Criterion 1: Readiness signs

Learning Objectives

By the end of this module, the trainee will be able to:

• Recognize when readiness depends on a medical safeguard, distinguish care that is separable from the administration (coordinate it, ideally through the client's own treating team) from care that is inseparable (a stop, not a caution), and route the legal question to counsel (Criteria 2 and 41).
• Explain the pharmacological reason that pre-session screening carries more weight in psychedelic work than in ordinary talk therapy, at the level of the 5-HT2A receptor and its effect on cortical priors.
• Describe the entropic-brain and relaxed-beliefs (REBUS) models as models, and use them to explain why the same session can strengthen a prepared person and destabilize an unprepared one.
• Connect the amplification mechanism to the neuroplasticity window that follows dosing, and explain why the state a person enters shapes what that window consolidates.
• Distinguish absolute psychiatric contraindications from relative cautions and from conditions that are frequently an indication for the work rather than a reason to exclude.
• Identify the cardiovascular and metabolic factors that determine physiological readiness, and state the mechanism behind the serotonin 2B valvular concern.
• Assess psychological readiness as a set of measurable capacities, trait absorption, distress tolerance, emotion regulation, and reflective function, rather than a global impression.
• Assess social readiness as a property of the environment a person returns to, not only of the person.
• Name what readiness is predicting toward, drawing on the acute-experience quality and psychological-flexibility literature, and use that to set preparation goals.
• Apply a three-domain plus timing framework to reach a defensible proceed, defer, or refer decision, and articulate the reasoning in writing.

Key Terms

Readiness. The presence of enough psychological stability, social support, physiological safety, and appropriate timing for a person to enter and metabolize an altered state without foreseeable harm. It is a positive capacity, assessed as a set of strengths a person brings, and it is not merely the absence of risk factors.

5-HT2A receptor. The serotonin 2A receptor, densely expressed on layer 5 cortical pyramidal neurons. Agonism at this receptor is the primary initiating action of the classic serotonergic psychedelics (Nichols, 2016).

Prior (predictive processing). A high-level expectation or belief the brain uses to organize and predict experience. Under predictive-processing accounts, perception and cognition are driven by the brain's models of the world, and psychedelics are modeled to relax the precision and the confidence weighting of these priors (Carhart-Harris & Friston, 2019).

Entropy (entropic-brain model). In this model, a measure of the disorder or uncertainty of large-scale brain activity. The entropic-brain hypothesis proposes that psychedelics raise the entropy of cortical dynamics, moving the brain toward a less constrained, more flexible state (Carhart-Harris et al., 2014).

Amplification. The clinical shorthand for the observation that psychedelics intensify material already present in a person rather than introducing new content from outside. What is stable is deepened; what is unstable is magnified.

Neuroplasticity window. A period following psychedelic administration during which markers of structural and functional plasticity, including dendritic spine growth, are elevated. Preclinical work shows psychedelics promote this plasticity, which is one proposed substrate of durable change (Ly et al., 2018; Shao et al., 2021).

Trait absorption. A stable disposition toward deep attentional involvement in sensory and imaginative experience. It is one individual-difference variable associated with the intensity of the acute psychedelic response and is relevant to reading how a person is likely to meet the state.

Distress tolerance. The capacity to withstand aversive internal states without acting to escape them prematurely. It is a central resilience marker for work that predictably produces periods of acute difficulty.

Reflective function. The capacity to understand one's own and others' behavior in terms of underlying mental states. It supports a person's ability to make meaning of an intense experience rather than being overwhelmed by it.

Absolute contraindication. A condition under which the intervention should not proceed at all in the setting under consideration, because the risk of serious harm is unacceptable.

Relative contraindication. A condition that raises risk and requires additional evaluation, mitigation, or a higher level of care, without automatically excluding the person.

Sympathomimetic effect. A physiological effect resembling activation of the sympathetic nervous system, here the transient rise in heart rate and blood pressure produced by classic psychedelics (Johnson, Richards, & Griffiths, 2008).

