Therapeutic Psychedelic Drugs: Unraveling The Mechanics
Lying in a room at Imperial College London, surrounded by low lighting and music, Kirk experienced a vivid recollection of visiting his sick mother before she passed away. “I used to go and see my mum in the hospital quite a lot,” recalls Kirk, a middle-aged computer technician who lives in London (he requested we use only his first name). “And a lot of the time she’d be asleep . . . [but] she’d always sense I was there, and after about five minutes she’d wake up, and we’d interact. I kind of went through that again—but it was a kind of letting go.”
Kirk choked up slightly while retelling his experience. “It’s still a little bit emotional,” he says. “The thing I realized [was that] I didn’t want to let go. I wanted to hold on to the grief, because that was the only connection I had with my mum.”
While this may sound like an ordinary therapy session, it was not what you would typically expect. Kirk was experiencing the effects of a 25-mg dose of psilocybin—the active ingredient in psychedelic “magic” mushrooms—which he had ingested as part of a 2015 clinical trial investigating the drug’s therapeutic potential.
After his mother died, Kirk says, he fell into a “deep, dark pit of grief.” Despite antidepressants and regular sessions with a therapist, his condition was not improving. “I was stuck in it for years,” he recalls. So when he heard Imperial College London was recruiting participants for an upcoming trial studying the impact of psilocybin on depression, Kirk decided to sign up.
The study, led by psychologist and neuroscientist Robin Carhart-Harris as part of the Beckley/Imperial Research Program, enrolled 12 patients with varying stages of treatment-resistant depression. Each participant took part in two guided treatment sessions, first with a low dose (10 mg) of psilocybin in pill form, then a high dose (25 mg) one week later. During each psychedelic session, subjects were closely monitored by at least one psychiatrist and an accompanying counselor or psychologist. “The guides [help] provide a safe space for the patient to have their experience,” Carhart-Harris explains.
In addition to the deeply emotional encounter with his deceased mother, Kirk also recalls moments of “absolute joy and pleasure” during his sessions. He remembers having a vision of the Hindu deity Ganesh (the “remover of obstacles”) and feeling an altered sense of self and his surroundings. “Your mind is always chattering and observing things,” Kirk says. “And that was all shut down. For me, there was a feeling of new space.”
Experiences like Kirk’s are common among people who have participated in a psychedelic session (or “trip,” as it was allegedly first called by US Army scientists in the 1950s). Reports consistently include feeling intense emotions, having mystical experiences, and entering a dreamlike state. Many also articulate a dissolving sense of a bounded self, coupled with a feeling of increased connectedness with others and the rest of the world.
When Carhart-Harris and his team assessed their study’s participants three months after treatment, they found that most of the participants showed reduced depressive symptoms, with 5 of the 12 in complete remission1—including Kirk. It’s now been two years since he received psilocybin therapy, and he says that he has not needed antidepressants or therapy since. “I got a new positivity that I didn’t have for some time,” he says.
These results are preliminary—the study tested a small sample size with no control group. But other recent trials, including some that were larger and included controls, have revealed additional therapeutic benefits. Last December, for example, two randomized placebo-controlled clinical trials of psilocybin in terminal cancer patients (51 and 29 patients, respectively) found that giving participants psilocybin in guided sessions could substantially decrease depression and anxiety—an improvement that persisted for at least six months after treatment. 2,3 In smaller pilot studies, psilocybin has also shown success in treating addiction. In two small trials, one involving smokers4 and the other alcoholics,5 most participants remained abstinent for months after treatment with the psychedelic.
A number of early studies have also reported evidence that other psychedelics, primarily lysergic acid diethylamide (LSD), have similar effects. Roland Griffiths, a psychiatry professor at Johns Hopkins University, describes the effects of psychedelics as a sort of “reverse PTSD” (posttraumatic stress disorder). With PTSD, there is “some discrete, traumatic event that produces some alteration in neurology and perception that produces [psychological] dysregulation going forward,” he says. In a similar but opposite way, treatment with hallucinogenic substances is a “discrete event that occurs to which people attribute positive changes that endure into the future.” While scientists are only beginning to understand the mechanisms behind these effects, what they’ve found so far already tells quite a compelling story.
Most psychedelics researchers believe that the session itself—the profound experiences individuals have during a trip—is key to the drugs’ therapeutic effects. But whether this is a cause or consequence of underlying neurobiological effects is still unclear. Studies show that psychedelics disrupt established networks in the brain, potentially allowing new connections to form. Recent work has also begun to reveal that these drugs’ effects—such as promoting neuroplasticity and reducing inflammation—are exerted through the serotonin 2A receptor.
