The Current State of Psychedelic Research
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Plant-derived psychedelics have been used by indigenous groups across the world for centuries.
There is evidence that peyote, the plant that produces the drug mescaline, has been used by Native American groups in religious and cultural rituals for more than 5,000 years. In South America, shamans from tribes around the Amazon Basin would use ayahuasca in religious ceremonies and as a way to diagnose disease. Certain African tribes around modern-day Gabon use the psychedelic properties of ibogaine, found in bark of the Tabernanthe Iboga shrub, in coming-of-age ceremonies. And there is evidence of historic psychedelic mushroom use across the world, from ancient Greece to Australia.
But it is only in the last few decades that Western scientific research groups have taken a keen interest in studying these compounds to better understand how they work, and to assess whether these psychedelics might be suitable for clinical use.
So, what have these research efforts uncovered?
Psilocybin – the active psychedelic ingredient in magic mushrooms – is one of the more well-known psychedelics being studied for therapeutic use. Nearly 60 clinical trials involving the drug are currently active around the world.
The compound has been granted a “Breakthrough Therapy” designation from the US Food and Drug Administration (FDA) for treatment-resistant depression (TRD) and major depressive disorder (MDD). Such designations are designed to expedite the development and review of drugs that research shows “may demonstrate substantial improvement” over pre-existing treatments, signaling an interest in the field at a federal level.
Psilocybin also has been the subject of multiple trials looking at the drug’s effectiveness in tackling addiction, anxiety, chronic migraine, and mild traumatic brain injury.
“With psilocybin, the main areas that are being studied are mood disorders and depression. There’s been work looking at a treatment of addiction, like tobacco or nicotine addiction, alcohol dependence, and cocaine,” Albert Garcia-Romeu, an assistant professor at the Center for Psychedelic and Consciousness Research at Johns Hopkins University, recently told Analytical Cannabis.
“The other big areas [are] more in the palliative care side, for patients with terminal illnesses who also have mental health challenges like anxiety, depression, and usually don't tend to respond very well to the normal course of antidepressant medications.”
Previous research from the team at Johns Hopkins University found psilocybin taken in clinical settings to give significant relief to patients with cancer-related existential anxiety or depression, with the majority of patients reporting ongoing relief up to six months after the last treatment session. More recently, the group has published the results of a randomized clinical trial in JAMA Psychiatry, which found psilocybin-assisted psychotherapy to be around four-times more effective at treating MDD than traditional antidepressants.
Researchers at Yale University have also recently conducted a small-scale psilocybin study, this time looking at the effect of the drug on migraine disorders. Compared to a group given a placebo, the participants who received low doses of psilocybin reported significant decreases in migraine-affected days as early as one week after receiving their first dose.
Further investigations into psilocybin and its effects on neurological problems, such as mild traumatic brain injury, are currently underway, as are trials looking at the drug’s effect on eating disorders, addiction, post-traumatic stress disorder (PTSD), and Alzheimer’s disease.
LSD was the first synthetic psychedelic, discovered by complete accident in the 1930s by a chemist who had been looking to make a blood and respiratory stimulant. But this accidental synthesis would kick off a whole new movement, leading to new innovations in understanding how serotonin works and laying the groundwork for the wider field of psychedelics research.
Unfortunately, early research into LSD was plagued by problems with ethics. This came to a head in the ‘60s with the widely publicized death of Tusko the Elephant after an LSD overdose sustained in an animal behavioral science experiment. After this, research gradually declined, with a few exceptions. Dutch psychiatrist Jan Bastiaans pioneered the use of LSD in combination with psychotherapy throughout the ‘60s and beyond, using the drug in his work with Holocaust survivors to treat their PTSD.
Today, LSD research is making a resurgence. There are over 60 unique LSD-related clinical trials listed in the US National Library of Medicine database, investigating the general action of LSD in the brain and the drug’s effects on conditions including depression, anxiety, and cluster headache. A recent literature review of randomized-controlled clinical trials for LSD concluded that the compound does have the therapeutic potential “to reduce psychiatric symptomatology, mainly in alcoholism.”