Set and setting. The extra-pharmacological determinants of a psychedelic response: set, the person's mindset, expectation, and preparation, and setting, the physical, social, and cultural environment. The evidence that these shape outcome is among the more robust findings in the field (Hartogsohn, 2016, 2017).

Why readiness screening exists: the amplification mechanism

Screening is the first real judgment a facilitator makes, and every function downstream inherits it. To understand why it carries the weight it does, we start with what the medicine does to the brain. The classic serotonergic psychedelics, psilocybin among them, act as agonists or partial agonists at the serotonin 2A receptor, which sits densely on the layer 5 pyramidal neurons of the cortex (Nichols, 2016). Those neurons carry much of the machinery that holds a person's high-level model of themselves and their world in place.

The leading mechanistic account of what follows is the relaxed beliefs under psychedelics model, or REBUS (Carhart-Harris & Friston, 2019). It builds on an earlier proposal, the entropic-brain hypothesis, which held that psychedelics raise the entropy of large-scale cortical activity and move the brain into a less constrained regime (Carhart-Harris et al., 2014). Under the REBUS account, 2A agonism relaxes the precision of high-level priors, the settled expectations the brain uses to predict, rationalize, and stabilize experience. When those priors loosen, the constraints that ordinarily keep a person's inner world fixed start to give way, and material which is normally held down can surface and reorganize. Both of these are worth stating as models rather than closed facts, because human evidence is still developing and the imaging findings are actively debated, but together they are the most coherent framework currently available, and they have direct consequences for screening.

The consequence is amplification. The medicine does not import new content from outside the person. It loosens the structures that hold existing content in check, so whatever is already present tends to intensify. A person who enters grounded, supported, and physically sound often finds their strengths deepened. A person who enters destabilized, isolated, or medically compromised often finds those same vulnerabilities magnified. Screening exists because you cannot safely amplify what you have not first understood.

The neuroplasticity window: why the entered state matters beyond the session

Amplification explains the acute risk. A second mechanism explains why screening decisions echo for weeks after the medicine has cleared. Psychedelics do not only perturb cortical dynamics during the session; they open a window of heightened neural plasticity that outlasts the acute effects. In preclinical models, a single dose of a psychedelic promotes structural and functional plasticity, including growth in the number and size of dendritic spines on cortical neurons (Ly et al., 2018). Work using psilocybin has shown rapid and, in part, persistent growth of dendritic spines in the frontal cortex after a single dose (Shao et al., 2021). These are animal findings, and the leap to a human therapeutic mechanism is a hypothesis rather than an established fact. However, the direction is consistent and reframes what a session consists of.

The practical reading is this. If a session opens a period of elevated plasticity, then the experiences, relationships, and meaning a person moves through during and immediately after that window are candidates for consolidation. A person carried through a difficult passage toward some resolution, in a supportive environment, has a chance of consolidating that trajectory. A person left alone in a destabilizing environment during the same window is at risk of consolidating the destabilization. This is the mechanistic reason readiness cannot be assessed as a snapshot of the dosing day alone. It must take in the arc of the weeks around it, which is why social readiness and timing are weighted as heavily in this criterion as psychological and physiological readiness. True readiness is not limited to the considerations of the acute phase; it bleeds over into the integration phase as well.

What readiness predicts toward

A screening framework is only coherent if it is oriented toward an outcome. Readiness is a prediction rather than an abstract virtue, a prediction that a given person, in a given context, can enter the state and move through it toward benefit rather than harm. The outcome literature gives that prediction some empirical shape, and it should inform both the screen and the preparation that follows a decision to proceed.

