Esketamine with acceptance and commitment therapy

1. Introduction

Version followed: the esketamine-plus-ACT ("AET") pilot design proposed by Mathai, Mora & Garcia-Romeu (2022, Frontiers in Psychology, Johns Hopkins / Baylor). ACT content follows the Association for Contextual Behavioral Science (ACBS) six-core-process model. Session-level ACT exercises are borrowed, and labelled as borrowed, from the open CHUM feasibility protocol of ACT alongside ketamine (Garel et al., NCT06620276, v5.0, 2025). That protocol uses racemic ketamine in people with alcohol use disorder plus treatment-resistant depression, not esketamine.

What it is. This is a proposed research model, not a manualised therapy. Mathai et al. describe a planned randomised pilot. People with treatment-resistant depression (TRD) who are starting standard esketamine (Spravato) treatment get either treatment as usual or treatment as usual plus "preparatory counseling and ongoing ACT during esketamine administration". The ACT sessions run during the medically supervised observation period after each treatment session. The pilot appears only as a proposal. No published manual, session content, therapist script or results are described (Rutgers EASS page; Mathai et al. 2022) [uncertain: whether the trial has since run or published]. Everything below that goes beyond the published design is marked [synthesis] or attributed to the source it is borrowed from.

Core idea of change. The authors place the model in the "psycholytic" family. In psycholytic work, psychotherapy happens during acute drug effects and uses them to deepen the therapeutic and relational work. They contrast this with high-dose "psychedelic" (preparation–session–integration) models and with "plasticity-oriented" models, which deliver therapy after acute effects in a supposed window of heightened neuroplasticity. They chose ACT because psychological flexibility (PF) is a transdiagnostic target that predicts psychotherapy outcome in TRD. PF has also been reported to mediate the link between acute psychedelic effects and reduced depression and anxiety. Their hypotheses are that the relational and therapeutic context shapes what the drug's subjective effects are worth clinically, and that PF-oriented work "may be key to supporting processes of change". The mechanism is a hypothesis under test, not an established finding. [source: Mathai, Mora & Garcia-Romeu 2022; Rutgers EASS spotlight]

Legal and regulatory status (as of sources, 2022–2026).

• USA: esketamine (Spravato) is FDA-approved for adults with TRD and for depressive symptoms in MDD with suicidal thoughts or actions. It is a Schedule III controlled substance (CIII). It is available only under the Spravato REMS: treatment happens in REMS-certified healthcare settings, and outpatients must be enrolled. A healthcare provider monitors the patient during and after each treatment and decides when the patient may leave. Patients must not drive or do alertness-dependent tasks until the next day after restful sleep. [source: FDA label/Medication Guide rev. 09/2026] Mathai et al. (2022) built the therapy slot around the then-required minimum post-treatment monitoring window. The 2026 Medication Guide wording leaves discharge to the monitoring provider and states no fixed minimum [uncertain: whether a fixed minimum still applies in your setting; check the current REMS].
• Racemic ketamine for depression is off-label prescribing (Mathai et al. discuss "evidence-based off-label prescribing"). In Canada the CHUM protocol delivers it as routine clinical care in a hospital neuromodulation clinic [source: NCT06620276].
• UK: NICE TA854 (Dec 2022) does not recommend esketamine for TRD, and NICE decided in June 2024 not to review that guidance. A marketing authorisation exists [source: NICE TA854 review decision] [uncertain: details of EU/UK authorisation].
• Your role: the psychotherapist does not prescribe, administer or medically monitor. Those are the responsibilities of the REMS-certified prescriber and medical staff. You deliver psychotherapy inside their setting and under their safety procedures. [source: FDA label; NCT06620276, where ketamine monitoring is done by the clinic, not the therapy team]

2. Framework

Structure of the proposed pilot [source: Mathai et al. 2022, Figure 2 and "A Specific Proposal"]:

• Format: individual, in person, at the certified treatment setting. Session length is not stated, but it is bounded by the observation period [inferred].
• Measures named by the authors: depression outcomes; subjective and dissociative-type drug effects (e.g. the CADSS, which they discuss); psychological flexibility (they cite the AAQ-II as the PF measure in psychedelic research); therapeutic alliance; need for maintenance treatment. These are licensed or published instruments; use the published versions and do not adapt the items.
• Criteria for moving between phases: the published design sets none. Phase transitions follow the medical treatment course, which the prescriber decides. [synthesis] Useful clinical checkpoints are: (a) before the first treatment session, the client can describe the plan, the therapist's role and a personal values direction; (b) by the end of induction, review PF and depression measures with the prescriber and agree whether ACT continues outside the protocol during maintenance; (c) at any point, a safety concern (suicidality, emerging psychosis, misuse) pauses ACT and goes back to the prescriber.
• Optional adaptation, a parallel weekly ACT course [borrowed from NCT06620276]: the CHUM protocol gives ACT as eight weekly 50-minute individual sessions alongside ketamine treatment, in person preferred (remote allowed), each combining teaching and experiential exercises: week 1 control strategies, the ACT matrix, a self-observation journal, anchoring and mindfulness; week 2 emotions and acceptance; week 3 shame; weeks 4–5 values; week 6 committed action; week 7 mindfulness, feedback and compassion; week 8 relapse prevention. [synthesis] Practical option: deliver the weekly course in ordinary sessions and use the brief in-window sessions to practise the process of that week.

3. Guiding principles

[source: Mathai et al. 2022 for 1–6; ACBS six core processes for 7–9; NCT06620276 for 10; FDA label for 11; the practical meanings are synthesis]

1. Medication-assisted psychotherapy, not drug-only treatment. The authors' hypothesis is that drug and psychotherapy are synergistic. Practice: treat every in-window session as therapy with goals, not as reassurance while time passes.
2. Psycholytic and relational stance. Therapy happens during acute effects and uses them to deepen the work. Practice: stay present, talk with the client, and invite them to notice and describe what is happening; this is not an eyeshades-and-music, inward-only session.
3. Context shapes the value of drug effects. Practice: manage the setting (a calm room, a predictable plan, consistent therapist) and the meaning the client gives to the effects; prepare before the first treatment session.
4. Subjective effects are clinically relevant, not just side effects. The authors argue that treating dissociation only as an adverse event may hide its meaning. They note that anxiety during treatment may predict poorer response, and that connectedness may need interpersonal engagement to be realised. Practice: ask about, normalise and work with dissociative, emotional and connection experiences, and respond early to anxiety.
5. Psychological flexibility is the target. Practice: every intervention should help the client open up to experience, stay present and move towards values. Symptom relief alone is not the session goal.
6. Standards of ordinary practice apply until the field has its own. Practice: work within your competence and existing medical and psychological standards, adapt to client characteristics, and keep to the prescriber's protocol.
7. Acceptance in the service of values, not as an end in itself. Practice: invite willingness when it makes valued action possible.
8. Change how the client relates to thoughts, not their content. Practice: do not dispute depressive thoughts; help the client hold them lightly.
9. Values are chosen qualities of action, lived moment by moment. Practice: watch for values chosen out of "should", compliance or avoidance.
10. No reliving of trauma required. The CHUM protocol presents this as lowering the risk of intense distress during ketamine treatment. Practice: do not run exposure-based trauma processing in the window unless it is a separately planned, consented intervention.
11. Safety and medical authority sit with the treating team. Practice: the monitoring provider decides physical safety and discharge; you report concerns and never override them.

4. Intervention inventory

Scope note: Mathai et al. (2022) name only three components, preparatory counselling, ACT during the post-treatment observation period and the shared maintenance/follow-up. They do not specify the exercises. Items 4.1–4.6 below are the treatment frame: the published design plus label requirements, with procedural detail marked [synthesis]. Items 4.7–4.19 are ACT methods, taken from the ACBS process descriptions and, where the source is named, from the CHUM ketamine-ACT protocol (NCT06620276). How they fit into the in-window session is [synthesis] unless stated. All example wording is illustrative.

