Smoking Toad

I generally try to keep my research and posts confined to medical and scientific journals for a couple of reasons. First and foremost is that well documented bias against psychiatrists and whatever version of monolithic psychiatry that authors and editors in the popular media choose to embrace. Secondly, the information content of professional journals is much higher and the theories and concepts are what I have been studying for decades at this point. For the purpose of this post, I am making an exception and will be writing about a story from the New Yorker about hallucinogens (1).

Being child of the 1970s and a psychiatrist starting a short time later, I have had plenty of academic and professional experience with hallucinogens.  Given that experience, I am very skeptical about how the new wave of hallucinogens have been portrayed as a panacea for psychiatric problems.  Even more problematic is the portrayal that these compounds are generally well tolerated and have no significant adverse effects. I will be the first to acknowledge that there is a selection bias. People don’t end up coming to see me because they had a good experience with hallucinogens. They see me because they had a very bad experience and that is generally severe anxiety, panic attacks, and hallucinogen persisting perceptual disorder (HPPD). HPPD is a permanent change in perception after exposure to hallucinogens.  That can range from looking down and seeing the carpet moving continuously to noticing that there are trailers streaming from objects moving across your visual field.

If you research HPPD or hallucinogen side effects – relatively little turns up in the medical literature. There are probably less than 100 papers written on HPPD since the 1960s.  They are typical case reports, anecdotal treatment, and a call for more research on treatment. A major LSD study documenting disability had to wait until recently for an analysis of side effects.  I contacted 2 current hallucinogen researchers and asked them for a copy of the consent form they are using for their research projects in order to see what adverse effects their were advising their patients about. That was two years ago and I have yet to receive a reply. It is against this backdrop that I am going to present some concerns noted in the New Yorker article. 

The bulk of the story involves a trained Mexican physician who first gained some fame in 2013 when he gave a testimonial about overcoming crack cocaine addiction by using a psychedelic produced by the Sonoran Desert Toad – Incilius alvarius.  This toad is in the family of true toads or Bufonidae and that may be why the toad is also referred to as Bufo alvarius using an incorrect genus name.  The Sonoran Desert extends through southern Arizona and California and along either side of the Gulf of California down the Baja Peninsula on the West and contiguous Mexico on the East.  This toad secretes a toxin to protect against predators.  The article points out that dogs have died as a result of this toxin. The toxin has been analyzed and it contains 5-methoxy DMT – the psychedelic claimed to treat the addiction. Since the research literature uses the abbreviation 5-MeO-DMT that is how I will refer to this compound. The usual superlatives are used to describe the psychedelic experience. Endorsements from celebrities are there endorsing the spread of toad medicine around the world.  The actual experience is described in eerie terms like: “completely dissolves reality as we know it” or “terror and a sense of ego dissolution” followed by what is described by uncertainty over what happened along the way.  I have abstracted the side effects listed in this article in the table below.

5-MeO-DMT Adverse Effects
General	Pain Shortness of breath
Cardiovascular	High blood pressure Tachycardia
Neuropsychiatric	Flashbacks Extreme anxiety Hyperventilation Insomnia
Intoxication	Agitation Aggressive behavior Vomiting
Death	The article lists about 6 deaths that occurred while smoking 5-MeO-DMT – one of these deaths was attributed to anaphylaxis

 The main focus of the article is a single practitioner who is described as actively promoting this treatment and at the same time is considered problematic for inadequate monitoring of the patients he treats with 5-MeO-DMT. Doses are approximate, patient monitoring is lax to non-existent, and he has run into some legal problems, problems with practitioners of ethnic medicine, cultural problems with a local tribe, and ecological problems due to toad depletion.  Against that backdrop are the usual testimonials that  5-MeO-DMT has cured intractable substance use problems and psychiatric disorders like depression and PTSD. There are also examples of substance use problems getting worse to the point of a fatality and the whole experience of causing PTSD as well as alleviating it. Expert opinion is included with the usual qualifiers about how clinical trials might provide clearer answers and venture capital funding being available for depression trials.  

