Psychedelic renaissance: A renewed focus on the clinical utility of hallucinogens

During the 1960s, several studies were conducted to test the therapeutic effects of hallucinogenic drugs, also known as psychedelics, on various disorders, such as major depressive disorder (MDD). However, the non-medical use of these substances became rampant due to their hallucinogenic effects, leading to their classification as narcotics in numerous countries by the 1970s. Since the 1990s, clinical research has resumed. Recently, powerful and rapid therapeutic effects, not observed with conventional psychotropic drugs, have been discovered, garnering global attention. In addition, clinical research in recent years has led to various clinical trials being conducted in the hope of using psychedelics as therapeutic drugs. Specifically, research is beginning to show that cannabidiol, ketamine, MDMA, and psilocybin, the main ingredient in "magic mushrooms," are effective for depression and post-traumatic stress disorder. In particular, patients with postpartum depression and premenstrual dysphoric disorder (PMDD) may benefit. Marijuana derives from cannabis, a plant that has its origin in Central Asia. It has been used for ceremonial and medicinal purposes since ancient times, owing to its euphoric and analgesic effects. The primary cannabinoid ingredient in marijuana is Δ-9 tetrahydrocannabinol (THC), which has psychotropic effects, and cannabidiol (CBD), which lacks such effects. Nonpsychoactive CBD received approval for medicinal use in 2018 and 2019 in the United States and Europe, respectively, based on numerous clinical effects. Studies have shown good safety features and tolerability without the common psychoactive effects of THC, in addition to demonstrating no signs of abuse, dependence, physical dependence, or tolerance. Currently reported clinical effects include antiepileptic effects on intractable epilepsy (such as Dravet syndrome); anti-inflammatory, analgesic, antiemetic, anxiolytic, and antipsychotic effects; and efficacy in the prevention and treatment of diabetes, cancer, Alzheimer's disease, and other disorders. Ketamine, synthesized in 1962 as a replacement for the anesthetic phencyclidine (PCP), is called a "dissociative anesthetic" because it causes dissociative symptoms, such as astral withdrawal. PCP and ketamine were widely abused by young people in the United States in the 1960s and 1970s and were regulated as drugs of abuse. However, in 2000, a research group at Yale University in the United States was the first to scientifically report the immediate and sustained antidepressant effects of ketamine in a double-blind, placebo-controlled study. The initial study that demonstrated the antidepressant effects of ketamine was conducted with only seven subjects. The study involved 2 days of intravenous treatment with ketamine hydrochloride (0.5 mg/kg) or saline under randomized, double-blind conditions. The results indicated that only the group that received ketamine showed significant improvement in depressive symptoms at 72 h.1 Subsequently, several clinical trials and meta-analyses have demonstrated its antidepressant effects, and nasal drops of the optical isomer of ketamine, esketamine, have been approved for the treatment of treatment-resistant depression (TRD) in the United States and Europe. Psilocybin, the hallucinogenic compound found in magic mushrooms, has been utilized in shamanistic ceremonies and other rituals throughout Asia and Latin America for centuries. Recently, clinical studies have demonstrated that psilocybin has the potential to improve depressive symptoms in patients with TRD. A Phase II double-blind, randomized, controlled trial compared psilocybin to escitalopram, a selective serotonin reuptake inhibitor, over a period of 6 weeks in patients with moderate to severe MDD.2 The study enrolled a total of 59 patients, and both groups experienced a decrease in depression scores on the 16-item Quick Inventory of Depressive Symptomatology–Self-Report at Week 6, indicating no significant difference in antidepressant efficacy between the two groups. However, it is worth noting that psilocybin was observed to improve depressive symptoms within hours and persist for several months, suggesting a faster onset and longer duration compared to conventional SSRIs. Similarly, ayahuasca, which is also used in shamanic rituals in Latin America and has been discussed in this review, exhibits similar antidepressant effects. The recent paper by Ruffell et al. provides an in-depth description of the antipsychotic effects and physiological content that are currently known and should be referenced.3 Hallucinogens have traditionally been used for witchcraft or religious rituals since ancient times. Since the 1960s, however, lysergic acid diethylamide (LSD) has been synthesized and its abuse and dependence have become major social problems. In many countries its possession and use are now prohibited by law. In recent years, however, the clinical utility of hallucinogens has received renewed attention, leading to a "psychedelic renaissance." Methylenedioxymethamphetamine (MDMA) has been reported to have a therapeutic effect on PTSD and recent research demonstrates potential for addressing other psychiatric disorders, particularly depression and anxiety disorders. Currently, there are reports on the effectiveness of various psychedelics for treating mental illnesses. However, it is important to note that these substances have been regulated by law for many years, even decades. The reports on effectiveness are based on small-scale experiments and have not yet been included in treatment guidelines for mental disorders. Psychedelics not only have direct side-effects, such as liver dysfunction, but they also increase suggestibility. There have been reports of sexual assault in some cases, and problems of abuse and dependence due to inappropriate use. It is important to avoid over-reporting effects in situations where neutrality is not guaranteed from a commercialist perspective, and to be aware of the dangers involved. To establish the safety and efficacy of hallucinogens as a treatment for mental illness, it is necessary to conduct neutral, scientific, large-scale clinical and basic research. The authors declare no conflicts of interest.