4.1 Joint eligibility screening with the prescriber

• Purpose / when: before the first treatment session, to confirm the client suits both the medication and in-session psychotherapy.
• Steps: (1) Confirm the REMS-certified prescriber has judged esketamine appropriate; medical contraindications are theirs to assess. The label lists aneurysmal vascular disease, arteriovenous malformation, history of brain bleeding, and hypersensitivity to esketamine or ketamine. It also asks patients to disclose heart, brain or liver problems, a history of psychosis, pregnancy and breastfeeding [source: FDA label]. (2) Take your own psychotherapy history: prior psychosis or mania, substance use (the label requires screening for misuse before and during treatment), dissociative disorders, trauma, cognitive impairment, current suicidality. (3) Apply the published exclusions of the related protocol where relevant: acute psychosis, severe unstable comorbidity likely to take clinical precedence, neurocognitive decline affecting capacity to do therapy, current parallel evidence-based psychotherapy, and inability to commit to the sessions [source: NCT06620276]. (4) Share your findings with the prescriber before you start.
• Example language (illustrative): "Your psychiatrist checks whether the medication is safe for you. I check whether talking during the treatment sessions is likely to help, so I need to ask about some experiences you may have had."
• Watch for: history of psychosis or a dissociative disorder, recent or active misuse of ketamine or other drugs, and suicidal crisis needing a higher level of care. The label states esketamine is no substitute for hospitalisation when that is needed.

4.2 Informed consent to the combined treatment

• Purpose / when: at intake, separately from the prescriber's medication consent.
• Steps: (1) Explain that ACT-during-treatment is an experimental proposal with no published efficacy data [source: Mathai et al. 2022]. (2) Explain what you will and will not do: you talk and do exercises; medical staff monitor and decide discharge; you never handle medication. (3) Give the label's practical restrictions: no driving or alertness-demanding tasks until the next day after sleep; possible sedation, dissociation, raised blood pressure and cognitive effects [source: FDA label]. (4) Explain the limits of confidentiality, including sharing with the treating team. (5) Explain that the client can stop the conversation at any time, or decline ACT entirely, without losing medication treatment (refusal does not affect clinical care in NCT06620276). (6) Check understanding with teach-back. NCT06620276 uses a brief comprehension quiz; write your own questions.
• Example language (illustrative): "You can say 'I'd rather just rest' at any point. That's fine, and we'll pick it up next time."
• Watch for: consent given under hopelessness-driven pressure to try anything. Slow down and check that the client actually understands.

4.3 Preparatory counselling session(s)

• Purpose / when: before the first treatment session; named in the design but not specified [source: Mathai et al. 2022]. The content below is [synthesis].
• Steps: (1) Ask about expectations and fears of the drug experience, including dissociation, feeling unreal and loss of control. (2) Give a plain-language description of possible acute effects, as the label lists them, without predicting a particular experience. (3) Introduce psychological flexibility through the client's own avoidance patterns (see 4.7). (4) Teach one portable anchoring skill (4.10) to use during treatment sessions. (5) Agree a stop-signal and a preference about being spoken to while effects peak. (6) Name one tentative values direction (4.13) as the "compass" for in-window work. (7) Agree what will be shared with the prescriber.
• Example language (illustrative): "During treatment some people feel detached or as if things aren't real. We won't try to push that away. We'll practise noticing it and staying in contact, and then see what it shows you about what matters."
• Watch for: rigid expectations ("I need a breakthrough") or catastrophic fears. Address both before the first treatment session.