“It’s very exciting that we seem to be at a threshold of establishing the neurobiological basis for the range of effects that hallucinogens have, and specifically, the therapeutic range of action,” says Charles Grob, a psychiatry professor at Harbor-UCLA Medical Center who conducted a pilot study of psilocybin for terminal cancer patients that was published in 2011.6 “I think there is growing knowledge and appreciation that this work can be conducted responsibly and safely, and that it has the quite compelling potential to offer us very new and exciting treatment models.”
The tripping brain
Understanding how hallucinogenic drugs affect different neural networks could shed light on their therapeutic potential.
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While on psychedelics, people commonly experience ego dissolution, a loss of the sense of a separate self, and an enhanced feeling of connectedness with the outside world. Recent neuroimaging studies have revealed that the intensity of this experience correlates with changes in brain activity, primarily in the default mode network (DMN)—a system of brain regions that is more active at rest than during tasks, and that is thought to be involved in, among other things, processing information related to the self.
To understand what happens in the brain during a trip, Carhart-Harris and colleagues have been dosing healthy participants with psychedelics and scanning their brains using functional magnetic resonance imaging (fMRI) to measure cerebral blood flow, a proxy measure of neural activity. In 2012, for example, the researchers found that, following an intravenous injection of 2 mg of psilocybin, 15 subjects displayed an overall decrease in cerebral blood flow as well as decreased connectivity between the posterior cingulate cortex and the medial prefrontal cortex, two hubs of the default mode network.7
Follow-up studies using both fMRI and magnetoencephalography (MEG)—a technique to detect the tiny magnetic fields generated by electrical activity in the brain—on subjects dosed with LSD have revealed similar effects. This work also revealed a correlation between decreased connectivity in the default mode network and subjective ratings of ego dissolution.8
But while the two psychedelic drugs “share signature psychological effects,” Carhart-Harris notes, “they differ in the potency [and] in their kinetics. The psilocybin trip is shorter, and for that reason is more manageable than an LSD trip.”
What’s been consistently found is that the brain or the mind during psychedelic states is in a different state of consciousness, and this is also reflected in how the brain is behaving.—Rainer Krähenmann, University of Zurich
Researchers have found similar neurological effects during meditation—another altered state of mind associated with psychological well-being. Expert meditators also show an acute reduction in the activity of the default mode network.9Conversely, an increase in activity and connectivity in this network has been found in some individuals with depression. “In some ways, it kind of makes sense that psilocybin, which brings people very powerfully into the present moment, would be more similar to meditation than it would be to depression,” says Griffiths. “In other words, people are riveted with interest in the present moment and what’s happening here and now, rather than in the future or in the past.” Griffiths and his colleagues at Johns Hopkins are currently conducting a neuroimaging experiment probing the brains of expert meditators on psychedelic trips.
Using MEG, Carhart-Harris and colleagues have also discovered that psilocybin and LSD alter neural oscillations, rhythmic brain activity linked to various perceptual and cognitive functions, across the default mode network.10 Individuals under the influence of these drugs experience a drop in so-called alpha rhythms, oscillations in the range of around 8 to 13 hertz, that correlate with their reports of ego dissolution. “When you plot out what rhythms contribute to the brain’s overall oscillatory activity, you get this huge peak in the alpha band—this really prominent frequency that, in some ways, sort of dominates the rhythmicity of the brain,” Carhart-Harris explains. “It’s a really curious rhythm, because it’s more prominent in humans than in any other species, and its prominence increases as we develop into adulthood. I see it as a kind of signature of high-level consciousness that adult humans have.”
In contrast to the decrease in activity and connectivity within the DMN, imaging studies have revealed an increase in functional links between normally discrete brain networks during a trip, and such activity also correlates with reports of ego-dissolution.11 Together with findings of changes in the default mode network and reduced alpha rhythms, these results are contributing to a hypothesis that the brain becomes “entropic”—more disordered, fluid, and unpredictable—during psychedelic use, disrupting certain pathways while allowing for new connections to be made. “What’s been consistently found is that the brain or the mind during psychedelic states is in a different state of consciousness, and this is also reflected in how the brain is behaving,” says Rainer Krähenmann, a psychiatrist and researcher at the University of Zurich. But, he adds, more research is needed to understand just what these changes mean. “I would not say that we can reduce it to certain areas or certain mechanisms,” Krähenmann says. “The brain is still too complex to really understand what’s going on.”
