NMDA antagonists with neuroprotective properties may be released in the proximity of death.” (Neurochemical models of near-death experiences: A large-scale study based on the semantic similarity of written reports, Martial, et al, 2019).

Here ketamine, like DMT, is hypothesized to act on similar receptors to form similar brainwaves, with similar subjective experiences related to proximity to death.

More here— https://psychedelic-institute-of-mental-health.ghost.io/does-the-psychedelic-experience-matter/

Experiences of Awe Mediate Ketamine’s Antidepressant Effects: Findings From a Randomized Controlled Trial in Treatment-Resistant Depression (Aepfelbacher, et al, 2024) https://pubmed.ncbi.nlm.nih.gov/38726038/

“ Ketamine infusion strongly induced heightened feelings of awe, and these experiences consistently mediated depression outcomes over a 1- to 30-day period, unlike general dissociative side effects. The specific awe-inspiring properties of ketamine may contribute to its antidepressant effects.”

Ketamine’s Role in Spirituality: How One Synthetic Drug Catalyzes a Natural Experience (Woods, 2020)

It brings up a player for me that plays the audio. I’ll find another link, tho!

February 2024: **Ketamine-Assisted Psychotherapy & Support Practicum **

Organizing our next round of ketamine therapy training for clinicians and non-clinician guides / trip sitters. Meeting 8 hours per week, this practicum includes 12 experiences with racemic ketamine in various routes of administration, 12 sessions of sitting with someone else under the medicine, 12 hours of didactic training, 12 hours of integration, 12 hours of individual clinical supervision totaling 96 hours of practical experience upon completion of all 12 modules.

Medical clearance by a prescribing clinician licensed in your home state or locality required.

The Psychedelic Institute of Mental Health & Family Therapy is located in Palm Springs, California. Practicum is held online 2 evenings per week, 3.5 hours each evening from 6-9:30pm PST, with an optional in-person retreat weekend.

Practicum Fee: $600 per person per 8 hour weekly module

https://psychedelicreview.com/compound/4-aco-dmt/