4.4 In-window ACT session (psycholytic, relational)

• Purpose / when: the core AET component. ACT is delivered during the supervised observation period after treatment, once acute effects are present, so the experience can be used therapeutically and relationally [source: Mathai et al. 2022]. Session structure is [synthesis].
• Steps: (1) Coordinate with monitoring staff before entering: confirm the client is medically stable and that staff are aware of the session; stay out of their way during their checks. (2) Open with present-moment contact: "What are you noticing right now?" (3) Let the client describe the experience; reflect it without interpreting it. (4) Pick one process according to what is showing up. Distressing thoughts lead to defusion (4.8). Strong emotion or resistance leads to acceptance (4.9). Detachment or a sense of observing leads to self-as-context (4.11). Felt connection or meaning leads to values (4.13). (5) Keep exercises short and simple, and use few words, since cognition may be slowed [synthesis; label lists cognitive effects]. (6) Close by linking the experience to a values direction and a small next step (4.14). (7) Make a brief note of what emerged, to carry into the next session (4.6).
• Example language (illustrative): "You said the sadness feels further away. Can you notice who is noticing that?" / "If the part of you that cares about your kids were speaking now, what would it say?"
• Watch for: the client being too sedated or dissociated to engage. Then simply be present, and leave content work for next time. Anxiety is a cue to anchor and slow down, since the authors note anxiety during treatment may predict poorer response. Physical warning signs (chest pain, severe headache, visual changes, seizures, breathing difficulty) are for medical staff immediately [source: FDA label].

4.5 Coordination with the medical team

• Purpose / when: throughout; the monitoring provider holds physical safety and discharge [source: FDA label; NCT06620276].
• Steps: (1) Agree in writing who calls whom for what. (2) Report suicidality, emerging psychotic or manic features, or suspected misuse to the prescriber the same day. (3) Never advise on medication changes. (4) Share PF and alliance measures at agreed reviews.
• Watch for: role blur. A client asking you whether they are "OK to go" gets referred to the monitoring provider.

4.6 Measurement-based review and carry-forward

• Purpose / when: to track the authors' secondary targets (PF, alliance, subjective effects) and to link in-window material across sessions [source: measures, Mathai et al. 2022; procedure, synthesis].
• Steps: (1) Give the published PF measure (AAQ-II) and an alliance measure at baseline, at the end of induction and at follow-up, under their licensing terms. (2) At the start of each in-window session, recall one point from the last session and the committed action, and ask how it went. (3) At the end of induction, review the scores with the client and prescriber.
• Watch for: PF scores improving while the client still avoids a lot. Use behavioural data (actions taken), not only scores.

4.7 Reviewing control strategies (D.O.T.S.) and the ACT Matrix

• Purpose / when: in preparation or week 1, to show the client how avoidance and control strategies have worked out for them, which opens the way to willingness. Both tools are named in NCT06620276, week 1. Their detailed content is not reproduced there, so the steps below are [synthesis] based on the names.
• Steps (D.O.T.S.): (1) List what the client does to get rid of low mood under four headings: Distraction, Opting out, Thinking strategies, Substances. (2) For each one, ask what it costs in the long run and whether it gets the client closer to what matters. (3) Don't argue; let the client weigh it up.
• Steps (Matrix): (1) Draw a cross. The horizontal line runs between moving away from and moving towards; the vertical line runs between inner experience and outward behaviour. (2) Fill in what matters (towards, inner), towards actions (outer), unwanted inner experiences (away, inner) and away moves (outer). (3) Use the drawing as the session map from then on.
• Example language (illustrative): "So staying in bed works for an hour. What does it do to the week?"
• Watch for: self-blame ("I've done it all wrong"). Answer that these strategies make sense and are what most people do.

