Learning Objectives

After the webinar, clinicians should:

1. Understand the historical basis for using psychedelics to treat mental illness  
2. Describe the therapeutic potential of psychedelic medicine 
3. Explain the data supporting the use of psychedelics in major depressive disorder and differences in the mechanism of action compared to standard antidepressants 
4. Identify the challenges associated with the development and clinical use of psychedelics

Transcript edited for clarity.

Hello everybody, and welcome to another Carlat Webinar Series. Today is going to be an exciting topic, and that’s the topic of psychedelics in psychiatric practice because one way or another, these medications are making their way into mental health treatment in the near future.

My name is Dr. Garrett Rossi. I’m an adult psychiatrist specializing in inpatient care as well as consultation liaison psychiatry. I have no conflicts of interest to disclose. 

Hallucinogens Over the Years 

Key points

• 1943 Albert Hofmann discovers lysergic acid diethylamide (LSD) 
• 1957 Hofmann isolates psilocybin from mushrooms 
• 1950s-1970 research into use of psychedelics to treat psychiatric disorders 
• Controlled Substances Act of 1970: Schedule I
• Today: Renewed interest in therapeutic value of these medications

The history of hallucinogens is relevant to our discussion. In 1943, Albert Hofmann discovered LSD, followed by his isolation of psilocybin from mushrooms in 1957. From the 1950s to 1970, numerous studies explored psychedelics as psychiatric disorder treatments. However, The Controlled Substances Act of 1970 classified most psychedelic medications as Schedule I controlled substances, severely hindering further research and funding. Despite limitations in current depression and post-traumatic stress disorder (PTSD) treatments, there is a renewed interest in the therapeutic potential of these medications, which we'll explore in this webinar.

Dyck E. CMAJ. 2015 Aug 4;187(14):1079-80

What Is a Psychedelic?

Let's begin by discussing the meaning of the term "psychedelic." Psychedelics refer to drugs that alter consciousness and perception. There are two main classifications: classic psychedelics, which encompass tryptamines and phenethylamines, and atypical psychedelics, which include substances like MDMA and dissociative anesthetics such as ketamine. These drugs induce various changes in perception and consciousness, forming the basis of our discussion.

Mendes FR et al, Addiction Neurosci September 2022 

How Do Psychedelics Work?

The classic psychedelics activate the serotonin 2A receptor, so the major mechanism of action I want you to take away from this webinar is that classic psychedelics activate serotonin 2A receptors. Atypical psychedelics work by various methods so they can be blocking an NMDA receptor such as ketamine, for example, or they may be modulating dopamine, norepinephrine, serotonin, and of course oxytocin which is seen with the medication MDMA, for example. 

Potential Therapeutic Uses 

Now that takes us to the potential therapeutic uses of these medicines. Now I want to point out briefly before we talk about the therapeutic uses that the medication is typically delivered in the context of psychotherapy before, during and after treatment. So there’s a period where you’ll meet with the patient and perform some psychotherapy before starting the treatment kind of priming the patient getting them ready for the psychedelic experience, and then you are going to act as a guide during the treatment, and then after to kind of take all of that information that this person has learned from the treatment and integrate it into their lives appropriately. So the potential therapeutic uses we see here can be various ones. We have mood disorder such as depression and anxiety; we have PTSD; we have OCD; we have pain and inflammation: cancer-related psychological distress; as well as addiction which may be surprising considering people might be concerned about the addictive nature of these drugs, but it can also be used in alcohol use disorder, smoking cessation, cannabis use disorder, and stimulant use disorder which are all potential areas of therapeutic use. 