One particularly hot area of research at the moment is on the effectiveness of microdosing – the practice of taking very low amounts of LSD to boost creativity and mood without triggering a full-on hallucinogenic trip. Earlier this month, researchers from Imperial College London published a paper in the journal eLife which cast doubt on this practice, concluding that many of the positive changes in wellbeing experienced by those who microdose might actually be explained by the placebo effect.
MDMA, short for 3,4-methylenedioxymethamphetamine, is a methamphetamine drug prohibited under Schedule 1 of the Controlled Substances Act in the USA, and is a Class A/Schedule 1 drug in the United Kingdom. Under the wording of both these laws, MDMA is restricted as a drug with “no currently accepted medical use” and a “high potential for abuse.”
But contrary to this, an ever-growing body of research now supports the use of MDMA in controlled, supervised environments as a tool for treating severe PTSD.
A recent literature review published in the European Journal of Psychotraumatology found MDMA-assisted psychotherapy (MDMA-AP) to have a particularly “impressive effect size” in reducing PTSD symptoms, dubbing MDMA-AP “the most promising novel treatment for chronic and often treatment-resistant PTSD”.
More work into exactly how MDMA affects the brain is ongoing, but it appears that the drug is able to enhance the release of monoamines (including serotonin and dopamine), hormones, and other downstream signaling molecules in such a way that it effectively modulates emotional memory circuits in the brain. This process can help people with PTSD to reprocess traumatic memories and to better engage emotionally with the different aspects of psychotherapy.
In light of such promising research, the FDA last year agreed to allow an Expanded Access Program for MDMA-Assisted Psychotherapy in PTSD. This program will allow some patients with severe PTSD who do not qualify for phase three clinical trials early-access to MDMA-AP treatments.
In addition to showing promise in treating PTSD, early research is also underway looking at whether MDMA-AP might be helpful for autistic adults who have severe social anxiety. In early results from a small-scale pilot study, participants reported that MDMA-AP helped reduce feelings of social anxiety by around 45 percent after just two sessions, but larger scale trials are needed to investigate this further before drawing any concrete conclusions.
Ketamine is somewhat unique in psychedelics research, as the drug has been used as an anesthetic in humans and animals for decades.
But in recent years, interest in ketamine and its enantiomer esketamine has grown further as more evidence comes out linking the dissociative anesthetic as a treatment for treatment-resistant depression.
In March 2019, the FDA approved a nasal spray formulation of esketamine, in conjunction with a traditional oral antidepressant, as a treatment for TRD in adults. Due to the sedative effects and possible potential for abuse, the actual dispensing of this nasal spray drug is still fairly restricted, but the FDA’s approval does reflect the strength of the short- and long-term studies cited in the announcement, which concluded esketamine can exercise a statistically significant and long-lasting reduction in depression symptoms.
A similar approval for esketamine was also handed down by the European Commission in 2019. Now ketamine treatment clinics that can serve people with severe depression are up and running in the United States, Canada, and in several locations across Europe.
Given ketamine’s existing use as an anesthetic, it is perhaps marginally less surprising that it is also gaining traction as a potential treatment for chronic pain. Literature reviews have found strong evidence of ketamine’s effectiveness in tackling post-operative pain and chronic pain (particularly chronic neuropathic pain), but there is a general lack of consensus around appropriate dosing. There is also some evidence that low-dose ketamine could help with refractory cancer pain, but this evidence base is quite limited.
Ayahuasca is the name given to a hallucinogenic drink made by brewing together the leaves of the Psychotria viridis shrub and the stalks of the Banisteriopsis caapi vine in water. This drink plays an important part in the cultural and religious ceremonies of indigenous groups around the Amazon Basin in South America.