4.8 Cognitive defusion techniques

• Purpose / when: when the client is fused with depressive thoughts ("I'm worthless", "this won't work"), in or out of the window. These are ACBS-named techniques [source: ACBS].
• Steps: use one of these at a time. (a) Watch the thought: the client notices the thought and describes it dispassionately, as an event. (b) Word repetition: the client says a key word aloud repeatedly until it is just sound. (c) Physicalising: the client gives the thought a shape, colour or speed. (d) Thanking the mind: the client thanks the mind for the thought. (e) Labelling: the client adds "I'm having the thought that…". (f) 3N (NCT06620276, week 2): name, note and neutralise the thought (no further detail in the source) [uncertain]. In the window, prefer (a), (c) and (e), which take few words [synthesis].
• Example language (illustrative): "Try saying: 'I notice I'm having the thought that nothing will change.' What happens to it?"
• Watch for: defusion used to make thoughts go away (control), or the client feeling mocked. Rule of thumb: it is working when the thought is still present but has less pull on behaviour.

4.9 Acceptance / willingness work

• Purpose / when: when the client struggles against emotion or sensation, including unfamiliar drug effects. Acceptance means actively embracing private experience without trying to change it, in the service of values [source: ACBS].
• Steps: (1) Name the struggle. (2) Use the quicksand metaphor (NCT06620276): struggling makes you sink, while spreading out and staying in contact helps [synthesis wording]. (3) Walk through the CHUM five-step acceptance sequence: resist, recognise, allow, welcome, adapt [source: NCT06620276; the step content is paraphrased synthesis]. Notice the resistance, recognise the emotion, allow it room, welcome it as part of now, then adapt by choosing a values-consistent response. (4) Locate the emotion in the body and breathe around it.
• Example language (illustrative): "What if, just for a minute, you let the heaviness be exactly as heavy as it is?"
• Watch for: "acceptance" used as a strategy to make the feeling go away. Acceptance is working when the client can stay with the feeling and still choose.

4.10 Present-moment anchoring and mindfulness practice

• Purpose / when: at every session start, when the client is anxious or overwhelmed, and as the portable skill taught in preparation. Present-moment work means non-judgemental contact with events as they occur [source: ACBS]. Anchoring and mindfulness instruction are in NCT06620276 week 1 (detail not given). The steps are [synthesis].
• Steps: (1) Feet on the floor, notice points of contact. (2) Name a few things seen, heard and felt. (3) Notice the breath without changing it. (4) Widen attention to include the emotion or drug effect and the room. (5) Return to the anchor whenever lost.
• Example language (illustrative): "Notice the chair holding you. Notice the sounds in the room. And notice whatever the medication is doing, alongside that."
• Watch for: in vulnerable people, mindfulness can bring on anxiety or dissociation. If so, use eyes-open, externally focused anchoring and shorten the exercise [synthesis].

4.11 Self-as-context (observer perspective)

• Purpose / when: when the client feels defined by depression or is in a detached, observing state. In ACBS terms, self-as-context is a perspective from which experience is observed, fostered with mindfulness exercises, metaphors and experiential processes [source: ACBS]. Using dissociative effects as a doorway is [synthesis] and is not stated by Mathai et al.
• Steps: (1) Ask the client to notice a thought, then notice that they are noticing it. (2) Point out that the noticer has been present through earlier life periods, both good and bad. (3) If detachment is present, invite curiosity: "Who is aware of feeling far away?" (4) Ground before closing.
• Example language (illustrative): "Depression is something you're experiencing, and there's a 'you' who's been there through all of it, watching."
• Watch for: depersonalisation becoming frightening. Then switch to anchoring (4.10) and don't deepen it. Do not frame drug effects as spiritual truths.

4.12 Self-observation journal / diary

• Purpose / when: between sessions, to track situations, inner experiences, away and towards moves, and willingness exercises [source: NCT06620276 weeks 1–2; the format is synthesis].
• Steps: (1) Agree on a simple form with columns for situation, what showed up inside, what I did, and towards or away. (2) Review it at the next session, staying curious. (3) Note how the days after treatment sessions differ from other days.
• Example language (illustrative): "No need to write a lot. One line a day about one away move and one towards move is plenty."
• Watch for: the diary turning into rumination or self-criticism. Make it shorter.