The quality of the acute experience is not incidental to the outcome. In treatment-resistant depression, the quality of the acute psychedelic experience has been shown to predict therapeutic efficacy, with more complete experiences associated with better clinical response (Roseman, Nutt, & Carhart-Harris, 2018). One mediating pathway that has held up across studies is psychological flexibility: acute psychedelic effects appear to reduce depression and anxiety in part by increasing a person's psychological flexibility, the capacity to stay in contact with difficult internal experience and still act in line with one's values (Davis, Barrett, & Griffiths, 2020). Readiness screening, then, is partly a read of whether a person can tolerate and make use of a complete experience rather than defend against it, and preparation is partly the work of building that capacity before the door opens.

This reframes the resilience markers shown below. Distress tolerance, emotion regulation, and reflective function are not generic virtues carried into the assessment for their own sake. They are the person-level capacities most plausibly connected to entering a complete experience and metabolizing it, which is what the outcome data suggest actually drives benefit.

Psychological readiness

The psychological question is whether a person has the stability to enter a strongly altered state and stay tethered to themselves while inside it. Three conditions sit at the center of the psychiatric concern, and they share a mechanism. A personal or first-degree family history of a primary psychotic disorder, and bipolar disorder with a history of mania, are currently treated as serious contraindications across the clinical trial literature, because the serotonergic action of these compounds can precipitate or worsen psychosis and mania, and the trials have excluded these histories for that reason (Johnson, Richards, & Griffiths, 2008; Davis et al., 2021).

The dimensional point matters more than the diagnostic label. A diagnosis in the chart is less informative than the person's current stability. A person with well-managed anxiety who is stable in ongoing therapy may be well prepared. A person in acute crisis is not, whatever their diagnosis. Note also that depression, anxiety, and post-traumatic stress are frequently the reason a person seeks this work rather than a reason to turn them away, since these are the conditions in which supervised psychedelic and entactogen therapy has shown benefit (Davis et al., 2021; Mitchell et al., 2021).

Reading for resilience means reading specific capacities rather than forming a global impression. Four are worth naming explicitly. Emotion regulation is the ability to modulate the intensity and duration of an emotional response without being carried away by it. Distress tolerance is the capacity to remain with an aversive internal state rather than acting immediately to escape it, and it is the single most load-bearing capacity for work that predictably produces acute difficulty. Reflective function is the ability to understand one's own and others' behavior in terms of underlying mental states, which supports meaning-making rather than overwhelm. Trait absorption, a disposition toward deep attentional involvement in imaginative and sensory experience, is associated with the intensity of the acute response and helps a facilitator anticipate how vividly a person is likely to meet the state. Screening for psychological readiness runs in two directions at once: ruling out the destabilizing conditions, and reading these capacities for the resilience that predicts a person can carry the work and has some prior ability to integrate difficult experience.

Social readiness

Readiness is contextual before it is anything else, and the context includes the world a person walks back into. The concept of set and setting is not simply decoration. It names the extra-pharmacological factors that shape the response to the drug, and the evidence that context is a genuine determinant of outcome is among the more robust findings in the field (Hartogsohn, 2016). The history of the concept shows that drug effects are, in a real sense, constructed by the environment and expectations surrounding them rather than read off the molecule alone (Hartogsohn, 2017). Setting extends past the room and past the day of the session into the relationships, the housing, and the obligations that will either hold a person or pull them under during the vulnerable weeks of integration. Preclinical plasticity findings provide a rationale for studying this period, but they do not establish a defined plasticity window in humans.

A person preparing to work through trauma while still living with an abusive partner is not ready in the way that matters, however willing they feel, because the environment will overwrite their work. A person surrounded by supportive relationships has a stronger foundation for the same material. Screening for social readiness means asking concretely about supportive relationships, safe living conditions, access to integration support, and the obligations, childcare, work, caregiving, that could compromise a person's ability to engage fully or recover afterward.

