So ask your doctor why ecstasy works on PTSD or LSD for a stroke treatment. Or psilocybin for depression since your incompetent? doctor didn't get you 100% recovered!
ecstasy (19 posts to November 2012)
LSD (5 posts to September 2018)
psilocybin (14 posts to May 2014)
magic mushrooms (10 posts to October 2014)
psilocybin (14 posts to May 2014)
If psychedelics heal, how do they do it?
Even
as clinical trials show promise and researchers pursue FDA approval,
the mechanisms of action remain elusive. Uncovering them could lead to
more effective treatments.
In
the past few years, at more than a dozen research centers across the
globe, adults suffering from post-traumatic stress disorder (PTSD) took
MDMA (3,4-methylenedioxymethamphetamine)—the psychedelic commonly known
as ecstasy. In cozy rooms with soft light and calming music, individual
participants worked through trauma with therapists. Half of the
participants took MDMA. The others swallowed placebo pills.
After
three such sessions, and additional therapy, many of the 100-plus
participants improved, according to the report, published last September
(1).
In the absence of MDMA and through therapy alone, more than 46% of
individuals no longer met the criteria for PTSD. For those who took
MDMA, it was more than 71%.
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The study is the
latest in a series of clinical trials suggesting that MDMA may safely
treat PTSD in many patients. In December, the treatment regimen’s
developer, MAPS Public Benefit Corporation, became the first company to
request Food and Drug Administration approval for a psychedelic drug.
More and more evidence suggests that psychedelics,
such as MDMA, LSD (lysergic acid diethylamide), psilocybin (commonly
known as magic mushrooms), and DMT (N,N-dimethyltryptamine;
the active ingredient in ayahuasca), can be useful tools—in conjunction
with psychotherapy—for easing difficult-to-treat mental health
conditions. But as these once-villainized drugs come closer to
mainstream medicine, a question remains: How do they work? “We need to
know so much more,” says neuroscientist Jennifer Mitchell of the
University of California, San Francisco, lead author of the MDMA study.
Scientists
don’t know how psychedelics improve mental health or why a patient’s
environment seems to influence the effect. They also don’t fully
understand what triggers the psychedelic experience commonly known as a
“trip”—and they’re unsure whether this trip is necessary for overcoming
symptoms.
Researchers and clinicians don’t
actually need those answers to administer psychedelics safely. But
revealing how psychedelics function could help pharmacologists design
more effective treatments. “The drugs work super well for some people,
but not as well for other people,” Mitchell says. “I’d like to know how
to maximize the therapeutic benefit of the drug. And I’d like to know
how to reach those people that right now are unreachable.”
Searching
for answers, neuroscientists are probing the effects of psychedelics
from the molecular level to the entire brain. Ultimately, they’ll need
to investigate aspects of drug use that are rarely explored in
detail—how individual differences and even the setting interact with
these drugs to shape the psychedelic journey and longer-term healing.
Changing Perspectives
Classic
psychedelics share a key feature: They have an impact on serotonin
receptors in the brain. Serotonin, a chemical messenger that helps
neurons communicate, is especially important for regulating mood.
Psilocin (a molecule metabolized from psilocybin), DMT, and LSD
stimulate neurons by activating many of the same receptors as serotonin.
MDMA, a different form of psychedelic, causes a massive release of the
brain’s own serotonin, which then activates receptors.
Serotonin
does, of course, activate its own receptors. And common antidepressants
increase the amount of serotonin available to stimulate receptors. Yet,
somehow, psychedelics acting on this same system can cause dramatic
effects, such as hallucinations or waves of empathy. And, it seems in
some cases, healing, which can persist long after the immediate effects
of the drugs have worn off. Ingrained patterns, such as compulsive
substance use or constant negative thinking, can be “upended,
interrupted, and really blown apart by these psychedelics,” says
psychopharmacologist Albert Garcia-Romeu of Johns Hopkins University
(JHU) School of Medicine in Baltimore, Maryland.
Researchers
recognized this therapeutic potential in the 1950s and ‘60s, when tens
of thousands of volunteers participated in psychedelics studies (2).
By today’s standards, the research lacked scientific rigor. By the
1970s, governments cracked down on psychedelic drug use due to safety
concerns, and the studies came to an end. Research ramped up again in
the 1990s, spurred, in part, by new tools for brain imaging (2).
