Top 3 Use Cases for Psychedelics, Understanding Ongoing Research

July 19, 2023 - Throughout the past decade, psychedelics have become a primary area of interest for ongoing clinical research. Scientists have hypothesized multiple clinical use cases for these medications despite primarily being scheduled or illicit drugs. Ongoing research is evaluating the use of psychedelics to treat anxiety and depression, post-traumatic stress disorder (PTSD), and substance use disorders (SUDs).

The American Association of Medical Colleges (AAMC) notes that the use of psychedelic drugs has been approved for clinical trials across dozens of medical centers in the United States. These psychedelic studies have explored the medications as interventions for drug abuse, alcohol addiction, eating disorders, PTSD, depression, prolonged grief, cluster headaches, and even burnout.

Scheduling these drugs has presented an additional barrier in their clinical exploration. The challenges and limitations in researching them — while necessary for patient safety and ethical practices — can also make it difficult to assess the psychopharmacology and effects of psychedelics fully.

However, recent rhetoric surrounding psychedelics and other alternative treatment methods, including cannabis, has facilitated a reconsideration of psychedelics. In 2019, the FDA approved a type of ketamine treatment for depression.

After extensive data promoted their potential therapeutic benefits, in June 2023, Australia became the first country to approve the prescription of 3,4-methylenedioxymethamphetamine (MDMA) and psilocybin for PTSD and depression. These drugs are part of a class of psychedelic medicines previously illicit in the country.

The Therapeutic Goods Administration (TGA) is the governing authority that approved the sale of these psychoactive drugs. According to an article published in Nature, the approval process took three years and included input from clinical experts.

While compassionate use for cancer patients and other terminally ill groups or research uses are approved in other jurisdictions, general prescriptions of these psychedelic therapies have only been approved in Australia thus far.

What Are Psychedelics and Dissociative Drugs?

The National Institute on Drug Abuse (NIDA), a subset of the NIH, notes that most psychedelic drugs are derived from plants and fungi; however, synthetic forms have been developed in recent years.

A 2021 study published in Risk Management and Healthcare Policy states that classic hallucinogens and psychedelic drugs — sometimes called serotonergic hallucinogens — impact perception, cognition, and mood.

Psychedelic substances alter sensory perception — commonly creating visual effects and changing cognitive processes, inducing introspection, self-consciousness, mystical experiences, and altered time passage. Hallucinogenic drugs are also known to change mood, characterized by bliss, euphoria, and joy.

Using classical hallucinogens may have some beneficial therapeutic effects; however, there are also some associated risks. One of the adverse events linked to hallucinogens includes a “bad trip,” which can cause an acute state of anxiety, dysphoria, and confusion. Users may also have unpredictable or uncontrolled behaviors. The article notes that psychedelic drugs may have antidepressant, anxiolytic, and anti-addictive properties.

NIDA divides psychedelic and dissociative drugs into three different groups:

1. Psychedelic drugs: NIDA includes psilocybin, lysergic acid diethylamide (LSD), dimethyltryptamine (DMT), and mescaline in the psychedelic category. According to Frontiers in Psychiatry, classical hallucinogens are theorized to be serotonin 2A receptor (5-HT2A) agonists. These psychoactive substances may also act as serotonin 2C and 1A receptor agonists.
2. Dissociative drugs: Comparatively, dissociative drugs, including ketamine and phenylcyclohexyl piperidine (PCP), block N-methyl-ᴅ-aspartate (NMDA) receptors in the brain.
3. Other psychedelic and dissociative drugs: The final class of drugs, which includes,4-methylenedioxymethamphetamine, ibogaine, and salvia, has a variety of mechanisms of action that lead to their psychedelic or dissociative effects.

Psilocybin

Psilocybin is extracted from Psilocybe mushrooms, sometimes called “magic mushrooms.”

According to a 2021 article published in Molecules, researchers at Johns Hopkins University began studying psilocybin use in 2006, marking the first research on psilocybin since the 1970s. The medication has been explored to address alcohol dependence, drug dependence, anxiety disorders, cancer-related depression, other depressive disorders, cluster headaches, chronic pain, phantom pain, demoralization, maladaptive narcissism, epilepsy, and other neurological and psychological disorders.