Key brain areas involved in the effects of psychedelic drugs are located in the default mode network (DMN), which is more active at rest than when attention is focused on the external environment. Neuroimaging studies have also shown that connectivity between brain networks is increased when psychedelics are administered.
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And of course, the biggest question that remains is how these neurological changes might be therapeutic. In a soon-to-be published study, Carhart-Harris and his colleagues found that changes in the connectivity of the default mode network predicted how well patients would do after psilocybin treatment, but the results are preliminary. “We know that there’s fascinating things happening acutely in terms of these changes in the synchronization across brain areas,” says Matthew Johnson, a behavioral pharmacologist at Johns Hopkins. “But the really tantalizing possibilities that a number of groups, including ours, are looking at is whether those types of changes persist and are related to long-standing clinical benefits.”
© SEAN MCCABEAll the classic psychedelic drugs—psilocybin, LSD, and N,N-dimethyltryptamine (DMT), the active component in ayahuasca—activate serotonin 2A (5-HT2A) receptors, which are distributed throughout the brain. In all likelihood, this receptor plays a key role in the drugs’ effects. Krähenmann and his colleagues in Zurich have discovered that ketanserin, a 5-HT2A receptor antagonist, blocks LSD’s hallucinogenic properties and prevents individuals from entering a dreamlike state or attributing personal relevance to the experience.12,13
Other research groups have found that, in rodent brains, 2,5-dimethoxy-4-iodoamphetamine (DOI), a highly potent and selective 5-HT2A receptor agonist, can modify the expression of brain-derived neurotrophic factor (BDNF)—a protein that, among other things, regulates neuronal survival, differentiation, and synaptic plasticity. This has led some scientists to hypothesize that, through this pathway, psychedelics may enhance neuroplasticity, the ability to form new neuronal connections in the brain.14 “We’re still working on that and trying to figure out what is so special about the receptor and where it is involved,” says Katrin Preller, a postdoc studying psychedelics at the University of Zurich. “But it seems like this combination of serotonin 2A receptors and BDNF leads to a kind of different organizational state in the brain that leads to what people experience under the influence of psychedelics.”
This serotonin receptor isn’t limited to the central nervous system. Work by Charles Nichols, a pharmacology professor at Louisiana State University, has revealed that 5-HT2A receptor agonists can reduce inflammation throughout the body. Nichols and his former postdoc Bangning Yu stumbled upon this discovery by accident, while testing the effects of DOI on smooth muscle cells from rat aortas. When they added this drug to the rodent cells in culture, it blocked the effects of tumor necrosis factor-alpha (TNF-α), a key inflammatory cytokine.
“It was completely unexpected,” Nichols recalls. The effects were so bewildering, he says, that they repeated the experiment twice to convince themselves that the results were correct. Before publishing the findings in 2008,15 they tested a few other 5-HT2A receptor agonists, including LSD, and found consistent anti-inflammatory effects, though none of the drugs’ effects were as strong as DOI’s. “Most of the psychedelics I have tested are about as potent as a corticosteroid at their target, but there’s something very unique about DOI that makes it much more potent,” Nichols says. “That’s one of the mysteries I’m trying to solve.”
After seeing the effect these drugs could have in cells, Nichols and his team moved on to whole animals. When they treated mouse models of system-wide inflammation with DOI, they found potent anti-inflammatory effects throughout the rodents’ bodies, with the strongest effects in the small intestine and a section of the main cardiac artery known as the aortic arch.16 “I think that’s really when it felt that we were onto something big, when we saw it in the whole animal,” Nichols says.
The group is now focused on testing DOI as a potential therapeutic for inflammatory diseases. In a 2015 study, they reported that DOI could block the development of asthma in a mouse model of the condition,17 and last December, the team received a patent to use DOI for four indications: asthma, Crohn’s disease, rheumatoid arthritis, and irritable bowel syndrome. They are now working to move the treatment into clinical trials. The benefit of using DOI for these conditions, Nichols says, is that because of its potency, only small amounts will be required—far below the amounts required to produce hallucinogenic effects.
In addition to opening the door to a new class of diseases that could benefit from psychedelics-inspired therapy, Nichols’s work suggests “that there may be some enduring changes that are mediated through anti-inflammatory effects,” Griffiths says. Recent studies suggest that inflammation may play a role in a number of psychological disorders, including depression18 and addiction.19
“If somebody has neuroinflammation and that’s causing depression, and something like psilocybin makes it better through the subjective experience but the brain is still inflamed, it’s going to fall back into the depressed rut,” Nichols says. But if psilocybin is also treating the inflammation, he adds, “it won’t have that rut to fall back into.”