After reading the New Yorker article I went to ClinincalTrials.gov and found 5 5-MeO-DMT current studies listed.  Three appeared to be safety studies in normal volunteers and one of these studies was a dose ranging study. There was another study for treatment of depression. Three studies were completed with no results available.  The fifth study was not yet recruiting subjects. 

By way of contrast, I thought I would look at a paper that surveyed subjects who had taken 5-MeO-DMT (3) at least once especially for the side effect profile.  This study used an anonymous Internet survey to look retrospectively at the epidemiological features of people who have used this compound. The study design is limiting in this case because it likely screens for people who have had positive experiences and in this case may be motivated to promote psychedelics (the incentive for subjects was a very modest donation to an organization that promoted the study and use of psychedelics. The researchers collected demographic data, data on 5-MeO-DMT and other substances used, patterns of use and the effects of use (Mystical Experiences Questionnaire/MEQ) (4) and possible side effects through the Challenging Experiences Questionnaire/CEQ (5) that was apparently designed to study the challenging experiences associated with taking hallucinogens. I encourage reading the entire paper for all of the details. The final version of the CEQ is 26 items that have been factor analyzed to measure fear, grief, physical distress, insanity (fear of losing one’s mind on a sustained basis), isolation, death, and paranoia.

The authors basically conclude that users of 5-MeO-DMT do in fact experience mystical experiences per the MEQ.  The MEQ was originally studied for hallucinogen experiences and the specific questions can be found in reference 4 as well as the body of reference 3. It is probably not surprising that a hallucinogen creates a mystical experience.  The poll here suggests that it may be more intense than the subjects experienced with other hallucinogens. At one point in the paper the authors suggest that the mystical experience is thought to be curative, but that is really unclear at this point. If it is true, the duration of the cure is also unclear. From the New Yorker article there were testimonials that 5-MeO-DMT was useful for substance use and some other psychiatric disorders – but there was also a question of worsening.

Although this was not a clinical trial, medical literature typically describes adverse effects or adverse drug effects (ADEs) from any medical intervention used to elicit a specific therapeutic effect.  Those ADE checklists are used to assess safety as well as producing the warning and side effect literature for the package insert of approved medications.  The literature on psychedelics seems to have taken the direction that the focus should be on what are described as psychological effects (see second column in the following table under neuropsychiatric side effects). This is problematic because it seems to assumes that discrete bodily systems (other than the brain and perhaps the heart) are not involved with potential drug related side effects. The term side effects and adverse effects tend to be avoided other than to say that some people may have an adverse effect from the psychedelic experience. The New Yorker article and even the survey of 5-MeO-DMT users suggests that medical safety is a potential concern and that no matter what the setting a person needs to be carefully monitored after ingestion of this drug.  

5-MeO-DMT Adverse Effects (References 3,4,5)
General	Pain Shortness of breath Nausea
Cardiovascular	High blood pressure Tachycardia
Neuropsychiatric	Flashbacks Extreme anxiety Hyperventilation Insomnia Fear Hallucinations Dissociation	Depersonalization Aggression Violence Confusion Paranoia Grief Insanity Isolation Death Paranoia
Intoxication	No clear distinction
Other

 

A reasonable summary of what is known about currently known this drug at this point is that it is a powerful hallucinogen. The safety and efficacy of this drug is currently unknown. Caution is required in looking at a survey study where the primary interest in taking the drug is wanting a mystical experience and treatment of a psychiatric disorder is a secondary effect and yet the psychiatric disorder tends to improve.  The New Yorker article is a cautionary tale and a counterpoint to a lot of the hype around hallucinogens right now that includes travelling to a foreign spa and having it administered by a self-proclaimed guru. The deaths mentioned in that article and some places in the literature are another red flag in contrast to the universal proclamations about hallucinogen safety. People with complications and severe outcomes don’t generally participate in surveys – therefore surveys are not the best ways to determine how a toad toxin can be used on a therapeutic basis.