Physiological readiness

The body has to be able to carry the session. The primary physiological concern is cardiovascular. Classic psychedelics produce sympathomimetic effects, transient increases in heart rate and blood pressure, so uncontrolled hypertension and significant cardiac disease raise real risk (Johnson, Richards, & Griffiths, 2008). A separate and less obvious concern is the serotonin 2B receptor. Several of these compounds show agonist activity at 5-HT2B, and sustained stimulation of that receptor is the established mechanism behind the valvular heart disease once seen with fenfluramine and certain ergot derivatives (McIntyre, 2023). The therapeutic model of one to a few widely spaced doses carries little of that liability. The same pharmacology is the reason frequent, repeated exposure, the pattern in unsupervised microdosing, warrants genuine caution, and a recent analysis comparing microdosing to known cardiotoxins argues the theoretical valvular risk of chronic frequent dosing should not be dismissed (Rouaud, Calder, & Hasler, 2024). A competent facilitator understands the receptor, not only the rule.

Beyond the heart, screening attends to seizure disorders, hepatic and renal function, and pregnancy. Metabolism matters here: psilocybin is a prodrug, rapidly dephosphorylated to its active form psilocin, which is then cleared through hepatic pathways, so significant hepatic impairment can alter exposure (Nichols, 2016). Operational screening tools, resting blood pressure, an electrocardiogram where cardiac history or risk factors warrant one, and a structured medical history, translate these concerns into practice. The specific numeric thresholds a program uses to trigger further evaluation or medical clearance are policy decisions that should be set with qualified medical oversight rather than improvised by a facilitator, and this module does not assign a citation to any single threshold because no single universal standard exists in the peer-reviewed literature.

Timing and life circumstances

Health does not settle the question of timing. A person in acute grief, mid-divorce, or newly bereaved may be medically clear and psychiatrically eligible and still not ready this month. Readiness is fluid and moves with circumstance. The plasticity window gives timing a second edge: scheduling a session during a period of acute upheaval risks consolidating that upheaval rather than a resolution. The facilitator evaluates whether now is the moment or whether stabilization and preparation should come first, and frames a decision to wait as sequence rather than refusal, paired with a concrete path back.

The screening posture and scope of practice

Two commitments hold this criterion together. The first is humility about scope. No facilitator and no program can hold everything, and some people need stabilization inside conventional care before this work is appropriate at all. Saying not yet is a clinical act, and a facilitator should be as skilled at it as at saying yes. The second is that the first trust is built or lost here. How screening is conducted, whether it feels mechanical and rushed or thorough and unhurried, tells a person what kind of program they have entered, and even a person who is turned away can leave the process feeling seen when the tone and the reasoning are honest. This criterion pairs with Criterion 2, which takes the coexisting medical, psychiatric, and pharmacological conditions this screen surfaces and routes them to the right professional.

When readiness depends on a medical safeguard: the threshold that ends screening

One screening finding deserves separate treatment, because it changes the nature of the decision rather than merely weighting it. Screening ordinarily sorts people into proceed, defer and prepare, or refer, and the middle option carries the implicit promise that a caution can be worked on and revisited. Some findings break that promise. Where a client's safe participation would depend on a medical intervention, and the substance they are seeking is Schedule I, the intervention that would make them safe cannot simply be arranged the way an ordinary medical referral can. The reasoning is developed in Criterion 2, and its legal structure is taught in Criterion 41; what matters at the screening stage is the conclusion. A facilitator screening a client whose safety would require, for instance, continuous cardiac monitoring with intravenous access through the session is not looking at a caution to be managed with a phone call. They are looking at a requirement that no one may lawfully meet under current US law.