Psychedelic Assisted Psychotherapy 

Psychedelic-assisted psychotherapy is a big topic. It will be delivered in a controlled setting, so of course it’s very important that these medications are taken in a place that’s safe, that’s comfortable, and that the person can be monitored appropriately. You’ll usually have one to two facilitators providing psychological support and guiding the experience. The initial session is then followed up by a brief course of psychotherapy, so there’s a brief course of psychotherapy like I said afterwards. And one of the things that we hope the research starts to tease out in the next several years is whether or not the pairing of psychotherapy with the use of psychedelic medicine is necessary to receive the therapeutic benefits. That’s a question that’s still kind of open to be answered; many people believe it is, however the data is lacking at this point. So indirect support for psychedelic-assisted psychotherapy comes from studies that follow up on CBT after ketamine treatment; so people who’ve receive ketamine treatments who subsequently go through a course of CBT seem to have better outcomes, and this provides some data that this may be the way to go when you’re using these types of medicines to treat disorders.

Wilkinson ST et al, Psychother Psychosom 2021;90(5):318–327

Mystical Experiences and Treatment Effect 

Let's briefly discuss the relationship between mystical experiences and treatment effects, which is a crucial point worth exploring. Many studies suggest that the therapeutic benefits are linked to the level of mystical experience a person has during treatment. There appears to be a correlation between how individuals feel during these experiences and the therapeutic outcomes. However, it remains uncertain whether an altered state of consciousness is necessary to derive these benefits. This is a question that demands further research in the near future.

Reduced activity in the default mode network has been observed during these experiences, enabling the brain to form new and healthier connections. One common factor among these medicines is their ability to increase neuroplasticity, which is our brain's capacity to form new connections. These connections are thought to develop in the context of psychotherapy, possibly explaining why the effects of treatments such as psilocybin can be prolonged even with just one or two doses.

Furthermore, animal model data provides encouraging evidence. In these models, blocking the serotonin 2A receptors still alleviated depressive behaviors, indicating the potential effectiveness of such treatments. Despite these positive findings, numerous unanswered questions remain, highlighting the need for further research in this field.

Wade BSC et al, Psychol Med 2022;52(12):2376–2386; Hesselgrave N et al, Proc Natl Acad Sci U S A 2021;118(17):e2022489118

Psilocybin 

Key points:

• Plant alkaloid that acts as a serotonin 2A agonist 
• Isolated from tropical and subtropical mushrooms found in South America, Mexico, and the United States 
• Common street names: Magic Mushrooms, Shrooms 

Let’s move on to talking a little bit about psilocybin specifically. So psilocybin is a plant alkaloid that acts as a serotonin 2A agonist and it’s going to activate those 2A receptors. It’s isolated from tropical and subtropical mushrooms found in South American, Mexico, and the United States. Common street names you might hear people say are “Magic Mushrooms” or “shrooms.” This usually refers to the medicine psilocybin. 

Effects of Psilocybin-Assisted Therapy for Depression 

We have data from a randomized controlled trial involving 24 participants with major depressive disorder (MDD). Although it was small, it was still a randomized and controlled trial. The participants underwent two psilocybin sessions, with session one receiving a 20 mg/70kg dose and session two a 30mg/70kg dose, making the doses slightly different. These dosages are typical in much of the research I've reviewed.

The participants were randomly assigned to either start treatment immediately or after an 8-week delay. Before the treatment began, their mean Hamilton Depression rating score at baseline was 22.8, indicating significant depression based on the HAM-D scores. At weeks 1 and 4, the individuals who received immediate treatment showed a notable reduction in Hamilton Depression rating scores, with scores of 8 and 8.5, respectively. The effect size was remarkably large, around 2.5 and 2.6, which is uncommon in the field of psychiatry, especially regarding medication for MDD.

Davis AK et al. JAMA Psychiatry. 2021;78(5):481-489

Trial of Psilocybin vs Escitalopram for Depression

Let's discuss a renowned trial published in The New England Journal of Medicine. It was unusual for this journal to publish psychiatric data, making it intriguing that they conducted a trial comparing psilocybin with escitalopram for depression. The study was a phase II double-blind randomized controlled trial involving participants with longstanding moderate to severe MDD. The goal was to observe the effects of psilocybin and escitalopram over six weeks. Participants received either two separate doses of 25 mg of psilocybin, three weeks apart, or daily escitalopram along with two separate doses of 1 mg psilocybin, also three weeks apart.