The Psychotria viridis leaves contain N,N-dimethyltryptamine (DMT), a natural psychedelic that is extracted from the leaves during the brewing process. DMT ordinarily has very low levels of bioavailability, as it is broken down quickly by enzymes in the liver, but enzyme inhibitors contained in the Banisteriopsis caapi vine stalks effectively counteract this. As a result, a powerful hallucinogenic beverage can be made by brewing the two plants together.
Recently, there has been a growing wave of non-indigenous ayahuasca use – largely from tourists wanting to seek out new experiences. The medical establishment has also grown increasingly more interested in the clinical use of ayahuasca and the active ingredient DMT as another form of psychedelic-assisted psychotherapy.
In late-2020 UK regulators gave approval to a new clinical trial on DMT-assisted psychotherapy for depression, modelled after similar assisted psychotherapy practices already used for psilocybin. The DMT-AP trial will also aim to set dosing guidelines for the drug that may be useful for future studies.
As well as DMT use for depression, researchers are also interested in the compound’s effect on addiction and problematic substance use. In one small-scale study supported by the Multidisciplinary Association for Psychedelic Studies, participants engaged in group counselling sessions alongside two expert-led ayahuasca ceremonies. After this weekend ayahuasca retreat, participants reported significant reductions in reported cocaine use, as well as significant increases in reported quality of life, with no major adverse effects.
Peyote is another psychedelic used by indigenous groups in the Americas, this time by Native American tribes in Mexico and the Plains region around Texas and Oklahoma. Peyote is the name of a small cactus, only a few inches large, which naturally produces the psychedelic compound mescaline. Dried peyote “buttons” – the name given to protrusions at the top of the plat – or the seeds of the peyote cactus are commonly used in religious ceremonies conducted by the Native American Church.
Within this church, peyote is known to be used as a remedy for alcoholism; where the general alcoholism rates of Native American people tend to be higher than the American average, alcoholism rates among members of the Native American Church are noticeably lower. Research suggests that this could be due to mescaline and other biochemical alkaloids found in the peyote cactus having certain pharmacological similarities to the neuroamine-derived alkaloids found in the brain during alcohol intoxication.
In traditional settings the cactus is also used medicinally for a raft of physical ailments, including fevers, headache, sunstroke, and arthritis.
But while advocates of other psychedelic plants and substances are fighting for the drugs to be decriminalized – allowing for easier research and more accessibility – the Native American Church itself is firmly opposed to the decriminalization of peyote. Church members are currently allowed to use peyote under US law, but the non-religious use of the plant remains prohibited. Many in the church fear that wider decriminalization could lead to unsustainable harvesting practices that might endanger the current population of peyote plants, which itself has already been ravaged by broken land treaties and ecological threats. Additionally, out of respect for the peyote plant and respect for the Native American people who fought to get federal recognition for the indigenous use of peyote, the Native American Church generally discourages non-indigenous use of the plant.
Moving forwards in psychedelic medicine
Research into psychedelics as medicine is a growing field with a vast potential for treatments and insights for depression, anxiety, PTSD, pain, migraine, and similar high-prevalence health conditions.
But as the research space moves forwards, researchers themselves are keen to learn from the past. As detailed in a recent article from the Journal of Psychedelic Studies, psychedelics research needs progress with the acknowledgment of the contributions made by indigenous medicine practitioners, and should look at how it can better include indigenous people and minority groups within modern psychedelics research culture.
“These substances have been used and revered by indigenous cultures for a long time,” Garcia-Romeu told Analytical Cannabis. “I think that is an important piece of the backdrop here, because there’s a long history of use in those cultures for spiritual and other types of ritualistic purposes.”
Researchers are also hoping that looking to the past will help to avoid another dead end for psychedelics research, as happened in the 1970s. Writing in JAMA Psychiatry, Garcia-Romeu’s colleagues in the Johns Hopkins University School of Medicine assert that today’s researchers “owe it to the next generation of researchers and clinicians, and to the millions of patients […] who may benefit from these treatments to ensure that no exceptions be made in the standards of research or clinical applications for psychedelics, regardless of their seemingly exceptional potential.”