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