Today, such treatments are moving through clinical trials for many
mental health conditions, including substance abuse disorders (3), eating disorders (4), and depression (5).
The
current treatments aren’t for everyone, cautions Garcia-Romeu. Studies
exclude people with conditions that could make a psychedelic experience
risky, such as those with a history of psychosis. But from the data
available, psychedelics seem to be safe and potentially effective for a
number of conditions, he says. And, yet, exactly why these drugs work,
often with effects persisting weeks or months after a single dose,
remains unknown.
On Target
Many
investigating this mystery start from the beginning—the moment that a
psychedelic enters the brain and triggers the serotonin receptor known
as 5-HT2A. This receptor seems to be necessary for a trip. When
scientists block it in mice or humans, the psychoactive drug effects
disappear (6).
(Researchers, of course, don’t know whether mice trip the way humans
do, nor how their environs affect the experience. But mice do a telltale
head twitch when under the influence of psychedelics.)
There’s
good reason to suspect that this receptor also underlies the
therapeutic benefits of psychedelics. Some researchers believe that some
psychological conditions occur because environmental or genetic factors
cause neurons in the brain’s prefrontal cortex to atrophy, diminishing
this executive brain region’s ability to regulate motivation, fear, and
reward (7).
In
animal models, common antidepressant drugs, if taken continuously,
prompt neurons to branch and establish new synapses with other neurons (8).
“They just do this very slowly and on a timescale that correlates with
their clinical efficacy,” says chemical neuroscientist David Olson,
director of the University of California, Davis Institute for
Psychedelics and Neurotherapeutics.
In 2018,
Olson reported that psychedelics also cause neurons to branch in the
prefrontal cortex of animal models, but at a rapid clip (7).
“You see those neurons grow back within 24 hours,” he says. “The other
thing that is really remarkable is that the effects last for a very long
time.” Other drugs that do not act through serotonin 2A receptors, such
as cocaine, can also cause neuron branching, but not necessarily as
rapidly, robustly, or as targeted to the specific brain regions where
this growth could alleviate depression, says Olson. In February 2023,
Olson published findings that could help explain why psychedelics cause
neurons to quickly branch in the prefrontal cortex (9).
In this brain region, a large portion of 5-HT2A receptors are located
inside neurons. The purpose of those seemingly sequestered receptors is
unknown, as the neuron’s membrane blocks serotonin from reaching them.
But psychedelics can pass through the membrane (9).
Working
with rat neurons in cell culture plates, Olson’s team found that
activating internal receptors with DMT or psilocin triggers neurons to
rapidly branch and form new synapses. When researchers helped serotonin
reach the inner receptors by using an electrical current to open holes
in the cell membrane, they again saw speedy branching. “The location of
the 5-HT2A receptor matters,” Olson says.
Relief Without the Trip
Other
receptors may matter, too. In addition to activating serotonin 5-HT2A,
each psychedelic targets a suite of other receptors (10). LSD, for example, activates additional serotonin receptors, as well as several dopamine receptors (11).
And a single receptor could trigger several cellular pathways within
the neuron, depending on the compound that activates it. These
variations might explain why some compounds that activate the 5-HT2A
receptor cause hallucinations, while others do not, says Jason Wallach, a
pharmacologist and medicinal chemist at Saint Joseph’s University in
Philadelphia, Pennsylvania.
“All of a sudden, there is no big boss man in this brain governing the show.”—Robin Carhart-Harris
Wallach
and his team are incrementally tweaking psychedelic compounds to make
them more specific to particular receptors and cellular pathways. In
doing so, Wallach hopes to identify more effective drugs, including some
that trigger healing without the trip. He and colleagues recently
found, for example, that they can control whether a 5-HT2A-triggering
molecule causes head twitches in mice by adjusting its ability to
activate one cellular pathway over another—potentially opening the door
to finding ways to modulate these drugs (12)
“There’s a big debate in the field whether or not the psychoactive
effects are necessary,” Garcia-Romeu says. “Myself and others feel that
those experiences that happen when people are under the influence are
actually an important part of the process.”
Researchers
often report links between treatment success and the mystical nature of
psychedelic experiences. In a 2015 pilot study, Garcia-Romeu and
colleagues found that 12 of 15 cigarette smokers who took psilocybin
along with therapy to break their addiction were smoke-free 6 months
after treatment (13).
The more intensely mystical they rated their experience, the larger
their decrease in cigarette cravings reported at the 6-month check-in.