It always seems to come back to controlled randomized clinical trials that are carefully optimized for patient safety. I have been the medical person responsible for the safety of patients in many of these trials and that typically involves weekly visits with physical examinations and any indicated labs.  It is a tedious and expensive process and there are no good short cuts. Until then I advise extreme caution with hallucinogens or psychedelics. It is always good to keep in mind that human biology varies greatly. What some people tolerate without a problem for years can cause severe side effects or even death for others. I expect that will eventually be documented for hallucinogens.  

 

George Dawson, MD, DFAPA

Supplementary 1:  For past links to posts here on hallucinogens please see the following:

Are Hallucinogens the New Miracle Drugs:  https://real-psychiatry.blogspot.com/2016/06/are-hallucinogens-new-miracle-drugs.html

JWH Compounds Make the NEJM:  https://real-psychiatry.blogspot.com/2017/01/jwh-compounds-make-nejm.html

Supplementary 2:  I am always looking for suggestions on how to improve this blog. I have considered a post that is basically a primer on hallucinogens and psychedelics. Let me know if you are interested or if there is anything that I can write about this general topic that you might be interested in. It is probably obvious that I am a skeptic about all of the hype suggesting that hallucinogens/psychedelics are the new miracle drugs. 

References:

1: De Greef K. Toad Smoke. New Yorker. 2022 Mar 28: 38-45.

2: Larsen JK. Neurotoxicity and LSD treatment: a follow-up study of 151 patients in Denmark. Hist Psychiatry. 2016 Jun;27(2):172-89. doi: 10.1177/0957154X16629902. Epub 2016 Mar 10. PMID: 26966135.

Revisits the Danish LSD Study and concludes that “Most of the patients suffered from severe side effects of the LSD treatment many years afterwards.”

3: Reckweg JT, Uthaug MV, Szabo A, Davis AK, Lancelotta R, Mason NL, Ramaekers JG. The clinical pharmacology and potential therapeutic applications of 5-methoxy-N,N-dimethyltryptamine (5-MeO-DMT). J Neurochem. 2022 Feb 11. doi: 10.1111/jnc.15587. Epub ahead of print. PMID: 35149998.

4:  Maclean KA, Leoutsakos JM, Johnson MW, Griffiths RR. Factor Analysis of the Mystical Experience Questionnaire: A Study of Experiences Occasioned by the Hallucinogen Psilocybin. J Sci Study Relig. 2012 Dec;51(4):721-737. doi: 10.1111/j.1468-5906.2012.01685.x. PMID: 23316089; PMCID: PMC3539773.

5:  Barrett FS, Bradstreet MP, Leoutsakos JS, Johnson MW, Griffiths RR. The Challenging Experience Questionnaire: Characterization of challenging experiences with psilocybin mushrooms. J Psychopharmacol. 2016 Dec;30(12):1279-1295. doi: 10.1177/0269881116678781. Epub 2016 Nov 17. PMID: 27856683; PMCID: PMC5549781.

“…challenging psychological experiences during the acute effects of psychedelics are not uncommon.”  p. 1279

6:  Murdaugh LB.  Adverse drug reaction reporting. In: Competence Assessment Tools. 2015. American Society of Health-System Pharmacists.  Bethesda, MD.  Accessed Online:  https://doi.org/10.37573/9781585284030.040

 

 

 

Why Has Suboxone Turned Into A Problem?