4.13 Values clarification

• Purpose / when: from preparation onward, to give the in-window work direction. Values are chosen qualities of action across domains such as family, work and spirituality, lived moment by moment rather than achieved [source: ACBS].
• Steps: (1) Go through life domains, asking what the client wants to stand for in each. (2) Bull's-eye exercise (NCT06620276, weeks 4–5): the client rates how close current living is to each value [synthesis description]. (3) Guided future visualisation (NCT06620276 uses a visualisation of celebrating a recovery anniversary). For depression, adapt it to imagining a future occasion where people describe how the client lived [synthesis adaptation]. (4) Test each value for "should", compliance or avoidance motives (ACBS).
• Example language (illustrative): "Not what you should want, what you'd choose if no one were grading you."
• Watch for: values stated as feelings or outcomes ("to be happy"). Reframe them as ways of acting.

4.14 Committed action, SMART goals and obstacles

• Purpose / when: at the end of each in-window session and from mid-course onward. ACT draws on behaviour therapy methods (exposure, skills training, shaping, goal setting) to build patterns of values-based action [source: ACBS]. SMART goals and an obstacles exercise are in NCT06620276, week 6.
• Steps: (1) Choose one small, specific step linked to a stated value. (2) Make it SMART. (3) Anticipate the inner obstacles (thoughts, feelings, urges) and plan a defusion or willingness response. (4) Write it down before the client leaves. (5) Review it next session without judgement, and shape the next step from what happened.
• Example language (illustrative): "What's one thing this week, small enough to do even on a bad day, that would be a step towards being the father you described?"
• Watch for: goals set while the client feels elevated in the window may be too big later. Halve them [synthesis].

4.15 Choice point

• Purpose / when: for decisions in the moment between away and towards moves (NCT06620276, week 2 optional; and week 8 "moment of choice") [synthesis description].
• Steps: (1) Pick a recent difficult moment. (2) Map what showed up inside, the away option and the towards option. (3) Rehearse noticing the choice point next time.
• Example language (illustrative): "Right there, when the thought hit, what were the two roads?"
• Watch for: framing the choice as willpower. Stress noticing instead.

4.16 Compassion work

• Purpose / when: when self-criticism and shame dominate (NCT06620276 week 7 includes compassion; weeks 2–3 address shame, including a personal "shame profile" in the AUD context). The exercise content is not given [uncertain]; the steps are [synthesis].
• Steps: (1) Notice the self-critical voice and defuse from it (4.8). (2) Ask how the client would respond to a friend in the same position. (3) Offer that stance to themselves, briefly and kindly.
• Example language (illustrative): "If your closest friend felt like this, what would you want them to hear?"
• Watch for: compassion feeling threatening ("I don't deserve it"). Treat that as a thought to defuse from.

4.17 Integration of acute-session material

• Purpose / when: in the next contact, to turn in-window insights into flexible behaviour. Mathai et al. do not specify integration for the AET arm. The related psilocybin–ACT frame (Sloshower et al. 2020, abstract) holds that drug experiences give direct contact with ACT processes, which ACT-informed follow-up sessions may reinforce. The procedure below is [synthesis].
• Steps: (1) Ask what the client remembers from the session (recall may be partial). (2) Name which process it touched, e.g. "you were able to watch the thought". (3) Link it to a value and a committed action. (4) Correct over-interpretations gently, and keep meaning-making the client's own.
• Example language (illustrative): "Last time you said the guilt felt like weather passing. Where could that matter this week?"
• Watch for: the client crediting change only to the drug ("it only works when I'm on it"). Point out the skills they used themselves.