The discipline this imposes at screening is a distinction rather than a blanket refusal. Ask whether the medical care the client would need is separable from the administration of the substance. Care that is separable stands on its own clinical footing and does not require a clinician to handle or give the substance: a cardiac evaluation and clearance beforehand, a prescriber managing the client's own medication, a treating physician managing their blood pressure, a clinician contracted to be present and respond to a medical emergency as they would at any gathering. That care can frequently be arranged lawfully, and the best route is usually the client's own treating team, whose involvement is both lawful and clinically superior to anything a facilitator could improvise. Screening that surfaces a need for separable care is doing exactly what screening is for, and the correct action is to coordinate it. Care that is inseparable from the administration is different. Where the safeguard functions only if it is delivered during the session and as an integral part of the administration, arranging it means arranging for a clinician to participate in an unlawful act, and no logistics solve that. A finding of that kind is a stop rather than a caution: the client is screened out of the unlawful setting and routed toward a lawful one, which in practice means an authorized clinical trial, a jurisdiction where a clinician may lawfully provide the care, or a different path altogether. Whether any particular arrangement is defensible is a legal question with real consequences for the clinician involved, and it belongs with an attorney rather than with a facilitator's judgment. What screening owes the client is the honesty to recognize the finding and to name it, rather than to treat as a logistics problem something that is in truth a gate.

Clinical and Decision Tools

Tool 1. Three-domain readiness indicators

Use this as a structured read across all three domains plus timing. It orients judgment; it does not replace it. A single Stop indicator halts the process pending evaluation. A pattern of Caution indicators calls for preparation before proceeding.

Tool 2. Psychological resilience read

Where Tool 1 screens for the presence of stop indicators, this tool structures the positive read of capacity that predicts a person can enter and metabolize a complete experience. It is a guide to inquiry, not a scored instrument, and it should be documented in narrative form.

Tool 3. Psychiatric conditions reference

Contraindication status reflects the setting under consideration. A condition that is absolute for an unsupported retreat may be manageable in a medically supervised clinical setting. When in doubt, refer for psychiatric evaluation before proceeding. Shaded rows mark stop-and-refer findings.

Tool 4. Physiological red flags and recommended action

Tool 5. Readiness-to-preparation map

A defer decision is only useful if it names what preparation must accomplish. This tool translates the most common caution findings into concrete preparation goals and a marker of what completion looks like, so that deferral becomes a plan rather than a delay.

Tool 6. Decision framework

Integrate the three domains and timing into one of three defensible outcomes. Document the outcome and its reasoning.

Proceed. All domains meet Proceed indicators, no Stop indicators present. Move to intake and preparation.

Defer and prepare. The person is fundamentally appropriate but a domain needs strengthening first, more support, better timing, a controlled medical condition. Use Tool 5 to set concrete conditions and a path back.

Refer out. A Stop indicator or an out-of-scope need is present. Route to the appropriate professional, warmly and with clear reasoning. See Criterion 2 and Core Function XII.

Worked Examples: Completed Readiness Evaluations

The following are models of the reasoning and documentation this criterion should produce. Details are fictional.

Worked Example 1: A defer-and-prepare decision

Client: R.M., 42, seeking psilocybin-assisted work for long-standing treatment-resistant depression. Referred by a treating therapist.

Psychological: Diagnosis of major depressive disorder, recurrent. No personal or family history of psychotic or bipolar disorder. In weekly therapy for two years with a stable alliance. Reports good distress tolerance and a prior history of using difficult experiences reflectively. No current suicidal ideation; passive ideation eighteen months ago, since resolved. Read: Proceed indicators present; depression is an indication, not an exclusion. On the resilience read, emotion regulation and reflective function are strong; prior integration is documented.

Social: Lives with a supportive spouse who is informed and on board. Stable housing and employment. Treating therapist willing to provide integration support across the plasticity window. Read: Proceed.

Physiological: No cardiac history; resting blood pressure within normal range on two readings. Currently tapering off an SSRI under psychiatric supervision, with an agreed washout before any session. No other interacting medications. Read: Caution pending completion of the supervised washout, then Proceed.

Timing: No acute stressor. Adequate time protected for integration. Read: Proceed.

Decision: Defer and prepare, with a single condition: complete the psychiatrist-supervised SSRI washout and confirm a stable baseline, then proceed to intake. Rationale documented and shared with the client and, with signed release, the treating therapist.