The short answer is that it is like very other drug and there was always the potential for a problem.  Any practicing physician realizes that when a drug is approved by the FDA for general release to the public there are all kinds of unintended consequences that are possible.  That is the basis of post marketing surveillance by the FDA.  There is invariably a lot of hype associated with the release of a drug, but as I have previously pointed out the FDAs approval process is not in place to guarantee a drug that is safe for everyone.  It is focused on a releasing a drug that is a potential tool for responsible practitioners.  That means any drug can potentially cause a small number of serious unexpected reactions (liver failure, cardiac arrhythmia)  that even the most experienced practitioners will not be able to predict.  There is also an implicit understanding that the practitioners prescribing the drug have a thorough understanding of its pharmacology, indications and contraindications.  Many practitioners advise against trying out a product that has just been released but that advice is tempered by the severity of individual circumstances and the hope of relief and also the general bias that new drugs are somehow better than the old ones.  That bias has been repeatedly disproven.

Suboxone prescribers have to take a special course in order to get a prescriber number in addition to their usual DEA number.  I took the Suboxone prescriber course about 7 years ago.  It was a total of 8 hours of lectures given in a convention center room in a hotel.  It was jointly sponsored by state medical association.  The morning sessions were largely a review of the pharmacology of the drug and the scope of the opioid addiction problem at the time.  The afternoon session focused on vignettes of patients with addictions of varying complexities and the exercise was to determine of Suboxone should be prescribed to that person and how the induction would be done.  That was the first suggestion that something was problematic.  There apparently were no contraindications to Suboxone.  The clear message was that it should be given to anyone with an opioid addiction no matter what their social circumstances or comorbid psychiatric diagnoses and addictions.  There was a definite implication that this was a drug that would revolutionize the treatment of opioid addiction.

 
Suboxone is a combination of buprenorphine and naloxone.  Buprenorphine is the active ingredient in terms of treating addiction.  In this post I will use Suboxone and buprenorphine interchangeably.  The pharmacological properties of buprenorphine that were interesting in terms of potential use for addiction included the fact that it was a opioid mu receptor partial agonist and antagonist at the kappa receptor.  The partial agonist effects relevant for addiction such as euphoria and sedation occur at the lower doses and the antagonist effects occur at higher doses.  The antagonist effects like preventing respiratory depression were thought to put a ceiling effect on this side effects and make it safer than pure mu receptor agonists that would produce dose related toxicities.  In the Suboxone course the mixed agonist/antagonist effects were described as producing less toxicity and less risk of abuse.  The naloxone component of Suboxone is a pure mu receptor antagonist.  In the course I took, the explanation for the combination of buprenorphine and naloxone was that it reduced the risk of intravenous drug use and that this had occurred in Europe and it resulted in several deaths.  The company also sold Subutex which was buprenorphine only and indicated for use in pregnant women.

The pharmacodynamics and pharmacokinetics in real life can differ quite a bit from the idealized cases that the initial marketing and advertising was based upon.  Like many medications it can be a life changing drug.  People can recover and break the cycle of addiction, recovery and relapse and go on to productive lives.  It is the outliers that physicians need to be most concerned about.  In real life there are always going to be people who get significant side effects even at low doses and cannot tolerate the drug.  There are also people who tolerate the drug at high doses and do not experience the ceiling effect of mu receptor antagonism.  The people are probably very low in number but they are significant because they are not protected by the ceiling effect that is supposed to be there from the drug.  Drug addiction always attracts or produces a significant number of people who become amateur pharmacologists and use the drug to facilitate their addiction.  The word gets out and suddenly buprenorphine has street value (about $1,000 for a 1 month prescription) and opioid addicts can use it when they run out of heroin or oxycodone.  In a few people it is their preferred opioid because it has a longer half life.