But
these are only correlations. It’s possible that isolating the
individual neural circuits involved could decouple the trip from other
effects. By tweaking the chemical structures of different psychedelics,
Olson identified several compounds that, at least in mice, cause neurons
to branch without triggering those telltale head twitches (14, 15).
His biotech startup, the Boston-based Delix Therapeutics, is now
conducting a Phase 1 clinical trial of one of these drugs in the
Netherlands. The participants are healthy volunteers, but the aim is
ultimately to treat major depressive disorder and treatment-resistant
depression (16).
“A single clinical trial may not give us a definitive answer,” Olson
says. “We may not know for many, many years because it is all about what
patient population, what disease indication.”
Olson
and Wallach both expect that, for some health conditions, a psychedelic
experience could help patients. Wallach speculates that when treating
depression, for example, a trip might prove useful. “[People] often talk
about meaningful transformative personal insights they have had during
the psychedelic experience,” Wallach says, and “how that influenced
their outlook and perspective in their everyday life.” Such testimonials
are prompting him and his team to make fully psychedelic compounds. But
for a condition less tied to one’s mental outlook, such as cluster
headaches (17),
Wallach questions whether the psychedelic experience is critical. “In
that case”, he says, “I think it is hard to make an argument that it’s
anything more than just this physiological effect.”
One
huge benefit of using psychedelics without prompting hallucinations
would be scalability. “To administer [psychedelics] safely, you have to
give them under the supervision of a healthcare professional,” Olson
says. “That dramatically increases the complexity of the treatment, as
well as the cost.”
A Whole-Brain Response
Other
researchers are zooming out to study how the brain as a whole changes
during a psychedelic trip. One leading theory: Psychedelics temporarily
topple the brain’s usual hierarchy (18).
This
idea rests on a longstanding cognitive science theory, which holds that
the brain’s executive control regions, including the prefrontal cortex,
create expectations about surroundings and that these expectations
dominate our perceptions. Input from other regions, including the visual
and auditory cortices, carries less weight in the grand calculation
that yields one’s impression of the world.
The
psychedelics theory known as the “relaxed beliefs under psychedelics
(REBUS) and the anarchic brain model” posits that a brain under the
influence of psychedelics gives less weight to executive control, while
allowing more input from elsewhere. “All of a sudden, there is no big
boss man in this brain governing the show,” says neuroscientist Robin
Carhart-Harris of the University of California, San Francisco, a
developer of the theory. This change in command might explain the
sensory experience of a trip.
In one recent
study, altered brain activity did appear to track with that subjective
experience. Carhart-Harris and colleagues monitored the brains of 20
healthy adults before, during, and immediately following DMT use (19).
While under the influence of the psychedelic, the brain’s waves of
electrical activity, captured by electroencephalogram (EEG), were more
irregular, indicating a greater complexity of brain activity, which the
researchers theorized could stem from information flowing more freely.
The level of complexity for each participant also correlated with the
individual’s own ratings of the intensity of the psychedelic experience.
Brain
imaging data from the same study, captured via functional MRI (fMRI),
suggest that a brain under the influence of DMT breaks down typical
brain networks and opens up communication between networks. For example,
Carhart-Harris’ team found that, on DMT, the default mode network—a
brain network known to remain active during self-reflection and
daydreaming—communicated less within itself and more with other brain
regions, mirroring similar results from his studies of psilocybin (20) and LSD (21).
If the temporary reorganization of the brain’s hierarchy allows for
greater flexibility in thought patterns that, with therapy, can be
shaped into a more positive outlook over time, Carhart-Harris and others
theorize that the REBUS model might also explain mental health
improvements lasting for weeks or even months after the psychedelic
experience (5, 22).
But the model itself is still a matter of debate in the neuroscience community (23).
And researchers don’t know yet whether such lasting cognitive changes
are related to physiological brain changes during a trip, such as the
branching neurons witnessed in animal models.
“You have to tailor these experiences in a way that we are just not accustomed to doing for other sorts of Western medicine. If the environment feels unsafe or threatening, the experience can go very dark very quickly.”—Jennifer Mitchell
Cognitive
neuroscientist Ceyda Sayalı, of JHU’s Center for Psychedelic and
Consciousness Research, is also looking at changes in another measure:
cognitive effort avoidance. Everyone avoids cognitive effort
sometimes—like using a precalculated tip rather than doing the math,
Sayalı says. “For people with major depressive disorder, anxiety, or
similar mental illnesses, this kind of effort-avoidance behavior can be
very pathological.”
