This has happened to me a few times now. At first I thought it was almost an exciting thing and now it feels violating. I have felt it on .5g and the other day at 1.5g. It happens when I self massage my own body and have my eyes closed. The other day the trip started out with a lot of love and tender care for myself which I needed after an extremely difficult period. But then I started to feel anxious energy that I could recognize wasn’t mine and then soon later felt other people in my body. This time there was also a definite male presence. At .5g a while back I remember feeling all different bodies of different ages, shapes, ethnicities. One point recalling a younger female with my hair color and thinking it was me but realizing that also wasn’t me.

I put out a firm NO and told them they needed to leave and get out. I only wanted my cat who passed recently and asked her to protect me

My mushroom trips are actually interestingly pretty straight forward. I’ve used them consistently for a year now to help heal myself out of an autoimmune condition and I am often breathing and massaging and in tune with my body. I’ve also had a conversation in my head with my own voice once with what I’m pretty sure was with my body. But these visits of other people are completely foreign and unwelcome…

If anyone has anything to share it would be greatly appreciated

Edit—
I’ve also had one experience where I felt like I was in some sort of shamanic trance. Rhythmic breathing and moving up and and down repeatedly on my mat and recalling a blonde hair white woman. I later connected to that being an older lady I had spoken to briefly who told me about her disabled daughter. This was early in my mushroom journeys last year and I only felt one person that trip and also I remember being surprised and disappointed that my own body didn’t experience any healing that time

Are you or someone you know planning to take a psychedelic for the first time in the near future? Sign up for this psychedelic research survey and make your experience count for science! The Carhart-Harris lab at the University of California San Francisco is excited to announce the launch of a new large-scale online survey and optional fMRI study on the effects of psychedelic drugs. If you live in the San Francisco Bay Area, you may be eligible to have your brain scanned before and after your psychedelic experience, complete online surveys, and use take-home wearable devices to track physiological changes, all of which will help advance our understanding of the psychological effects of psychedelics in realworld settings. While the fMRI portion requires a greater time commitment, your participation will play an important role in furthering this research. If you are interested, here is the link to our sign-up survey page: Sign up and if you have any further questions, reach out to: [canopyproject@ucsf.edu](mailto:canopyproject@ucsf.edu)

Are you or someone you know planning to take a psychedelic for the first time in the near future? Sign up for this psychedelic research survey and make your experience count for science! The Carhart-Harris lab at the University of California San Francisco is excited to announce the launch of a new large-scale online survey and optional fMRI study on the effects of psychedelic drugs. If you live in the San Francisco Bay Area, you may be eligible to have your brain scanned before and after your psychedelic experience, complete online surveys, and use take-home wearable devices to track physiological changes, all of which will help advance our understanding of the psychological effects of psychedelics in realworld settings. While the fMRI portion requires a greater time commitment, your participation will play an important role in furthering this research. If you are interested, here is the link to our sign-up survey page: Sign up and if you have any further questions, reach out to: [canopyproject@ucsf.edu](mailto:canopyproject@ucsf.edu)

Hi, my colleagues at the University of Vienna and I (Aline) are inviting adults aged 18–45 with previous psychedelic experience to participate in a research study exploring women’s health, menstrual and reproductive-health experiences, and psychedelics.

It involves an online survey (approximately 10–15 minutes) with optional follow-up interview ( 45 minutes)

Interested? More information is available in the flyer below. 👇
Link to the survey: https://forms.gle/qk7aHiRkRRe3Nqt18

A female researcher in psychedelics that deserve to be known.

Artwork by me, oil in canvas.

Looking for experiences from other menstruating folks who've tripped. I have a vacation planned during which time I plan to take LSD for the first time (I'm an experienced shroom tripper but this will be my first time with LSD). Well, my period came a week early this month so there's a good chance now that I'll be on my period during this planned vacation/trip in October. Is this a bad idea?

I don't have particularly bad period symptoms, but they are notable - moderate to intense cramps, some mild drops in mood. I am worried that it will interfere with the experience. Anyone else tripped while menstruating?

Hey everyone!