The politics of Suboxone are as complicated as you will find in the pharmaceutical industry.  There are plenty of conflicts of interest in terms of how the drug was initially marketed and plenty of crossover between regulators and the company who developed, marketed and sold it - Reckitt-Benckiser.  According to a New York Times article last fall, the company was granted a period of exclusive sales that ended in 2009.  After that they went on the offensive to suggest that their new product - a Suboxone film was superior to the generic tablets especially in the area of child safety.  They stopped selling the Suboxone tablets at that point.  Insurance companies can work any controversy to their advantage and people on buprenorphine maintenance have been cut off based solely on the amount of time they have been taking the drug.  There are no scientific guidelines for how long a person should take buprenorphine and like most drugs used for maintenance therapy there will never be a study that looks at that question due to the expense.  Most experts would agree that if you have a severe addiction and have recovered based on buprenorphine there is no reason why you would be cut off.  In fact discontinuing buprenorphine seems to present a more significant problem as dose is tapered to 2 mg and  lower.   We also have a familiar political theme in the issue of opioids with the government seeming to create the problems in the first place and now saying: "Trust us we have the solution."  That may have explained the desperation in the descriptions of how public health officials were trying to increase Suboxone prescribers to address a public health opioid epidemic that was a likely result of government initiatives to improve the treatment of pain.

Suboxone has become a problem for the same reason that every other drug becomes a problem - unrealistic expectations, conflicts of interest, and a knowledge deficit on the part of the practitioners.  The title of the New York Times article illustrates how the press can look at the dual nature of drugs and imply that there is a larger problem.  I don't know of two many drugs that do not have a "Dark Side".  The negative trends in buprenorphine use can be reversed but it will take more than the suggested strategy in the NY Times article.  Here are a few ideas:

1.  The CDC needs to get involved and look at Suboxone/buprenorphine related deaths and study it in the same manner that they studied methadone.  It would be very instructive to see exactly where Suboxone/buprenorphine falls on the spectrum of deaths/100 kg MME (milligram morphine equivalents).  The expectation of some in the article is that it is much safer, I would prefer to see the numbers.  Only the CDC has access to the detailed data to look at this issue.  I would take it a step farther and suggest that the CDC recalculate this table on an annual basis as a key metric in reversing the significant public health problem of accidental opioid overdose deaths.

2.  The physicians prescribing the buprenorphine need to be highly motivated and well versed in prescribing medications to individuals with addictions.  The NY Times article suggests that there are many who take an entrepreneurial approach to the prescription of buprenorphine with cash only practices that vary from $100 - $250 a visit.  I have no problem with cash only practices if there is a quality approach.  By definition that involves a lot more than handing someone a prescription in 5 minutes.  The problem is the rest of what happens during that time is poorly defined.  The original prescribing information said that the physician needed to refer the patient to counseling services.  In many presentations of research that I have seen there is a clear movement to illustrate that - counseling adds little to nothing to outcomes when buprenorphine is prescribed.  There are problems drawing that conclusion about this research given the modest outcomes of the buprenorphine treatment.

3.  At least part of the interview of any patient recovering from the severe addiction that occurs with opioids is assessing their functional capacity.  What are they doing on a day to day basis and is that routine consistent with both recovery and a lack of cognitive side effects from the buprenorphine?  Being able to corroborate that improvement with a third party makes it even more reliable.

4.  A big part of the unconscious aspects of addiction is the behaviors that are present to continue the addiction despite the best conscious efforts of the person affected.  Good examples include craving, lying, and hiding use from others.  That requires prescribing physicians to engage their patients at this level and not develop a law enforcement transference.  A lot of physicians don't know how to respond to an accusation of: "You don't trust me!" when there is a question of the need for a toxicology screen or a discussion of a positive toxicology.  The interpersonal aspect of treatment is very important and it received no attention in the standard Suboxone prescribing course.

5.  Continued work on a model of treatment looking at all of the potential positive factors is needed.  There is nothing worse in medicine than to treat a scientific topic like a political one and not have a rational approach to the person with the problem.  Like the original course I took, there are  people out there who say that buprenorphine prescribed out of a physicians office is all that is needed.  Is that the case when you have a person who takes two to three times the prescribed amount to get high?  Or the person who is crushing it and snorting or injecting it?  Or the person who is selling it on the street to get purchase heroin?  Or the person who can't function due to cognitive problems at 2 mg a day?  Or the person who is hospitalized for recurrent bowel obstructions due to severe constipation?  As the prescribing physician - are  you confident that you can accurately screen for these problems?  What about competing approaches like the long acting mu antagonist naltrexone injections?  Where does 12-step recovery like Narcotics Anonymous fit in?  Where do sober housing and residential treatment fit in?  And finally - where can a person get detoxified and should anyone be forced to go through acute opioid withdrawal when they are incarcerated?