Although the results slightly favored psilocybin over escitalopram, the difference was not statistically significant, leaving the study's ultimate findings unclear. It seems the trial indicated that psilocybin was relatively safe, with few side effects reported. However, an important consideration is that participants were likely aware of whether they were taking psilocybin or escitalopram, even with the 1 mg dose used to mitigate this issue. People tend to sense the effects of psychedelics, which is a factor that future trials should address and control for.

Carhart-Harris R et al. N Engl J Med 2021;384:1402-11

Single-Dose Psilocybin-Assisted Therapy in MDD

Key points:

• Double-blind randomized controlled trial with 52 participants
• Psilocybin group showed symptom severity decrease at 14 days (effect size 0.97)
• 54% of psilocybin group met remission criteria (effect size uncommonly high) compared to traditional antidepressants (effect size ~0.3)

Single-dose psilocybin-assisted therapy in MDD was a slightly larger study. It involved 52 participants with MDD, randomly assigned to receive either a single dose of psilocybin or a placebo along with psychological support. 

The primary endpoints were the change in baseline Beck Depression Inventory and MADRS Scale at 14 days. The psilocybin group exhibited a significant decrease in symptom severity at 14 days, with a remarkably large effect size of 0.97, which is quite unusual compared to the effect size of around 0.3 seen in most antidepressant medications. Moreover, 54% of the participants in the psilocybin group met remission criteria, indicating promising results.

Von Rotz R et al, EClinicalMedicine 2022;28;56;101809

Psilocybin and Treatment-Resistant Depression 

Treatment-resistant depression is going to be one of the major areas of interest. We have many medications for depression, but not everyone experiences full relief or remission of symptoms. Psilocybin in treatment-resistant depression showed a positive result in an industry-sponsored randomized controlled trial of 223 participants who failed 2 to 4 antidepressants, indicating true treatment-resistant cases. 

Compared to the placebo group, those who received psilocybin had a sustained response of 20.3% vs. 10.1% three months after the initial dose. While the trial had a considerable number of participants, more research is needed to confirm and replicate these results.

Goodwin G et al, Poster Presentation, APA New Orleans 2022; Goodwin G et al, N Engl J Med 2022;387(18):1637-1648

Psilocybin-Assisted Therapy in Life-Threatening Cancer 

Key points:

• Psilocybin popular in end-of-life treatment and life-threatening cancer.
• 68-participant trial with terminal cancer + 3 small randomized trials.
• 70% showed large response after one dose.
• Benefits maintained at 6 months.
• Long-term follow-up (4-1/2 years) with 15 original participants.
• 60-80% met criteria for significant antidepressant and anti-anxiolytic responses.
• Encouraging long-lasting effects for responders.

Psilocybin gained initial popularity and promotion in end-of-life treatment. Let's examine the data on psilocybin-assisted therapy in life-threatening cancer, which includes a 68-participant trial with terminal cancer and 3 small randomized crossover trials. Though the data may not be extensive, let's analyze it.

Out of the two studies, both showed positive results, with 70% of participants exhibiting a large response after a single dose. These benefits were sustained even at the 6-month mark. Moreover, a long-term follow-up was conducted on the same individuals 4-1/2 years later, involving 15 of the original 16 participants from one of the trials. Remarkably, 60-80% of these participants still met criteria for clinically significant antidepressant and anti-anxiolytic responses, suggesting that the positive effects of the medication endured over the years.

These data are encouraging as they indicate the effects of psilocybin-assisted therapy are long-lasting and individuals who respond well to it tend to fare positively in the long-term.