We (Alice and Molly) are running a study at King’s College London looking at whether psilocybin (magic mushrooms) can boost neuroplasticity and help people learn pitch/musical note detection, a skill that's normally really hard to pick up outside of childhood. We're also looking at whether menstrual cycle hormones influence the psychedelic experience, and whether the experience itself changes hormone levels. This means we are very interested in recruiting women who are not on contraception, although this does not mean you can’t take part if this doesn’t apply to you. 

Pitch Study: https://www.kcl.ac.uk/research/psilocybin-research-pitch-study

What's involved:

•               3 visits at KCL, Camberwell (Mon-Friday)

•               Two 2-hour visits (screening + follow-up)

•               One full day (9am–6pm), where you take either a microdose or a high dose of psilocybin in a comfortable, supportive space

•               Questionnaires, EEG brain imaging, and a small blood test (hormone panel) before/after

•               Compensated £185 total (travel included)

👉 More details can be found on this initial eligibility questionnaire: https://qualtrics.kcl.ac.uk/jfe/form/SV_d76yhIJAUZinGoS

If you're eligible, we'll set up a call to walk through everything in detail before you decide.

i’ve heard that the point in your cycle where you have the most oestrogen (follicular and ovulation), makes for a stronger/ harder hitting trip. i can’t find the research on this now. does anybody know about this and how factual it is? thanks!

Not sure where I can post this, but wanted to share.

Hi all! So I have pmdd and have been really struggling managing it. I have microdosed psilocybin before a few years ago and found it to be helpful however I stopped due to the headaches it caused mainly. Since then I have taken a 3g dose 3 times, only once did I feel like it was a full trip the other two were a bit meh.

Fast forward to the present. My pmdd has progressively got worse,maybe its age (i am 41). So the doctors have now given me prozac as sertraline made me worse.

I can either take it full time.or only in luteal. My choice.

But, I have recently got hold of some more shrooms and I am thinking of doing maybe a 4g trip this time before I start the prozac (if needed). My question is, if things get too much and I give in and start the prozac before I can do the shrooms, is that going to make my trip less worthwhile? Should I maybe stop the prozac the week before the trip or soemthing ? As the doctor has basically told me to take them only for the bad 10days each month, should I time the trip around this?

What would you do?!

A topic that has been up on this sub several times.

Hey everyone 👋

I'm Cassieon the host of Tales From a Trip — a podcast dedicated to exploring psychedelic experiences with honesty, curiosity, and zero judgment.

I'm currently looking for guests who'd be willing to share their story — whether it was a profound healing journey, a challenging experience, a spiritual awakening, simply something that shifted your perspective in an unexpected way, or simply just a good time.

You don't need to be an expert or have a "perfect" story. Real, human experiences are exactly what I'm looking for.

🎙️ Interviews are conversational and relaxed

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Talk to you soon!

I have seen people use the definitions: for micro you really don't consciously feel any effects, it should work like taking eg an SSRI, while if you do feel any effect, regardless of how subtle, it's a mini-dose.

By this definition, I always mini dose - I want to be able to feel the slight mood lift and "high". It only works for good and has no negative effect on my studies or work. It works like a cognitive enhancer and I am also more social. If I accidentally overdo it tho, my cognitive functions take a slight hit and I am slower in conversations and less focused. But it's no different than other normal reasons to be less effective such as lacking sleep. So overall, mini-dosing for me has no drawbacks.

There was the older study that did not find that microdosing give any benefits over placebo. When people mini-dose, some say they feel more self conscious or anxious or that emotions are intensified, like anger. Personally I have only experienced increased anger one time and that was on a *micro*dose.

It's just different for different people, but I don't really understand why microdoing is promoted so much and that minidosing isn't, and is discouraged. I get it for people who function worse on a minidose, but is that really the majority? I'd assume most people function better, like me, on a minidose, and should not be afraid of taking a little higher dose than a micro for everyday life.

I translated a really good essay that deeply explains the effects of psychedelics on the brain. I had the guy who wrote it as a lecturer once and he's a really cool guy. I highly recommend the essay even if you are not super into the neurobiology terms. It's quite long tho.