All of these questions are currently unanswered.  But like most treatments in medicine, the solution is typically a lot more than a pill.  Drugs with addictive potential always add the complication of significant financial gain from a captive audience.        

George Dawson, MD, DFAPA

Deborah Sontag.  Addiction Treatment With A Dark Side.  New York Times. November 16, 2013.

SAMHSA.  Clinical Guidelines for the Use of Buprenorphine in the Treatment of Opioid Addiction.  A Treatment Improvement Protocol.  TIP 40.

NICE.  Naltrexone for the management of opioid dependence. 2010.

NICE.  Methadone and buprenorphine for the management of opioid dependence.  2010.

Why Psychiatrists Should Agree with David Healy

One of the big media stories today is about David Healy's address to the American Psychiatric Association's Psychiatric Services meeting.  Like many of the psychiatrists turned critic his celebrity and notoriety status depend a lot of the amount of controversy that he is associated with and he comments on that in the opening remark.  If you carefully read through this article, you will find that the financial conflicts of interest alluded to in the article are largely historical at this point.  The elephant in the room for these critics is that practically all antidepressants are generics these days and they are no longer marketed by pharmaceutical companies.

I was an early adopter of maintaining  clear boundaries with pharmaceutical companies and for the past 20 years or so - did not see detail salespeople, did not accept food and did not accept any gifts.  On the other hand, I have always found pharmaceutical companies to be a rich source of data in addition to the usual FDA approved package insert.  As an example, I am looking at a disc sitting on my desk right now entitled "Iloperidone unsolicited slides - for education use only."  I gave a lecture on newer atypical anti psychotics several years ago and contacted the scientific divisions of three pharmaceutical companies looking for basic science data on the new drugs and they all supplied me with complete clinical trials data and basic science information on the receptor profiles that I wanted.  I will also call them up with possible adverse events and get detailed information about that frequently via fax the same day.

Healy appeared to have made a controversial remark about psychiatrists committing "professional suicide" by their affiliation with pharmaceutical companies.  In his previous remarks he make the comment about professional suicide as a preface to the second paragraph below:


"Healy noted further that when data surfaced showing a link between antidepressant use and risk of suicide in children, the APA issued a statement proclaiming that “we believe that antidepressants save lives.”

“What I believe they should have said is that the APA believes that psychiatrists can save lives because it takes expertise to manage the risks of risky pills,” he said; if psychiatrists’ only role were to dole out drugs, then less-trained physician’s assistants could easily replace them, he noted."

I have seen the comment on his blog at least 6 months ago and there should be complete agreement with this statement.  Just in the past month I have had to diagnose and address drug induced liver disease, serotonin syndrome, eosinophilia, antidepressant associated hypertension, and spent a considerable larger amount of time making sure that antidepressants could be safely prescribed and that they were not making pre-existing medical problems worse.   Recognizing those problems goes beyond the diagnostic process to coming up with a plan to monitor and treat it.  A considerable amount of my time is, if not most of my time is spent managing side effects and protecting the health of my patients.

Although Healy takes positions that I would consider to be inaccurate, in this case he is dead on.  It is professional suicide to collude with the idea that the treatment of any mental illness resides in a pill.  Marketing genius maybe, but certainly not reality.  Drugs don't treat and cure depression, psychiatrists do and it goes far beyond selecting a medication.  Monitoring the patient for these complications and recognizing rare complications takes time and that time needs to be available - even in visits that are supposed to be focused on "medication management".

George Dawson, MD, DFAPA