Scientists have discovered that a number of psychedelics can reduce inflammation throughout the body. Animal studies with one of these drugs, DOI, which is an especially potent anti-inflammatory compound, are starting to reveal the mechanism behind these effects. According to one hypothesis, DOI binds to and activates the serotonin 2A (5-HT2A) receptor to recruit protein kinase C (PKC). This is thought to block the downstream effects of the binding of tumor necrosis factor-alpha (TNF-α) to its receptor (TNFR), which is known to initiate a signaling cascade that promotes the transcription of proinflammatory genes.
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If it turns out that psychedelics do have anti-inflammatory effects in the brain, the drugs’ therapeutic uses could be even broader than scientists now envision. “In terms of neurodegenerative disease, every one of these disorders is mediated by inflammatory cytokines,” says Juan Sanchez-Ramos, a neuroscientist at the University of South Florida who in 2013 reported that small doses of psilocybin could promote neurogenesis in the mouse hippocampus.20 “That’s why I think, with Alzheimer’s, for example, if you attenuate the inflammation, it could help slow the progression of the disease.”
© SEAN MCCABEAlthough researchers have only recently started to test psychedelics’ effects in controlled clinical trials, evidence that these drugs could help treat conditions such as depression and terminal cancer–related anxiety has existed since the middle of the 20th century. (See table below.) Despite promising results, the counterculture that emerged around LSD use led to the criminalization of it and other psychedelics in 1966. Since 1970, almost all of these compounds have been Schedule I controlled substances, which imposes strict prohibitions on their use, even in research.
“If the drug war hadn’t started, and we didn’t have this demonization [of psychedelics], we’d know a lot more about what makes people happy, sad, depressed,” says David Nichols, a professor emeritus of pharmacology at Purdue University and a pioneering psychedelics researcher (also the father of Charles Nichols). “That’s the tragedy—that none of that has happened because [the research] basically died in 1970.”
Now, psychedelics research is slowly starting to regain ground, though it’s still not easy to win federal funding for these studies. But with support from private organizations such the Heffter Research Institute and the Multidisciplinary Association for Psychedelic Studies (MAPS), scientists have begun to probe the mechanisms underlying the drugs’ psychological effects and the enduring changes they can bring about. The answers to these mysteries may help scientists gain insight into what happens to the brain in disease, and perhaps learn more about the nature of consciousness itself.
“There are many different questions to ask, and in some ways, the therapeutic ones are among the most mundane,” says Griffiths. “Our understanding is so primitive that I think it’s important that we not be so naive as to think that our current technologies are going to be able to unravel the many, many subtleties that account for some of these kinds of sustained effects. That’s why [the study of psychedelics is] such an interesting, important, and rich field of investigation for neuroscience.”
CLINICAL STUDIES WITH PSYCHEDELICS
Anxiety in terminal cancer patients
1950s to 1970sUnblinded trials suggested that psychedelics such as LSD could reduce anxiety and depression in terminal cancer patients.
2011A small placebo-controlled trial of 12 subjects with advanced-stage cancer reported that treatment with psilocybin reduced anxiety for up to six months after treatment.
2016Two larger randomized, placebo-controlled clinical trials, at Johns Hopkins University and New York University (NYU), found that psilocybin can substantially reduce death-related anxiety and depression in terminal cancer patients.
2016A pilot study at Imperial College London found that psilocybin had antidepressant effects that persisted for more than three months in a subset of participants.
2017Researchers at the Federal University of Rio Grande do Norte in Brazil published a preprintfor their randomized, placebo-controlled trial of ayahuasca for 35 patients with treatment-resistant depression, reporting improved symptoms one week after treatment.
2017At the University of Zurich, researchers are in the process of developing a double-blind, randomized, placebo-controlled trial of psilocybin as a treatment for major depression that is scheduled to start later this year. Similar plans are currently underway at Imperial College London.
1950s to 1970sResearchers conducted early studies of therapeutic use of LSD for treating alcoholism and heroin addiction, showing that the psychedelic could reduce substance abuse.
2014A small study of 15 cigarette smokers at Johns Hopkins University found that psilocybin treatment led to an 80 percent abstinence rate at six months.
2015At New York University, researchers found positive effects in a small study of 10 participants who underwent psilocybin-facilitated treatment for alcohol dependence.
2014 to 2017Survey studies show that people who have taken psychedelics subsequently choose to abstain from cigarettes, alcohol, and other drug dependencies.