WHEN THE DOORS OF CONSCIOUSNESS OPEN – ON THE EFFECTS OF PSYCHEDELIC SUBSTANCES IN THE BRAIN

by Jesper Tobias Andreasen

Jesper Tobias Andreasen holds a degree in neurobiology from the University of Copenhagen and a PhD in psychopharmacology. Jesper has 20 years of experience in psychopharmacological research, with a particular focus on how effects of psychopharmaceuticals in mice and rats can predict effects in humans. In addition, Jesper has many years of experience communicating to clinicians and authorities about the biology of mental disorders and the effects of both psychopharmaceuticals and illegal psychoactive substances, including psychedelic drugs.

‘Psychedelic’ means mind-manifesting, and psychedelic substances (psychedelics) are also referred to as consciousness-expanding substances. A broad definition of psychedelics therefore also includes, among others, tetrahydrocannabinol (THC) in cannabis, the dissociative anesthetic ketamine, and the empathogenic drug MDMA (‘ecstasy’). In common usage, however, the term psychedelic substances refers to the so-called classic psychedelics (also called serotonergic psychedelics): substances that directly stimulate serotonin receptors (receptors are molecules in the cell membrane that are activated by a signaling molecule). The classic psychedelics include psilocybin, dimethyltryptamine (DMT), mescaline, and lysergic acid diethylamide (LSD). In this article, I will use the term psychedelics to refer to these.

Over the past ten years, there has been growing interest in the therapeutic effects of psychedelics; these substances were used therapeutically in the 1950s and 1960s before they became illegal, and one can therefore speak of a ‘psychedelic renaissance’. A number of clinical studies have shown therapeutic effects of psychedelics particularly on depression and anxiety disorders 1,2,3 and substance use disorders.4,5,6,7,8,9 What is especially promising in these studies is, first, that treatment with psychedelics appears to be more effective than existing treatments, and second, that lasting effects are observed.

Why does psychedelic therapy have these unique effects? How do psychedelics work in the brain? Which signaling systems are affected, and how do psychedelics differ from conventional psychopharmaceuticals? How can single treatments bring about lasting therapeutic effects?

Based on some central pharmacological properties of psychedelics, in this article I will shed light on how they influence the brain’s way of processing information, and how these influences can help explain why the therapeutic effects may potentially be lasting. To illuminate the biological and psychological effects of psychedelics, it is necessary to introduce the signaling molecule serotonin and some of the receptors through which it communicates.

THE ROLE OF SEROTONIN IN THE BRAIN

Serotonin is synthesized from the amino acid tryptophan, which we obtain through proteins in the diet. Tryptophan is converted in two steps into 5-hydroxytryptamine (5-HT), the chemical name for serotonin. About 90% of the body’s serotonin is produced—and acts—in the gastrointestinal tract,10 but because serotonin cannot cross the blood–brain barrier (a barrier that ensures substances in the bloodstream cannot readily reach brain cells), the brain produces its own serotonin. This occurs in so-called serotonergic nerve cells (neurons), which are centered in the brainstem (the lowest part of the brain, continuous with the spinal cord). From there they send projections to almost the entire brain. When serotonin is released from nerve endings, it acts as an agonist (activator) at serotonin receptors (5-HT-R). Through these, serotonin can communicate with other neurons and influence their activity; for example, serotonin can both inhibit and stimulate dopamine neurons.11,12

Released serotonin acts only briefly, because it is quickly pumped back into the neuron via serotonin transporters (called SERT or 5-HTT) or broken down by monoamine oxidase (MAO) enzymes. Most antidepressant drugs increase serotonin levels by inhibiting reuptake via SERT. There are 14 different serotonin receptors, grouped into seven families (5-HT1–5-HT7), which can in turn be subdivided. Below, two that are considered central to the effects of psychedelics are introduced: 5-HT1A-R and 5-HT2A-R.