LSD

A 2020 article published in Frontiers in Psychiatry notes that LSD was discovered by a Swiss chemist in 1938. Shortly after its discovery, throughout the 1940s, researchers explored LSD as a therapeutic psychiatric treatment.

The US government banned LSD in 1967, siloing efforts to research it for clinical purposes. “LSD remains one of the most stigmatized and legally restricted agents among psychoactive substances. It is still included in Schedule I of the United Nations classification of drugs, restricting its use in research and making it difficult to potentially use it as a therapeutic tool in medicine,” researchers noted in the article.

Currently, LSD is a Schedule I drug in the US, with its precursors, lysergic acid and lysergic acid amide, classified as Schedule II. As scheduled drugs, LSD and its precursors may not be sold or administered in the United States without a special license from the DEA.

While there are no approved indications for LSD today, many non-FDA-approved indications exist, including depressive disorders.

The active doses of LSD range between 0.5 and 2 mcg/kg, with an average half-life of three hours. Depending on the amount, tolerance, weight, and age, the psychoactive effects may last up to 12 hours. A systematic review published in Frontiers in Psychiatry revealed that most clinical trials exploring the therapeutic benefits of LSD use a single dose of oral LSD; however, some studies use dose-escalation approaches.

MDMA

Beyond the classic psychedelic drugs researched in the early to mid-90s, a new class called entactogens was discovered. This class of medications improves empathy and emotional openness. One of the most widely incorporated entactogens in psychedelic research is 3,4-methylenedioxymethamphetamine (MDMA), commonly called ecstasy.

MDMA has a broad therapeutic potential. Currently, it is being assessed for managing social anxiety in autistic patients, end-of-life anxiety, and PTSD. Unlike classic hallucinogens, MDMA acts as a monoamine reuptake inhibitor, which causes oxytocin release.

Ketamine

Ketamine therapy has been explored by clinicians and researchers as a part of treatments for major depression. Ketamine is known to reduce depression symptoms, including thoughts of suicide, much faster than traditional drug use.

To date, ketamine is the only legal psychedelic medication in the US. There are two kinds of ketamine used for treatment-resistant depression, racemic and esketamine. Racemic ketamine is a mixture that includes (S)- and (D)-enantiomers, which is typically infused intravenously.

Meanwhile, there is also an FDA-approved form of nasal ketamine comprising just the (S)-enantiomer of ketamine, called esketamine, (S)-ketamine, or asketamine.

Researchers are also developing a form of oral ketamine that is given as an extended-release tablet, mitigating some of the risks associated with infused ketamine.

Psychedelics for Anxiety and Depression

Anxiety and depression are two of the significant use cases for psychedelics. Commonly lumped together, these conditions are typically treated with a combination of psychotherapy and antidepressant or anxiolytic medications. However, there are many challenges linked to the currently available drugs. Psychedelics may supersede these barriers, treating patients more readily and effectively.

In 2014, a study in Switzerland evaluated the effects of LSD-assisted psychotherapy on patients with anxiety associated with terminal illness. Only 12 participants were enrolled in the study that supplemented traditional psychotherapy sessions with LSD-assisted psychotherapy sessions roughly 2–3 weeks apart. At a two-month follow-up, the researchers found that LSD improved state anxiety with no significant changes in trait anxiety. Additionally, the therapeutic benefits were sustained at the one-year mark.

Psilocybin has also been used for end-of-life anxiety. Studies have shown that the drug, alongside psychotherapy, can improve mood and reduce anxiety. Recent studies have explored the use of psilocybin for patients with treatment-resistant depression (TRD) and major depressive disorder (MDD).

A 2021 study published in the New England Journal of Medicine explored the anti-depressant properties of psilocybin compared to established mental health treatments.

The phase 2 double-blind, randomized controlled trial evaluated patients with long-standing moderate-to-severe major depressive disorder. Half the patients were given two 25 mg doses of psilocybin three weeks apart and a daily placebo. The other group of patients was given two doses of 1 mg psilocybin three weeks apart and a daily dose of escitalopram, a selective serotonin reuptake inhibitor (SSRI).