Worked Example 2: A refer-out decision

Client: D.L., 34, self-referred, seeking psilocybin work for what they describe as a spiritual crisis and periods of feeling that thoughts are being placed in their mind.

Psychological: Reports two prior episodes over the past three years involving disordered thinking and a sense of external control over thoughts, neither formally evaluated. A sibling was hospitalized for a psychotic episode. Read: Stop. A first-degree family history of a primary psychotic disorder together with a personal history suggestive of psychotic-spectrum experience is an absolute contraindication in most settings, because 2A agonism can precipitate or worsen psychosis (Johnson, Richards, & Griffiths, 2008).

Social and physiological: Not the limiting factors here and not the basis of the decision. A stop indicator in one domain halts the process regardless of strength elsewhere.

Decision: Refer out. Route to psychiatric evaluation, framed as care rather than rejection: the experiences described warrant assessment in their own right, and that assessment has to come first. Document the reasoning. Do not schedule. This is a case where saying not yet, and possibly not at all in this setting, is the competent clinical act.

Case Vignettes

Work each vignette across all three domains plus timing, reach a Proceed, Defer, or Refer decision, and write one paragraph defending it. The fillable response sheets are in the companion worksheet PDF.

Vignette A

A 29-year-old arrives motivated and psychologically curious, with good insight and no psychiatric red flags. They live alone, recently moved to a new city, and have no local support network. They want to do deep trauma work.

Guided questions: Which domain is the limiting factor here? What specifically would you want in place before proceeding? Is this a Refer, or a Defer-and-prepare, and why? How does the plasticity window bear on the missing support?

Vignette B

A 51-year-old is physically active, medically confident, and dismissive of the preparation process, describing it as unnecessary hand-holding. They are currently taking a selective serotonin reuptake inhibitor and want to attend an ayahuasca retreat in three weeks.

Guided questions: What is the specific pharmacological hazard in this profile? What has to happen before this person could safely proceed, and who has to be involved? How do you address the dismissiveness toward preparation without losing the alliance?

Vignette C

A 38-year-old is medically healthy, well supported, psychologically stable, and lost a parent to suicide five weeks ago. They feel an urgent pull to do psychedelic work to process the grief.

Guided questions: Is medical and psychological stability sufficient here? What does the timing indicator tell you, and how does the plasticity window sharpen the concern? How do you frame a decision to wait so that it lands as care rather than rejection?

Vignette D

A 45-year-old with well-managed generalized anxiety, stable in therapy for three years, presents for psilocybin work. On the resilience read they show strong reflective function but describe a lifelong pattern of avoiding intense emotion and leaving situations the moment discomfort rises. Medically clear, well supported, good timing.

Guided questions: There is no stop indicator here. What in the resilience read still gives you pause? How does low distress tolerance interact with a complete experience and the outcome data? Is this a proceed, or a proceed-after-targeted-preparation, and what would preparation specifically build?

Vignette E

A 60-year-old with treatment-resistant depression is a strong psychological and social fit. Medical history includes hypertension, currently uncontrolled on their most recent two readings, and they mention occasional chest tightness on exertion that they have not had evaluated.

Guided questions: Which domain halts this, and why does it halt it regardless of the strong fit elsewhere? What is the sympathomimetic concern in concrete terms? What specific clearance and evaluation do you require, and is the undisclosed chest tightness a defer or a stop?

Role-Play and Practice Scripts

Practice these in pairs, one facilitator and one client, then switch. The goal is to gather what safety requires while communicating that the person is being met rather than examined.

Opening the psychiatric history

“I am going to ask some direct questions about mental health, including things people do not always get asked about. This is how I make sure this is safe for you, and it is not a test you can fail. Have you or anyone in your immediate family ever experienced psychosis, mania, or been diagnosed with schizophrenia or bipolar disorder?”

Reading resilience, not just risk

“Tell me about a time something in your life was genuinely hard to sit with. What did you do, and what did you take from it afterward?” Practice listening for distress tolerance, reflective function, and prior integration rather than steering the person toward a right answer.