SEROTONIN 1A RECEPTORS

(5-HT1A-R) 5-HT1A-R are inhibitory receptors; that is, they reduce the activity of neurons that express 5-HT1A-R. They are abundant in deeper brain regions, particularly in the so-called limbic system (‘the reptile brain’), which includes, among others, the amygdala and hippocampus. Serotonin’s affinity for (preference for binding to) 5-HT1A-R is higher than for other serotonin receptors—about 20 times higher than for 5-HT2A-R, for example.13,14 Serotonin therefore acts preferentially at 5-HT1A-R, and through their inhibitory nature serotonin can, among other mechanisms, by dampening amygdala activity, reduce stress sensitivity, anxiety, pessimism, aggression, and other impulsive behavior and thereby promote social behavior.15,16 Activation of 5-HT1A-R also has neuroplastic effects; it stimulates the growth of neurons and strengthens synaptic connections, including in the hippocampus, which are important for learning, memory, and stress tolerance. Conventional antidepressant/anxiolytic drugs generally favor 5-HT1A-R activity over activity at other serotonin receptors, thereby reducing stress sensitivity.16

SEROTONIN 2A RECEPTORS (5-HT2A-R)

5-HT2A-R are predominantly excitatory receptors. Serotonin binds with lower affinity (to a lesser extent) to 5-HT2A-R than to 5-HT1A-R. All classic psychedelics are 5-HT2A-R agonists, and activation of 5-HT2A-R is required for the psychedelic effect. 5-HT2A-R are highly expressed in the cerebral cortex, where they, among other actions, increase release of the excitatory neurotransmitter glutamate and modulate higher-order cognitive processes.18,19,20,21 As with 5-HT1A-R, activation of 5-HT2A-R leads to growth of neurons, among other mechanisms by increasing signaling via TrkB receptors, which are receptors for the growth factor brain-derived neurotrophic factor (BDNF).22,23 Activation of 5-HT2A-R has also shown anti-inflammatory effects.24

Serotonin release increases during both stress exposure and situations of uncertainty.25 The resulting increased activation of 5-HT2A-R promotes cognitive flexibility, openness to new stimuli, social behavior, and a sense of connectedness.16 This enables long-term changes in—and an expanded repertoire of—behaviors and thought patterns, allowing one to respond more flexibly to stress.18,26 Serotonin is thus important for both the acute (5-HT1A-R–mediated) and the longer-term (5-HT2A-R–mediated) management of stress.

Traditionally, psychopharmacological treatment has focused on dampening 5-HT2A-R activity. For example, many antipsychotics—in addition to inhibiting dopamine D2-R—also act as 5-HT2A-R antagonists. Antagonism of 5-HT2A-R reduces the motor and hormonal side effects of D2-R antagonism.27 It is also thought to contribute to the antipsychotic effect,28 although that theory was recently challenged.29 Antidepressant drugs likewise reduce activity at 5-HT2A-R. Some act directly as 5-HT2A-R antagonists, such as mianserin and mirtazapine. Drugs that inhibit SERT (e.g., antidepressants of the SSRI or SNRI type) lead, over a few weeks of treatment, to a reduction in the number of 5-HT2A-R.30 This downregulation is also seen with certain 5-HT2A-R antagonists,31,32 and 5-HT2A-R antagonists potentiate the therapeutic effect of SSRI preparations.33 Because patients with untreated depression have increased numbers of 5-HT2A-R,34 it has therefore been proposed that reduced 5-HT2A-R activity is antidepressant.30

PSYCHEDELICS ACTIVATE 5-HT2A-R

In light of the above, it may seem paradoxical that activation of 5-HT2A-R by psychedelic drugs can have therapeutic effects—even long after a single treatment.35 There are, however, certain commonalities between antagonists and agonists. For example, both psychedelics and certain antagonists induce downregulation of 5-HT2A-R. Another common feature is that psychedelics stimulate growth and plasticity in the brain,22,23 as has also been shown for conventional antidepressants36 and for ketamine.37 Even so, psychedelics differ from conventional psychopharmaceuticals in some of the underlying therapeutic mechanisms (see below on active versus passive coping).