Dodd S et al, CNS Spectr 2022;11:1–11; Agin-Liebes GI et al. J Psychopharmacol. 2020 Feb;(2):155-166

Microdosing Psilocybin

Key points:

• Increasingly popular (Reddit, podcasts, etc.)
• Involves 5%-10% of standard dose
• Some benefits without intense hallucinatory effects
• Positive changes in well-being, anxiety, depression, and emotional stability reported after 4 weeks
• Challenges include legal issues and varying individual responses

Microdosing psilocybin is very popular on Reddit forums, in other articles, and on podcasts. People talk about it all the time, and it seems to be a superpower if you take it. Microdosing is defined as taking only 5% to 10% of the standard dose, significantly less than the doses discussed in the previous studies I presented. 

Despite the low doses, there is evidence of some benefits without causing intense hallucinatory experiences. So, the question is whether hallucinatory experiences are necessary to get the benefits.

MDMA: 3,4-Methylenedioxymethamphetamine

Key points:

• AKA “Ecstasy” or “Molly” 
• Similar structure to methamphetamine and mescaline
• Causes release of monoamines through reversal of transport proteins and reuptake inhibition (serotonin and norepinephrine primarily) 
• Modulates glucocorticoids through HPA axis, decreases amygdala and hippocampal activity, and increases PFC activity 
• New data indicating efficacy in the treatment of PTSD 

We're discussing “Ecstasy” or “Molly,” also known as MDMA. It shares structural similarities with methamphetamine and mescaline. Its mechanism of action involves the release of monoamines by reversing transport proteins and reuptake inhibitors. This affects serotonin and norepinephrine mainly, while also modulating glucocorticoids through the hypothalamic-pituitary-adrenal axis. 

MDMA decreases amygdala and hippocampal activity while increasing prefrontal cortex activity. It has a significant impact on various brain areas associated with conditions like PTSD or depression. Though primarily studied for PTSD, MDMA may eventually find applications in other areas, such as depression.

MDMA Benefits for Fear Extinction in Exposure Therapy

Key points:

• Increases blood flow to the vmPFC that decreases amygdala activation 
• Increases cortisol which interacts with glucocorticoid receptors in the hippocampus improving memory 
• Elevates elevate brain-derived neurotrophic factor (BDNF) 
• Elevates oxytocin to decreases activity in the amygdala and enhance connectedness with the therapist 
• Increased serotonin resulting in prosocial behavior and positive affect

Exposure therapy (or some form of it) is an effective treatment for PTSD, but it can be difficult for some patients to tolerate. It takes a long time, unfortunately, for it to work well. 

MDMA increases blood flow to the ventral medial prefrontal cortex which decreases amygdala activation so it’s one of the things that we are going to want to do for patients with PTSD. It boosts cortisol, which interacts with glucocorticoid receptors in the hippocampus to improve memory. 

It can also raise BDNF, which enhances memory and might ease depression since BDNF has antidepressant effects. Moreover, it increases oxytocin, reducing amygdala activity and fostering a stronger connection with the therapist during the therapy session. Additionally, there's a rise in serotonin, leading to more pro-social behavior and a positive mood. With all these effects, MDMA may offer various benefits for individuals with PTSD.

Initial MDMA Trials

What do the initial MDMA trials show us? The first data came from six small randomized controlled trials involving a total of 105 participants. This was a combination of military and civilians with PTSD. 

When the data is pooled it registered a large effect size; so when you take all this data together the effect size was considered large. We generally think of large effect sizes as 0.8 or better. One year later remission rates increased from 56% to 67%, so about two-thirds of individuals who used MDMA who had a diagnosis of PTSD according to this data experienced remission. 

Jerome L et al, Psychopharmacology (Berl) 2020;237(8):2485–2497

Phase III RCT Granting MDMA Breakthrough Status

The Phase III randomized controlled trial that granted MDMA breakthrough status by the FDA is an important study to be familiar with if you're considering using this medication in clinical practice. 

The study included 89 participants and found that the treatment with MDMA was both safe and well tolerated, which is crucial for its clinical utility. 

Approximately 67% (about two-thirds) of the participants achieved full remission from PTSD. There are upcoming studies exploring the potential of MDMA for alcohol use disorder and eating disorders, so keep an eye out for their publications in the future.