Asking about suicidality

“Have you had thoughts of ending your life, recently or in the past? If yes, can you tell me about when, and what things are like for you now?” Practice staying calm and unhurried, and knowing your program’s threshold for pausing the process and referring.

The medication and supplement review

“I need the full list of everything you take, prescription, over the counter, and supplements, including anything you take only occasionally. Some combinations are genuinely dangerous with these medicines, so this part matters.” Practice recognizing the SSRI-plus-ayahuasca and MAOI combinations as stop-and-refer moments, and hand off to Criterion 2 for the full review.

Assessing the return environment

“Walk me through the two weeks after a session as they would actually look. Who is around you, where are you living, what obligations are pulling on you?” Practice hearing the setting a person returns to as part of the readiness picture, not an afterthought.

Delivering a not-yet decision

“Based on everything we have discussed, I do not think now is the right time, and I want to tell you exactly why, because it is not a no forever. Here is what I would want to see in place first, and here is how we get there.”

Self-Assessment and Reflection

Knowledge check

1. At the level of the receptor, why does screening matter more for psychedelic work than for ordinary talk therapy? Name the receptor and the effect on cortical priors.
2. State the entropic-brain and REBUS models in one sentence each, and explain why each is described as a model rather than a settled finding.
3. Explain the neuroplasticity window and why it makes social readiness and timing safety-relevant for weeks after the session, not only on the dosing day.
4. List the three psychiatric histories most often treated as serious contraindications, and state the shared mechanism.
5. Name the four psychological resilience capacities this module foregrounds, and explain how distress tolerance connects to the outcome literature.
6. Explain the 5-HT2B valvular concern and why it bears on repeated dosing more than on a single supervised session.
7. Give one profile in which a person is medically and psychologically ready but should still be told not yet.

Reflection

1. Recall a time you, or someone you observed, let enthusiasm for an outcome override a safety judgment. What indicator was missed, and what would have caught it?
2. Where is the edge of your own scope of practice? Name one type of client you should refer rather than hold, and identify the professional you would refer to.
3. Consider a person who meets every proceed indicator except that their return environment is thin. Knowing what you now know about the plasticity window, how much weight do you give that gap, and what would you require before proceeding?

Summary

Screening is where the work becomes safe or fails to, and Criterion 1 is its foundation. Because 2A agonism relaxes the priors that hold a self stable, the medicine amplifies whatever is already present, which means a facilitator must understand a person across three domains and their timing before opening that door. The entropic-brain and REBUS models give this a mechanistic frame, and the neuroplasticity that follows a dose extends the stakes of the decision across the weeks of integration, not just the dosing day. Psychological readiness rules out the destabilizing conditions and reads for specific resilience capacities, emotion regulation, distress tolerance, reflective function, and prior integration that the outcome literature connects to entering and metabolizing a complete experience. Social readiness assesses the world a person returns to. Physiological readiness centers on the cardiovascular system and the specific receptor-level risks these compounds carry. Timing can override an otherwise clear profile. Held with humility about scope, the criterion produces one of three defensible outcomes: proceed, defer, or refer, each documented with its reasoning, and it hands its coexisting-condition findings to Criterion 2 for routing.

References

Carhart-Harris, R. L., & Friston, K. J. (2019). REBUS and the anarchic brain: Toward a unified model of the brain action of psychedelics. Pharmacological Reviews, 71(3), 316–344. https://doi.org/10.1124/pr.118.017160

Carhart-Harris, R. L., Leech, R., Hellyer, P. J., Shanahan, M., Feilding, A., Tagliazucchi, E., Chialvo, D. R., & Nutt, D. (2014). The entropic brain: A theory of conscious states informed by neuroimaging research with psychedelic drugs. Frontiers in Human Neuroscience, 8, 20. https://doi.org/10.3389/fnhum.2014.00020