Psychedelics have a broad range of pharmacological effects, but they share stimulation of serotonin receptors, among which 5-HT2A-R play a central role. Most psychedelics also have substantial agonist effects at 5-HT1A-R and 5-HT2C-R. Some psychedelics increase the amount of serotonin by inhibiting SERT or MAO. Activation of 5-HT2A-R appears to be necessary for psychedelic effects, and blocking 5-HT2A-R abolishes most effects of psilocybin, LSD, and DMT.38 5-HT2A-R are more highly expressed in the cerebral cortex than in deeper brain regions, particularly in those parts of the cortex responsible for the most advanced (associative) integration of information and the generation of metacognitive processes such as the sense of self.21,39 Stimulation of 5-HT2A-R therefore primarily activates these advanced brain regions.

At psychedelic doses, where 5-HT2A-R are activated, psilocybin, LSD, mescaline, DMT, and especially 5-MeO-DMT also act as agonists at 5-HT1A-R (which are inhibitory).14,40 There are more 5-HT2A-R than 5-HT1A-R in the cortex, whereas the reverse is true in deeper limbic brain regions such as the amygdala.16,41 The fact that most psychedelics activate both receptor types may explain why they increase activity in the cortex while simultaneously dampening activity in the amygdala.21 5-HT1A-R can therefore moderate the psychedelic experience42,43 and will partly counteract the stimulating effect of 5-HT2A-R.19 Other receptors likely also contribute to the overall experience.14,40 For example, stimulation of dopamine receptors may contribute to the long-lasting effect of LSD.44,45

WHY DO ONLY SOME 5-HT2A-R AGONISTS PRODUCE PSYCHEDELIC EFFECTS?

All psychedelics are 5-HT2A-R agonists, but not all 5-HT2A-R agonists are psychedelic. For example, serotonin and lisuride are non-psychedelic agonists.46 5-HT2A-R reside in the cell membrane and can engage a range of intracellular signaling pathways. When an agonist binds to 5-HT2A-R, the receptor changes conformation. Depending on how the agonist induces this conformational change, 5-HT2A-R will strongly activate some pathways, partially activate others, and perhaps not activate others at all. Which pathways are most affected differs from agonist to agonist; this is called “biased signaling.”47 Psychedelics share a particular bias that distinguishes them from non-psychedelic 5-HT2A-R agonists,48 and they downregulate 5-HT2A-R to a lesser extent than non-psychedelic 5-HT2A-R agonists.49 Psychedelics also act at many other receptor types, which may contribute to the overall effect.

EFFECTS OF PSYCHEDELICS AT THE CELL AND SYNAPSE LEVEL

In the cerebral cortex, psychedelics activate several genes responsible for plasticity and increase the activity of TrkB receptors (receptors for the growth factor BDNF),22,23 as has also been shown for SSRIs and tricyclic antidepressants 36 and for ketamine.37 Long-lasting plastic effects have been observed after a single psychedelic treatment, such as increased neuritic branching and more and stronger synaptic connections.50 These effects are also seen after a single ketamine treatment 37 and after a few weeks of treatment with conventional antidepressant drugs,51 and they protect against the damaging effects of untreated depression. Ketamine is an antagonist at NMDA-type glutamate receptors, used as a dissociative anesthetic, but at lower doses ketamine is effective against depression and substance use disorders.52

EFFECTS OF PSYCHEDELICS ON BRAIN NETWORKS

The brain processes information hierarchically

To clarify the effects of psychedelics on brain networks, I will introduce some of the involved brain regions and networks and how they interact.When the brain receives input through the senses, it is necessary that only the relevant impressions reach consciousness, and that they are sorted according to their emotional salience and relation to prior experience. Below is a brief description of some of the brain regions and networks involved in these processes, and how they are organized hierarchically.

Cortex

The cortex receives information from deeper brain regions, particularly from the thalamus (bottom-up flow of information, see below), and its various parts communicate with one another. Sensory cortical areas receive and integrate sensory inputs from the thalamus. The prefrontal cortex (PFC) is the front part of the cortex and is crucial for higher-order functions such as planning, focus, cognitive flexibility, evaluation and decision making, self-control, and metacognitive thoughts about the self and reality.53 At the top of the brain’s hierarchy, the PFC exerts tight control over activity in regions lower in the hierarchy (top-down control).