4.18 Relapse prevention and maintenance planning

• Purpose / when: at the end of induction or the final ACT session (NCT06620276 week 8 covers relapse prevention, craving management with "the wave" and the moment of choice, a breathing exercise called SOBRE, and a "safe box" of coping tools, all in an AUD context; content not given). Adaptation to depression is [synthesis].
• Steps: (1) Write down early warning signs of depressive relapse. (2) List the client's most useful ACT skills, as their "safe box". (3) For urges or low-mood waves, practise noticing the rise, peak and fall without acting on them. (4) Agree who the client contacts if things get worse, including the prescriber during maintenance.
• Example language (illustrative): "What will you notice first if things start sliding, and what's your first move?"
• Watch for: an end to therapy that leaves the client with no link to support while maintenance treatment continues.

4.19 Real-time support during distressing acute effects

• Purpose / when: when the client becomes frightened, overwhelmed or disoriented in the window. NCT06620276 states that an ACT-trained therapist can give real-time support and coping strategies if ketamine causes unsettling experiences. The steps are [synthesis].
• Steps: (1) Slow your voice and lower the stimulation. (2) Orient the client: where they are, that this is a medication effect, that it is time-limited, and that staff are present. (3) Anchor (4.10). (4) Invite willingness rather than control (4.9). (5) Tell monitoring staff about any physical concern or any distress that doesn't settle. (6) Debrief in the next session.
• Example language (illustrative): "You're in the clinic, I'm here, the nurse is here. This is the medication, and it will ease. Feel your feet on the floor."
• Watch for: distress that rises despite grounding, or signs of medical emergency. That is staff's responsibility at once.

5. Handling problems

The published design has no problem-handling guidance. Items rest on the FDA label, NCT06620276, Mathai et al. (2022) and ACBS where tagged; everything else is [synthesis].

• Client too sedated or dissociated to engage in the window. Don't push content. Offer quiet presence and brief anchoring, and check in with monitoring staff. Do the ACT work in the next contact (4.17). If this happens every time, discuss with the prescriber and team whether in-window therapy suits this client, or move to a parallel weekly course (Section 2). [synthesis; label lists sedation and dissociation]
• Anxiety or fear during acute effects. Orient, anchor and invite willingness (4.19, 4.10, 4.9). Mathai et al. note that anxiety during treatment may predict poorer response, so respond early and review the preparation afterwards. [source: Mathai et al. 2022; response is synthesis]
• Overwhelm, or trauma memories surfacing. Don't process the trauma in the window. NCT06620276 positions ACT as not needing re-living of trauma. Ground the client and acknowledge the memory. If it is clinically indicated, plan separate trauma-focused treatment with consent. [source: NCT06620276; synthesis]
• Stuck: "nothing is changing". Separate drug response (the prescriber's area) from flexibility work. Review values and committed actions, not only mood. Use creative-hopelessness-style questioning about control strategies (4.7). Check whether goals were set too big. [synthesis]
• Resistance to ACT ("I just want the medicine to fix it"). Respect the choice, since ACT is optional. Explore what the client hopes the medication will let them do, which opens a values conversation. Don't argue. [synthesis]
• Non-adherence to homework. Shrink the task. Treat the barriers as content to defuse from or accept. Use the in-window session to rehearse the action. [source: ACBS on barriers being worked through the other processes; synthesis]
• Ruptures (e.g. feeling unheard while impaired, embarrassment about things said in the window). Name the rupture directly in the next sober session. Ask what was difficult. Restate confidentiality and the stop-signal agreement. Track the alliance (one of the authors' measured outcomes). [synthesis; Mathai et al. 2022 for the alliance measure]
• Suicidality. Esketamine is indicated for some people with suicidal thoughts or actions, and the label carries antidepressant-class warnings. It is not a substitute for hospitalisation. Follow standard risk assessment at every contact: ideation, intent, plans, preparatory behaviour, protective factors. Use a structured measure where your service uses one (NCT06620276 repeats the Beck Scale for Suicide Ideation). Do safety planning and lethal-means counselling (safe storage, removal). Report to the prescriber the same day, and escalate per local emergency procedures. [source: FDA label; NCT06620276; standard practice]
• Misuse, craving or dependence concerns. The label warns of abuse, misuse and dependence and asks for screening before and during treatment. Ask non-judgementally about use of ketamine or other substances outside the clinic and tell the prescriber. Note that the CHUM protocol targets people with comorbid alcohol use disorder and excludes other recent substance use disorders. [source: FDA label; NCT06620276]
• Client using ketamine or psychedelics outside clinics. Your role is harm reduction and integration support, never facilitation. Assess what happened and the current risk. Make a safety plan. Educate in general terms about risks (combining with other sedatives or alcohol, driving, psychiatric destabilisation, bladder and cognitive effects as the label lists them) without discussing amounts or sources. Refer to medical care, and offer ACT integration of the experiences. [synthesis]
• Emerging psychotic or manic symptoms. Pause in-window work and contact the prescriber. History of psychosis is a disclosure item on the label. NCT06620276 excludes acute psychosis while allowing bipolar TRD at the psychiatrist's discretion. [source: FDA label; NCT06620276]
• Physical warning signs in session (chest pain, severe headache, vision changes, seizure, breathing difficulty). Alert medical staff at once; this is not a psychotherapy task. [source: FDA label]
• Pressure to leave early or to drive. Refer to the monitoring provider, who decides discharge, and restate the label's no-driving-until-next-day rule. [source: FDA label]
• Over-valuing or spiritualising the experience ("it showed me my true self"). Treat it as a meaningful private experience. Use self-as-context and values to keep the client's own meaning, without endorsing metaphysical claims. [synthesis]
• End of induction with no response. The medical decision belongs to the prescriber. Offer to continue ACT without the drug, since PF work stands on its own. Watch for hopelessness spikes and reassess risk. [synthesis]
• Competence and setting limits. Mathai et al. note there is no formal approval route for such combined therapies and that provider training in specific modalities matters. Get ACT training and supervision, and practise in-window work only in a REMS-certified (or equivalent) setting with medical staff. [source: Mathai et al. 2022; synthesis]