Mitchell JM et al, Nat Med (2021);27:1025–1033

MDMA Risks

Key points

• Reports of death from hyperthermia, cardiotoxicity, and seizures 
• Psychiatric side effects include worsening mood, suicidality, and psychosis/mania 
• It’s unknown if these same risks carry over for doses used clinically 

Some issues of concern are reports of death from hyperthermia, cardiotoxicity, and seizures, primarily associated with recreational use of the medication. Psychiatric side effects may include worsened moods, suicidality, psychosis, or mania, making it unsuitable for individuals with diagnoses like schizophrenia or bipolar disorder. 

However, it remains unknown whether these risks apply to the doses used clinically. Therefore, further research is necessary to clarify these aspects before considering these medications as viable treatments for our patients.

Costa G and Gołembiowska K, Exp Neurol 2022;347:113894

Abuse Potential

Key points

• Psilocybin, MDMA are Schedule I drugs 
• These drugs do not seem to hijack the brain’s reward center like opioids 
• Repeated use of psilocybin does not lead to physiological dependence or withdrawal 
• Psilocybin is decriminalized in 9 US cities and readily available in nonmedical settings in Oregon

Abuse potential is a major concern for many when it comes to substances like psilocybin and MDMA. Both drugs are classified as Schedule I, federally illegal, and not recognized for therapeutic benefits. Unlike opioids, psychedelics do not appear to target the brain's reward center in the same way, specifically the ventral tegmental area and nucleus accumbens.

Regarding psilocybin, repeated use does not seem to lead to physiological dependence or withdrawal, although more research is needed to confirm this definitively. Currently, there is a consensus that it is less likely to cause physical dependence compared to other substances.

Interestingly, psilocybin has been decriminalized in nine US cities, and in places like Oregon, it is available in nonmedical settings. However, this trend may be developing prematurely since not all the necessary data has been gathered. It would be prudent to conduct further research before making decisions about making these substances readily available for therapeutic use.

Summary

There is a growing interest in utilizing psychedelics to treat psychiatric disorders, with ongoing investigations focused on conditions such as MDD and post-traumatic stress disorder. Psychedelic-assisted psychotherapy is a promising approach under heavy exploration, but its effectiveness in delivering therapeutic benefits requires further examination.

Despite the potential benefits, it is crucial to acknowledge the risks associated with psychedelics, including adverse effects and legal consequences. At this stage, psychedelics may not be fully ready for widespread prescription and use, but they offer an exciting and novel option for treating conditions like major depression and PTSD.

In summary, while psychedelics hold promise as therapeutic agents, more research and caution are necessary before they can be integrated into regular treatment practices.

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REFERENCES:

Agin-Liebes GI et al. J Psychopharmacol. 2020;(2):155-166

Anderson T et al. Harm Reduct J 2019;16(1):43

Carhart-Harris R et al. N Engl J Med 2021;384:1402-11

Costa G and Gołembiowska K, Exp Neurol 2022;347:113894

Davis AK et al. JAMA Psychiatry. 2021;78(5):481-489

Dodd S et al, CNS Spectr 2022;11:1–1

Dyck E, CMAJ. 2015 Aug 4;187(14):1079-80

Goodwin G et al, N Engl J Med 2022;387(18):1637-1648

Goodwin G et al, Poster Presentation, APA New Orleans 2022

Hesselgrave N et al, Proc Natl Acad Sci U S A 2021;118(17):e2022489118

Kaertner LS et al, Sci Rep 2021;11(1):1941

Jerome L et al, Psychopharmacology (Berl) 2020;237(8):2485–2497

Mendes FR et al, Addiction Neurosci September 2022 

Mitchell JM et al, Nat Med (2021);27:1025–1033

Wilkinson ST et al, Psychother Psychosom 2021;90(5):318–327

Wade BSC et al, Psychol Med 2022;52(12):2376–2386)

Von Rotz R et al. EClinicalMedicine. 2022 Dec 28;56;101809

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