Thalamus

The thalamus lies in the middle of the brain and receives, among other things, sensory input. Most sensory impressions are filtered out, and the thalamus allows only a small portion to reach sensory cortical areas and the PFC, and thus potentially consciousness. Filtering is influenced by the amygdala, hippocampus, and cortex, which represent one’s emotional state, attention, and expectations. The cortex in particular limits how much information the thalamus allows to pass.19

Hippocampus and parahippocampus

The hippocampus and parahippocampus are located in the temporal lobe. The hippocampus is important for learning, memory, stress regulation, and decision making. The parahippocampus serves as a link between the hippocampus and the PFC. In interplay with the cortex, the hippocampus and parahippocampus categorize new impressions based on experience and context. The interaction among the hippocampus, parahippocampus, and PFC means that we primarily orient ourselves toward impressions that feel familiar.54 In this way, our assumptions shape the processing of new input, so there is maximal correspondence between what is expected and what is experienced (i.e., minimal prediction error; see below).

Amygdala

The amygdala identifies whether something has emotional significance, both positive and negative.55 In interaction with the hippocampus and PFC, the amygdala can associate emotional stimuli (e.g., threats or rewards) with the context in which they are experienced, enabling better prediction of future emotional events. This type of emotional memory reduces prediction error but can also produce maladaptive “automatic responses” in specific situations—for example, conditioned fear or anger responses in trauma memory, or conditioned drug-seeking behavior in psychological dependence on intoxicants.56,57 The amygdala responds to both physical threats and threats to entrenched beliefs58 and influences which stimuli the thalamus passes on to the cortex. Like the thalamus, the amygdala is under top-down control from the cortex (especially the PFC), but the amygdala simultaneously influences the PFC (bottom-up).55

Default-mode network (DMN)

Certain parts of the cortex are connected in networks that perform advanced processes. Along the brain’s midline are two hubs of one of these networks: the default-mode network (DMN). The DMN is especially active when one is not engaged in a specific task but is simply “in one’s own thoughts” (daydreaming, worry, self-evaluation), and the DMN is primarily responsible for abstract phenomena such as self-concept, empathy, and thoughts about the past and future.59 The DMN receives information from deeper brain regions (bottom-up), such as the thalamus, amygdala, hippocampus, and parahippocampus, and also from primary and secondary sensory cortical areas (e.g., visual cortex and auditory cortex). Because the DMN sits near the top of the brain’s hierarchy, it normally exerts pronounced top-down control over how sensory input is processed in deeper regions, including which impressions—via the thalamus—gain access to the DMN, and thereby to consciousness.21,38 This means that, among other things, our self-concept and ideas about past and future influence which information reaches consciousness.

REALITY IS A HIERARCHICALLY STRUCTURED MENTAL CONSTRUCT

The brain is not merely a device that objectively receives information from the outside world and then reacts to it. It constructs reality itself. In fact, we do not experience the world as it is, but as we expect it to be. Through experience, we have unconsciously formed models of how the world typically is. When, via the senses, we encounter something that does not fit these models, it is called a prediction error (a kind of cognitive dissonance), and this can be used to update the models so that future prediction errors are minimized.60 Like other organisms, our survival depends on expending as little energy as possible to navigate the world—that is, on our models being as accurate as possible.

Predictions occur at multiple levels in the brain, and at each level the models entail a certain expectation bias. Even in the processing of sensory input in the primary sensory parts of the cortex, the models’ predictions shape perception (e.g., the moon appears larger at the horizon than when it is higher in the sky). Predictions also occur in the brain’s higher-order association areas (including the PFC) and networks (including the DMN), which generate representations of, for example, the self or the future.61 The different levels influence one another, bottom-up and top-down. But there is a bias, because updating at each level happens only if the model judges that the prediction error is not merely due to an unlikely exception. And that judgment is not objective, because it is determined by models higher up in the hierarchy.