At baseline, the psilocybin-only group had a Quick Inventory of Depressive Symptomology Self-Report (QIDS-SR) score of 14.5, while the escitalopram group had an average score of 16.4.

By the end of the six-week study period, the psilocybin group had an average QIDS-SR score reduction of 8.0 points, while the escitalopram group’s average reduction was only 6.0. More patients (70%) responded to the psilocybin treatment than the escitalopram treatment (48%).

Based on these results, researchers concluded that the effects of psilocybin are more significant than traditional antidepressants; however, they maintain that additional research is required for an accurate evaluation.

Additionally, a 2022 study published in the New England Journal of Medicine found that a single dose of psilocybin can reduce the Montgomery–Åsberg Depression Rating Scale (MADRS) score in patients with treatment-resistant depression.

Beyond psilocybin and LSD, ketamine therapy has proven to be an effective treatment for treatment-resistant depression. In a 2023 study published in the New England Journal of Medicine, researchers revealed that ketamine therapy is as effective as electroconvulsive therapy in managing treatment-resistant depression.

Post-Traumatic Stress Disorder

According to an article published by New York University Langone Health, many patients with PTSD do not respond to traditional antidepressants and antipsychotics, leaving them to deal with the adverse side effects without any therapeutic relief.

The organization notes that many researchers have considered psychedelics an alternative and potentially more effective treatment pathway. A 2013 study from researchers at the University of South Florida hypothesized that psilocybin stimulates neurogenesis, which can help manage PTSD symptoms.

Additionally, a 2021 randomized, double-blind, placebo-controlled phase 3 study published in Nature Medicine evaluated MDMA-assisted therapy for treating severe PTSD. The study recruited 90 patients with severe PTSD, not excluding comorbidities such as dissociation, depression, alcohol or substance use disorders, and childhood trauma.

Patients had a medically supervised psychiatric medication washout that lasted for a minimum of five half-lives plus one week. After the washouts, patients had a baseline evaluation, including an assessment of PTSD symptoms using the Clinician-Administered PTSD Scale for DSM-5 (CAPS-5) and functional impairment using the Sheehan Disability Scale (SDS).

All participants underwent three preparation therapy sessions and nine integrative therapy sessions; half received MDMA, while the other half were given a placebo. Patients were reassessed two months after their last session. The MDMA group had an average CAPS-5 score reduction of 24.4, compared to the average decrease of 13.9 in the placebo group.

Substance Use Disorders

Addiction is another critical research area for psychedelics. Psilocybin-assisted alcohol dependence therapy reduced the percentage of drinking and heavy drinking days by over 50%.

Additionally, a pilot study exploring psilocybin-assisted psychotherapy for tobacco dependence induced smoking cessation in 12 of the 15 participants.

Many clinical trials analyzed the use of LSD in patients with alcohol use disorder (AUD). For example, one study published in the American Journal of Psychiatry in 1969 maintained that LSD improved patients’ Drinking Behavior Scale scores compared to dextroamphetamine. Although many studies point to a positive impact of LSD on AUD, some studies note a lack of significant improvement, indicating a need for additional research.

Research Challenges

Recreational use of LSD and psilocybin have caused psychedelics to be highly stigmatized. Alongside their scheduled status, the stigma surrounding these drugs has presented additional challenges for funding, developing, and conducting clinical trials, hindering scientists’ understanding of their therapeutic potential.

One of the most challenging parts of studying psychedelics is that their effects can vary dramatically. Factors impacting the drug’s effect include the dose, potency, and an individual’s biology, age, sex, personality, mood, expectations, mindset, or environment.

Just as these drugs' therapeutic benefits or positive effects can vary from person to person, the adverse effects may also vary. Some common side effects include headache, nausea, and altered heart rate. Aside from the physical side effects, psychological side effects such as fear and anxiety may be dangerous for some patients.

Although these challenges exist, many regulatory organizations are working on guiding researching psychedelic drugs. For example, the US FDA recently issued its first draft guidance on using psychedelic drugs in clinical trials, offering recommendations for chemistry, manufacturing, clinical pharmacology, and abuse potential.

With more healthcare professionals and regulatory organizations understanding the potential therapeutic benefits of these drugs, additional research may provide a broader insight into uses and best practices surrounding psychedelics.