Sources

Sources:

• Toward Synergies of Ketamine and Psychotherapy (Mathai, Mora & Garcia-Romeu 2022), Frontiers in Psychology PDF
• Toward Synergies of Ketamine and Psychotherapy, Frontiers text page
• ACT in Patients with AUD and Comorbid TRD Undergoing Ketamine Intervention: feasibility protocol NCT06620276 (CHUM, v5.0)
• ACBS: The Six Core Processes of ACT
• Spravato (esketamine) prescribing information and Medication Guide, FDA, rev. 09/2026
• NICE TA854 review decision (esketamine for treatment-resistant depression)
• Rutgers EASS speaker spotlight: psychedelics in psychotherapy
• ACBS page: Sloshower et al. 2020, Psilocybin-assisted therapy of MDD using ACT as a therapeutic frame (abstract only)
• ACBS page: Watts & Luoma 2020, ACE model (abstract only)
• Role of Non-Specific Effects in the Treatment of Depression With Esketamine, NCT05910775 protocol (Yale; checked and found not to be an ACT protocol, so not used)

Cited works:

• Mathai DS, Mora V, Garcia-Romeu A (2022). Toward synergies of ketamine and psychotherapy. Frontiers in Psychology, 13:868103.
• Sloshower J, Guss J, Krause R, et al. (2020). Psilocybin-assisted therapy of major depressive disorder using Acceptance and Commitment Therapy as a therapeutic frame. Journal of Contextual Behavioral Science, 15, 12–19 (abstract only).
• Watts R, Luoma JB (2020). The use of the psychological flexibility model to support psychedelic assisted therapy. Journal of Contextual Behavioral Science (abstract only).

[uncertain] Further reading (not drawn on): any published manual, session-level content, or results of the Hopkins esketamine-ACT pilot; full texts of Sloshower et al. and Watts & Luoma; the current REMS document; details of EU/UK marketing authorisation.