In the last 20 years, psychedelic research has blossomed to unprecedented heights. Going from research that happened at a handful of universities by pioneering researchers, it’s now being done by hundreds of research groups worldwide. Where once one could only study the negative effects of psychedelics (e.g. on driving ability), most current-day research focuses on the therapeutic outcomes.
In our database of psychedelic research, we cover around 2000 research articles. Which – speaking from experience – is a lot to cover. Therefore, this brief covers the must-read articles with the most citations.
Citations by themselves don’t mean that a research article is the one-and-only to read to understand a field. New research that has come out in the past few years hasn’t had time to be cited and could be just as seminal. But it does mean the study has remained relevant for the field (and beyond it).
The articles covered here show how ketamine’s therapeutic effects were discovered, the frame-breaking studies showing lasting positive effects from psilocybin, and a look inside the psychedelic brain state.
You can also view these studies – and all other psychedelic studies – in our Papers by Citation Overview page.
Top 10 Psychedelic Papers by Citations
It’s the year 2000 and psychedelic research is still in a dormant state. Ketamine – widely considered adjacent to psychedelics but not a ‘classical’ psychedelic – has been used for nearly 30 years as an anaesthetic. But astute clinicians notice that patients receiving ketamine also show improvements in depression ratings.
So, Robert Berman and colleagues – under the guidance of John Krystal – investigate the antidepressant effects of ketamine in seven patients. The study tests ketamine versus placebo and sees that ketamine produces positive effects within 72 hours. The findings of this study would be replicated over several thousands of studies that took place in the last 20+ years.
2. Psilocybin can occasion mystical-type experiences having substantial and sustained personal meaning and spiritual significance
Six years later, the cat is out of the bag for psychedelic research. In 2006, Roland Griffiths and colleagues publish the results of a double-blind study on the effects of a high dose of psilocybin in ‘healthy normals’ (not patients). They confirm results established during the Marsh Chapel (Good Friday) experiment, showing that most participants had full-on mystical experiences.
Not only do the researchers show acute mystical experiences, but a subsequent follow-up study indicates that participants had lasting benefits resulting from the experience. Those who had a ‘fuller’ mystical experience were also those who reported the most positive long-term outcomes.
3. Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial
Doing research with psychedelics is still a difficult undertaking. As they are scheduled drugs (Schedule I – the most restrictive category) researchers can’t access them easily (it’s easier for ketamine – placed in Schedule III). One area where the review board (IRB) is more likely to say yes to a research request is in people who are suffering from a life-threatening disease (cancer). So, this is where three of the most-cited research articles focus on (next to a handful of other reasons).
This article shows that with relatively little therapy, patients with life-threatening cancer significantly improved in measures of depression and anxiety. After six months, 80% of them still reported clinically significant decreases in depressed mood and anxiety.
As we go down the list of most-cited articles, we now find ourselves at David Nichols‘ seminal article on hallucinogens from 2004. It’s a tome of an article, clocking in at 51 pages and is still a go-to resource to start understanding psychedelics. The term used by Nichols – hallucinogens – isn’t preferred nowadays (psychedelics is) but was used more widely at that time.
Our understanding of how psychedelics work has evolved since then, but most conclusions from the article hold. It shows how psychedelics influence the serotonin receptors (specifically the 5-HT2a receptors) and prophetically indicates the possibility of psychedelics in treating alcoholism, substance use disorders, and psychiatric disorders.
The next three articles we cover here all were published in 2016 (as was the third article). This one reviews animal studies on the mechanisms through which ketamine works. It specifically investigates if a metabolite (a substance made when breaking down a drug) of ketamine could also exert antidepressant effects.
It finds that it does do so, and does this through early activation of glutaminergic AMPA receptors, independent of NMDA receptor inhibition typically induced by ketamine. Though it’s a review of animal studies – which don’t always translate to humans – it indicates the specific route through which ketamine produces antidepressant-like effects (possibly opening the way to novel molecules being developed that target this pathway).
6. Psilocybin with psychological support for treatment-resistant depression: an open-label feasibility study
We have now arrived at the first study to directly test the anti-depressant effects of psilocybin in depression (outside life-threatening diseases). Robin Carhart-Harris and colleagues show that a high dose of psilocybin (in combination with supportive therapy) significantly reduced depressive symptoms up to three months later.
About a dozen other publications about these patients follow showing a multitude of interesting aspects. One study shows sustained effects six months later. Another shows that the quality of the acute experience – as we saw in Griffiths’ study too – predicts the therapeutic efficiency. And the final study I’ll highlight here is that – in this study – psychedelics influenced personality markers such as reducing neuroticism up to six months later.
7. Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial
Similar to the third study, and the next one, this study finds positive effects on depression and anxiety after treatment with psilocybin (and combined therapy). This study was conducted by Stephen Ross and colleagues and NYU Langone Health.
If we look at secondary outcomes psilocybin-assisted therapy (PAT) decreases cancer-related demoralization and hopelessness, improves spiritual well-being, general life satisfaction, and quality of life, and could serve as a buffer against negative clinical outcomes.
The three end-of-life studies discussed so far wouldn’t have been possible without this study from 2010 taking place first. Charles Grob, Alicia Danforth and Gurpreet Chopra used a moderate dose of psilocybin (about two-thirds of the most commonly used dose). Similarly to the studies discussed, they found positive effects in anxiety up to six months after treatment.
9. Antidepressant Efficacy of Ketamine in Treatment-Resistant Major Depression: A Two-Site Randomized Controlled Trial
As we near the end of this overview of the most-cited studies, we return one last time to a study on ketamine’s antidepressant effects. This rigorous randomized controlled trial with 73 patients found immediate positive effects after ketamine over the placebo (midazolam).
Though the effects of ketamine – without surrounding therapy or redosing – usually don’t last beyond the first seven days, this study still shows the immediate benefits the drug can convey. This study looked specifically at treatment-resistant depression (TRD), but other studies also show the positive effects of ketamine on suicidal ideation (SI).
Finally, we cover one of the first studies into the psychedelic brain state. This seminal fMRI study found decreases in blood flow of hub regions in the brain (thalamus, ACC, PCC). The study is the first to report on these findings with psilocybin (2mg iv ~15mg oral). There was a decoupling between the medial prefrontal cortex and the posterior cingulate cortex, and this decoupling is hypothesized to be responsible for the psychedelic state.
Though the mechanisms through which psychedelics work are still hotly debated, examining them through fMRI (and other measures) is now showing both how they work and possibly helping us understand how consciousness itself arises from mere brain signals.
The psychedelic renaissance is built on the shoulders of pioneering researchers who persevered despite the challenges of studying these controversial compounds. The studies covered in this brief showcase the therapeutic potential of psychedelics, particularly for mental health conditions like depression, anxiety, and addiction.
While much work remains to integrate these substances into mainstream psychiatry, it’s clear that psychedelics represent a promising new approach for treating some of humanity’s most pernicious afflictions. With an expanding evidence base and a more open cultural attitude, we may be on the verge of a paradigm shift in understanding and healing the suffering psyche.
The next decade of psychedelic science promises to be as enlightening as an inner journey to the core of consciousness itself.
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