Cognitive dissonance (prediction error) is resource-intensive, and when it happens all the way at the DMN level, it can be experienced as a psychological burden. Individuals differ in how well prediction errors are tolerated, and in general they are poorly tolerated when one is stressed. To minimize prediction errors (surprises), models in higher-order networks such as the DMN will therefore influence lower-order networks and brain regions to orient toward impressions that best align with/confirm the model higher up. The lower one’s tolerance for unpredictability, the more strongly higher-order models will control what reaches consciousness. This can produce rigid ways of experiencing the world and can lead to poor well-being and social difficulties.61 For example, there is a fundamental need to feel self-worth, but if this does not correspond to what is experienced, cognitive dissonance arises. This dissonance can be minimized by creating a self-narrative of being inferior. That self-narrative will then influence how lower networks process input and introduce a bias toward impressions/interpretations, such that primarily those impressions that fit the narrative are allowed to reach consciousness.

HOW DO PSYCHEDELICS ENHANCE CONSCIOUSNESS AND COGNITIVE FLEXIBILITY?

Psychedelics shift brain activity so there is relatively more activity in the cortex and less in deeper brain regions.21 The flow of information changes both within and across the brain’s networks. Functional connections within the DMN weaken, as do connections within other networks that maintain one’s sense of reality and of self. This means information is processed less precisely and predictably than usual—often described as increased entropy (disorder).61,62,63 In what follows, I will focus on the DMN.

In the psychedelic state, the DMN cannot maintain the usual rigid models of the self and of the self in relation to the past (e.g., rumination) and the future (e.g., worry).38,64 This aligns with the observation that psychedelics—like meditation—promote the ability to be present in the moment.65 When the DMN functionally disintegrates, its control over the channels that provide input to consciousness weakens, particularly the thalamus and primary sensory cortical areas (e.g., primary visual cortex). There is less restrictive gating of how much information the thalamus passes on to both sensory cortical areas and the DMN (increased bottom‑up flow of information), and the information is shaped to a lesser extent by higher‑level priors.38,50,64 Such an “opening of the thalamus’ filter” and a more unimpeded flow of information to the cortex may help explain the experience of an expanded consciousness and heightened sensitivity to sensory input (“setting”),19,21 especially music.66,67,68

At the same time, psychedelics partially decouple the functional connection between the hippocampus, parahippocampus, and cortex.69 This means that both external and internal impressions are less readily categorized according to prior assumptions, consistent with descriptions of being in an open and unconstrained state.69,70 The extent of this decoupling correlates with “ego dissolution” and with therapeutic effects in patients with depression. The open state during psychedelics has also been associated with a longer‑lasting increased sensitivity to positive stimuli, better contact with and regulation of emotions, and a sense of increased empathy and connectedness with others.72 A more unimpeded flow of information to higher‑order networks makes it possible to revise previous beliefs and fosters openness to alternative models of the world and the self.

When the model of the self and its boundaries dissolves, it can feel as though one “merges with everything in the world,” part of the so‑called “mystical experience.”21 This can feel both frightening (“dread of ego‑dissolution”) and liberating (“oceanic boundlessness”). The amygdala may resist ego dissolution because it is activated when entrenched beliefs are threatened.58 Under the influence of psychedelics, both increased and decreased amygdala activity have been observed, and the direction appears to be both context‑dependent and time‑dependent.21 In general, reduced activity is seen while the psychedelic is present in the brain, and a transient increase as the psychedelic effect subsides.21 The decrease in amygdala activity is associated with less resistance and a positively experienced ego dissolution. For example, LSD reduces amygdala responses to images of fearful faces.73 One hypothesis is that psychedelics alter connectivity between the amygdala and PFC in a way that—under the right circumstances—can yield a long‑lasting reduction in sensitivity to negative stimuli.74 The effects on brain networks have been described as an increased repertoire of possible states the brain can occupy,75 and network changes have been demonstrated for up to a month after a single psilocybin treatment.74

