There is no hotter topic in the world of psychiatry than the reemergence of psychedelics as therapeutic tools for the treatment of mental illness. When esketamine was approved by the FDA in March of 2019 it opened the doors for medications like MDMA, psilocybin, and mescaline as possible therapeutic agents. 

I’m excited about these new options for therapy but I also want to make sure the science backs up the personal experiences of individuals who use these medicines in uncontrolled settings. 

Introduction:

The psychedelic era was a time of social, musical, and artistic change influenced by the use of psychedelic drugs that occurred between the mid-1960s and mid-1970s. Although this era lasted for some time it largely fell out of favor for legal reasons and wasn’t a topic in modern psychiatric training until just recently. It seems like overnight there are New York times articles, Netflix documentaries, and evening news coverage about psychedelics.

What’s the story are we ready to prescribe everyone psilocybin and MDMA as a form of mental health treatment? 

History of Hallucinogens in Medicine

For over 5 millennia humans have been attempting to alter their state of consciousness. Some have argued it goes even further back to primate ancestors who consumed large quantities of ripe fermented fruit to alter their state of consciousness (drunken monkey hypothesis). I’m not sure how correct this theory is but it’s safe to say psychedelics have been around for a long time. 

In 1943 Albert Hofmann a chemist by training, invented LSD by accident. He started the research in 1938 and announced that he sampled the chemical in 1943. Not only did he synthesize it, but he was getting high on his own supply. In 1957 this same chemist isolated psilocybin from the hallucinogenic mushrooms.

In the 1940’s LSD was marketed as a drug to assist psychotherapy, the so-called drug assisted psychotherapy which is making a comeback today. Unfortunately, of the 1000 studies published looking at psychedelics as a model for psychosis and as therapy were small and uncontrolled. 

In the 1970’s most of these medicines were placed into schedule I status making it exceedingly difficult to study the medicines further for therapeutic effects in a controlled setting. A Randomized controlled trial is considered by many to be the highest standard of scientific evidence. 

Classes of Hallucinogens 

For years people thought of psychedelics as LSD or psilocybin, the term now includes other medicines. The term psychedelic is derived from two Greek words meaning mind manifesting. Essentially psychedelic and hallucinogen are being used interchangeably these days but do have separate meanings.

Classic Hallucinogens 

-Tryptamines: psilocybin, LSD, and DMT 

-Phenethylamines: Mescaline 

Non-Classic Hallucinogens 

-3,4-methylenedioxymethamphetamine (MDMA)

-Dissociative Anesthetics: Ketamine, PCP, Dextromethorphan 

Therapeutic Targets for Psychedelic Use

Disorders Under Investigation: 

-Depression 

-Anxiety

-PTSD

-OCD

-Cancer related stress and psychological issues 

-Addiction 

-Smoking cessation 

-Sexual dysfunction 

-headaches 

-inflammatory disorders 

Maybe the best studied area is in end of life and palliative care settings. 

Mechanism of Action

-The primary mechanism of action is 5-HT2A receptor stimulation 

-5-HT2A is the most abundant serotonin receptor in the central nervous system and cortex of the brain. 

-Stimulating the 5-HT2A receptors will increase the release of glutamate in the cortex 

-Stimulation of 5-HT2A receptors in the visual cortex can lead to visual hallucinations. Stimulation in the ventral tegmental area can produce a situation like that of schizophrenia with delusions and hallucinations. 

-Most atypical antipsychotics bind to and block 5-HT2A receptors and would mitigate the effects of psychedelics 

Neurobiology

People often make comments like we don’t know how much serotonin is enough, then conclude that medications do work or the therapies we are using are invalid. That’s because they are thinking about mental illness and these medications too simply. Most psychiatrists do not believe in or talk about the chemical imbalance theory of treating mental illness. We think about mental illness and problems with neural circuits, nodes, and networks. What medications including the psychedelics achieve is an alteration in the connectivity of these networks and the ability to form new connections. 

We have a default mode network which is famously active when a person is not focused on the outside world and the brain is just daydreaming. What psychedelics do is decrease brain connectivity in this default mode network followed by the establishment of new connections. 

Hypothetically this rewiring of the brain allows for the replacement of faulty connections resulting in mental illness and the formation of new healthy connections through psychotherapy provided during treatment. This may be why the antidepressant effects last far beyond other interventions with less frequent dosing. 

There are identifiable changes in network connectivity that coincide with subjective improvement. 

The Mystical Experience: Is Tripping Required for a Therapeutic Effect

-There is a mystical experience questionnaire that has been validated and used in these studies. It seems that the more profound the mystical experience the better the treatment effect subjectively 

-While the spiritual experience many individuals have while taking these medicines is profound and meaningful to the individual, we are not sure that having a “trip” is required to produce a therapeutic effect. 

Side Effects of Psychedelic Use 

While some may claim there are no adverse effects from plant-based medicine that is not true. 

Things like increased blood pressure, berating rate, and body temperature have been reported. 

-Loss of appetite, dry mouth, sleep disturbance, uncoordinated movements, panic, paranoia, psychosis, and bizarre behaviors 

Long-Term Effects: 

Persistent Psychosis: A series of continuing mental problems including 

-visual disturbances

-disorganized thinking

-paranoia

-mood changes 

Hallucinogen Persisting Perception Disorder (HPPD) 

-Recurrences of certain drug experiences such as hallucinations or visual disturbances 

-These experiences often happen without warning and may occur within days of last use or even years after taking the drug 

-These experiences can be mistaken for neurological disorders such as strokes or brain tumors. 

Conclusion

At this time what we can say about the current state of psychedelics in psychiatry is they are under investigation. We do not know yet if they are safe and effective for treatment of mental illness on a mass scale. We have some encouraging evidence but there is an absence of large randomized controlled trials proving efficacy and safety. Psychedelics are not ready for clinical practice and should not be recommended as a treatment for mental illness until the proper studies have been conducted.