In her previous work with
healthy participants, cognitive task seekers were better at reducing
activity in their default mode networks (dialing down that daydreaming
function), while, at the same time, increasing activity in the frontal
parietal network, a necessity for task completion (25).
Sayalı is now enrolling patients diagnosed with both major depressive
disorder and alcohol use disorder in a study that will combine simple
number tasks and fMRI imaging to test whether cognitive effort—and the
networks that support it—improves a week after psilocybin use.
If
these measures do improve, that still would not explain the underlying
reason for the persistent change. One challenge in tying the drugs’
effects to their neural substrates is limited funding. The present wave
of psychedelic research has been supported in large part by nonprofits
and private donors rather than government grants or large pharmaceutical
companies (22).
Without substantial financial support, clinical trials are often small
and lack neural imaging. Complicating matters, even some of the larger,
most high-profile studies, including the recent MDMA trials, have been
criticized for methodological flaws, such as failing to truly blind the
studies (26–29).
A Personalized Approach
Even
if psychedelics can be effective, it’s clear that they don’t work for
everyone. Researchers are beginning to explore differences among
patients that could predict success. “Everyone has a slightly different
organization of their brain,” says neuropsychologist Katrin Preller of
the Psychiatric University Hospital Zurich in Switzerland. She’s testing
how differences in the way brain networks synch up could predict
patient outcomes.
The microbiome, too, may
impact psychedelic therapy, in part because bacteria in the gut could
influence how the body metabolizes these drugs (30). Garcia-Romeu and colleagues are analyzing how gut microbiome composition influences treatment results.
And
then there’s genetics. Some people lack a working version of a gene
that codes for an enzyme that metabolizes LSD, for example. For these
individuals, trips are longer and more intense, according to a 2021
report by researchers at University Hospital Basel in Switzerland (31).
Increasingly,
researchers are taking this sort of personalized medicine approach to
many drugs—not just the mind-altering sort. But the psychedelics field
has long catered to the individual because of two major additional
variables: set and setting.
“Set” is the
mindset that someone brings to treatment. “Setting” is the environment
where the drug is administered, including everything from music to throw
pillows. “You have to tailor these experiences in a way that we are
just not accustomed to doing for other sorts of Western medicine,”
Mitchell says. “If the environment feels unsafe or threatening, the
experience can go very dark very quickly.”
This
experiential nature of psychedelics complicates clinical trials. It’s
hard to truly “blind” studies. Patients typically know whether they’ve
taken a psychedelic, even when researchers offer a lower dose or a
nonpsychedelic drug as a placebo (32).
So expectations of healing could change people’s outlooks and lead
researchers to overestimate the drug’s direct effects. The environment
where the drug is administered, which includes the therapists being
present, could also sway treatment outcomes in ways that differ between
clinics, or even between patients in the same clinic.
Aiming
to make these factors more transparent, researchers from Imperial
College London recently called on over 70 psychedelics researchers,
study participants, and therapists to recommend components of setting
that should be reported in clinical trials. The consensus, shared in
late summer 2023 at a set and setting workshop in the Netherlands,
includes a long list of variables, from whether therapists gave
participants verbal instructions to whether flowers were in the room.
The
importance of the vast majority of these variables, however, has not
been tested experimentally. Instead, therapists rely on their own
experience and the shared wisdom of their craft. But that wisdom may not
always hold up to scientific scrutiny.
Western
classical music, for example, is a standard choice for ambience setting
in psychedelics treatments. In a pilot study of psilocybin use for
smoking cessation, Garcia-Romeu and colleagues swapped the Western
classical soundtrack for one that included instruments such as gongs and
a didgeridoo in one of a patient’s two sessions. They then let patients
choose between the two soundtracks in a third session. Six of 10
patients selected the non-Western music. And there was no statistically
significant difference in treatment outcomes (33).
Mitchell
worries that results from recent clinical trials will convince people
that the drugs are safe anywhere, when, in reality, researchers are
still figuring out under what conditions they actually help. All of this
work also continues to take place in the shadow of a complicated
history. The psychedelics research community is still recovering from
when these drugs lost favor in the 1970s, Mitchell says. Credible, safe
treatments, she says, will only come through sound experimental
approaches that “evaluate exactly when and how and if and why the drugs
are effective.”
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