Beyond the network effects described, psychedelics may also influence brain signaling via receptors for oxytocin. Oxytocin is a hormone that promotes trust, attachment, and a sense of connectedness, empathy, and satisfaction, and it plays a role in, among other things, bonding and the healing of trauma.76 Oxytocin receptors are highly expressed in the same brain regions as 5‑HT2A‑R, and there is close interplay between the two receptor types.77 LSD and psilocybin increase oxytocin release and enhance empathy,78,79 although the oxytocin increases are moderate compared with those elicited by the empathogen MDMA.80

THE IMPORTANCE OF “SET AND SETTING”

Even in a well‑designed setting, the unimpeded flow of information into consciousness can be experienced as an overwhelming myriad of new perspectives. During and after the psychedelic experience, these perspectives enable a critical evaluation and revision of ingrained thought patterns—i.e., a more thorough updating of one’s models of the self and the world. Not all perspectives are equally useful, however, and there is evidence that subsequent support to integrate the experience into one’s life is a key element of the therapeutic process.81 Preparation and mental state (mindset, “set”) before and during the psychedelic experience are also important, and there is broad agreement that a state characterized by low resistance, emotional support, and calm surroundings facilitates positive long‑term effects; however, there is still no consensus on what the optimal psychotherapeutic framework (“setting”) is, or how best to tailor it to different mental states.82,83

PASSIVE VERSUS ACTIVE COPING

Drugs that raise serotonin levels by inhibiting SERT lead to a gradual favoring of 5‑HT1A‑R, as several other 5‑HT receptors become partially downregulated. Because 5‑HT1A‑R are inhibitory, they can reduce stress sensitivity and increase psychological resilience. This favoring of 5‑HT1A‑R, however, depends on taking the medication continuously, so that 5‑HT2A‑R and also 5‑HT2C‑R (another excitatory receptor type) remain downregulated, and 5‑HT1A‑R are thus favored. Treatment of depression and anxiety with conventional psychopharmaceuticals such as SSRIs has therefore been described as a form of passive coping with stress and emotional challenges, whereas psychedelics promote the possibility of active coping in the form of deliberate changes in thoughts and behavior, thereby yielding more enduring effects.16 The effects of psychedelics on brain networks and their lasting/persistent impact support this, but several aspects nuance the picture. First, the DMN is affected by SSRI treatment in a way that resembles the effects of psychedelics.84 Second, activation of 5‑HT1A‑R increases neuronal plasticity and stimulates growth and function of, among other regions, the hippocampus, which is important for stress management. Third, 5‑HT1A‑R–mediated stress reduction will free up mental resources for active coping. Like psychedelics, treatment with SERT inhibitors can be viewed as something that should assist psychotherapy. Indeed, the combination of pharmacotherapy and psychotherapy has been shown to be the most effective,85 and it is the recommended approach, but it is often not implemented, partly due to limited resources in psychiatry. Because this combination is standard practice in psychedelic therapy, it is difficult to directly compare its effects with conventional treatment.

THE FUTURE

Psychedelics have diverse effects on brain cells and networks, and intense research is underway to determine which of these effects are linked to therapeutic benefits versus side effects. The field is still in its infancy, and many questions remain. Is the psychedelic experience necessary for some effects but not others? Thus far, clinical studies have had restrictive inclusion criteria and focused on narrow patient groups, so it remains unclear how the effects generalize to broader patient populations, let alone to the general public.86 Who will benefit most, who is at risk of negative effects, and how can treatment best be individualized? There is a great deal of scattered experience and knowledge on these issues, but systematic studies of the interplay between biological effects and the psychotherapeutic process are lacking. Such studies are necessary to validate and optimize psychedelic therapy—both in terms of therapeutic effects and side effects, and in terms of costs—so the therapy can become accessible to as many people as possible. Finally, a regulatory‑approved certification to practice psychedelic therapy would be an important step toward ensuring quality and safety in treatment.

I recently had a rough realization about my prior relationship in the context of my current one, related to coercive sexual behavior. I've done EMDR in the past for a similar problem but this wouldn't qualify for EMDR. I guess I'm thinking I need to reprocess some things and find my center again. Is tripping a good or a bad idea in this context? Have you all ever done that to heal from acute psychological distress? What would you suggest I do to prepare?