2017Researchers at both Johns Hopkins and NYU are currently conducting larger, randomized trials with control groups for both smoking and alcohol dependence. A group at the University of Alabama at Birmingham is currently conducting a pilot trial of psilocybin-assisted treatment for cocaine addiction.
1950s to 1970sPsychiatrists examined LSD treatments for schizophrenia patients. Preliminary studies, many with small sample sizes and no control groups, reported beneficial effects in some children who received this treatment. Around the same time, state-approved tests of psychedelic drugs were also conducted on inmates in the U.S. diagnosed with schizophrenia by doctors who believed in the drugs’ therapeutic potential. Some psychiatrists also examined the effects of various psychedelic drugs on healthy individuals as a way to elucidate the experiences of patients with schizophrenia and to improve treatment.
1990s to 2000sRecent studies have focused on using these drugs to model psychotic states rather than to treat them.
- R.L. Carhart-Harris et al., “Psilocybin with psychological support for treatment-resistant depression: An open-label feasibility study,” Lancet Psychiatry, 3:619-27, 2016.
- R.R. Griffiths et al., “Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: A randomized double-blind trial,” J Psychopharmacol, 30:1181-97, 2016.
- S. Ross et al., “Rapid and sustained symptom reduction following psilocybin treatment for anxiety and depression in patients with life-threatening cancer: A randomized controlled trial,” J Psychopharmacol, 30:1165-80, 2016.
- A. Garcia-Romeu et al., “Psilocybin-occasioned mystical experiences in the treatment of tobacco addiction,” Curr Drug Abuse Rev, 7:157-64, 2014.
- M.P. Bogenschutz et al., “Psilocybin-assisted treatment for alcohol dependence: A proof-of-concept study,” J Psychopharmacol, 29:289-99, 2015.
- C.S. Grob et al., “Pilot study of psilocybin treatment for anxiety in patients with advanced-stage cancer,” JAMA Psychiatry, 68:71-78, 2011.
- R.L. Carhart-Harris et al., “Neural correlates of the psychedelic state as determined by fMRI studies with psilocybin,” PNAS, 109:2138-43, 2012.
- R.L. Carhart-Harris et al., “Neural correlates of the LSD experience revealed by multimodal neuroimaging,” PNAS, 113:4853-58, 2016.
- K.A. Garrison et al., “Meditation leads to reduced default mode network activity beyond an active task,” Cogn Affect Behav Neurosci, 15:712-20, 2015.
- S.D. Muthukumaraswamy et al., “Broadband cortical desynchronization underlies the human psychedelic state,” J Neurosci, 33:15171-83, 2013.
- E. Tagliazucchi et al., “Increased global functional connectivity correlates with LSD-induced ego dissolution,” Curr Biol, 26:1043-50, 2016.
- R. Kraehenmann et al., “Dreamlike effects of LSD on waking imagery in humans depend on serotonin 2A receptor activation,” Psychopharmcology, 234:2031-46, 2017.
- K.H. Preller et al., “The fabric of meaning and subjective effects in LSD-induced states depend on serotonin 2A receptor activation,” Curr Biol, 27:451-57, 2017.
- F.X. Vollenweider, M. Kometer, “The neurobiology of psychedelic drugs: Implications for the treatment of mood disorders,” Nat Rev Neurosci, 11:642-51, 2010.
- B. Yu et al., “Serotonin 5-hydroxytryptamine(2A) receptor activation suppresses tumor necrosis factor-α-induced inflammation with extraordinary potency,” J Pharm Exp Ther, 327:316-23, 2008.
- F. Nau et al., “Serotonin 5-HT2A receptor activation blocks TNF-α mediated inflammation in vivo,” PLOS ONE, 8:e75426, 2013.
- F. Nau et al., “Serotonin 5-HT2 receptor activation prevents allergic asthma in a mouse model,” Am J Physiol Lung Cell Mol Physiol, 308:L191-L198, 2015.
- E. Setiawan et al., “Role of translocator protein density, a marker of neuroinflammation, in the brain during major depressive episodes,” JAMA Psychiatry, 72:268-75, 2015.
- C. Cui et al., “Neuroimmune mechanisms of alcohol and drug addiction,” Int Rev Neurobiol, 118:1-12, 2014.
- B.J. Catlow et al., “Effects of psilocybin on hippocampal neurogenesis and extinction of trace fear conditioning,” Exp Brain Res, 228:481-91, 2013.
Correction (September 16): In the table, two addiction studies incorrectly listed the years of publication. The study of 15 cigarette smokers was published in 2014; the study of 10 participants who underwent psilocybin-facilitated treatment for alcohol dependence was published in 2015. The Scientist regrets the errors.