Davis, A. K., Barrett, F. S., & Griffiths, R. R. (2020). Psychological flexibility mediates the relations between acute psychedelic effects and subjective decreases in depression and anxiety. Journal of Contextual Behavioral Science, 15, 39–45. https://doi.org/10.1016/j.jcbs.2019.11.004

Davis, A. K., Barrett, F. S., May, D. G., Cosimano, M. P., Sepeda, N. D., Johnson, M. W., Finan, P. H., & Griffiths, R. R. (2021). Effects of psilocybin-assisted therapy on major depressive disorder: A randomized clinical trial. JAMA Psychiatry, 78(5), 481–489. https://doi.org/10.1001/jamapsychiatry.2020.3285

Hartogsohn, I. (2016). Set and setting, psychedelics and the placebo response: An extra-pharmacological perspective on psychopharmacology. Journal of Psychopharmacology, 30(12), 1259–1267. https://doi.org/10.1177/0269881116677852

Hartogsohn, I. (2017). Constructing drug effects: A history of set and setting. Drug Science, Policy and Law, 3, Article 2050324516683325. https://doi.org/10.1177/2050324516683325

Johnson, M. W., Richards, W. A., & Griffiths, R. R. (2008). Human hallucinogen research: Guidelines for safety. Journal of Psychopharmacology, 22(6), 603–620. https://doi.org/10.1177/0269881108093587

Ly, C., Greb, A. C., Cameron, L. P., Wong, J. M., Barragan, E. V., Wilson, P. C., Burbach, K. F., Soltanzadeh Zarandi, S., Sood, A., Paddy, M. R., Duim, W. C., Dennis, M. Y., McAllister, A. K., Ori-McKenney, K. M., Gray, J. A., & Olson, D. E. (2018). Psychedelics promote structural and functional neural plasticity. Cell Reports, 23(11), 3170–3182. https://doi.org/10.1016/j.celrep.2018.05.022

McIntyre, R. S. (2023). Serotonin 5-HT2B receptor agonism and valvular heart disease: Implications for the development of psilocybin and related agents. Expert Opinion on Drug Safety, 22(10), 881–883. https://doi.org/10.1080/14740338.2023.2248883

Mitchell, J. M., Bogenschutz, M., Lilienstein, A., Harrison, C., Kleiman, S., Parker-Guilbert, K., Ot’alora G., M., Garas, W., Paleos, C., Gorman, I., Nicholas, C., Mithoefer, M., Carlin, S., Poulter, B., Mithoefer, A., Quevedo, S., Wells, G., Klaire, S. S., van der Kolk, B., … Doblin, R. (2021). MDMA-assisted therapy for severe PTSD: A randomized, double-blind, placebo-controlled phase 3 study. Nature Medicine, 27(6), 1025–1033. https://doi.org/10.1038/s41591-021-01336-3

Nichols, D. E. (2016). Psychedelics. Pharmacological Reviews, 68(2), 264–355. https://doi.org/10.1124/pr.115.011478

Roseman, L., Nutt, D. J., & Carhart-Harris, R. L. (2018). Quality of acute psychedelic experience predicts therapeutic efficacy of psilocybin for treatment-resistant depression. Frontiers in Pharmacology, 8, 974. https://doi.org/10.3389/fphar.2017.00974

Rouaud, A., Calder, A. E., & Hasler, G. (2024). Microdosing psychedelics and the risk of cardiac fibrosis and valvulopathy: Comparison to known cardiotoxins. Journal of Psychopharmacology, 38(3), 217–224. https://doi.org/10.1177/02698811231225609

Shao, L.-X., Liao, C., Gregg, I., Davoudian, P. A., Savalia, N. K., Delagarza, K., & Kwan, A. C. (2021). Psilocybin induces rapid and persistent growth of dendritic spines in frontal cortex in vivo. Neuron, 109(16), 2535–2544.e4. https://doi.org/10.1016/j.neuron.2021.06.008