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International Review of Psychiatry
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Learning how to make use of dissociative
therapies
David S. Mathai
To cite this article: David S. Mathai (23 Sep 2024): Learning how to make use of dissociative
therapies, International Review of Psychiatry, DOI: 10.1080/09540261.2024.2406329
To link to this article: https://doi.org/10.1080/09540261.2024.2406329
Published online: 23 Sep 2024.
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REVIEW ARTICLE
INTERNATIONAL REVIEW OF PSYCHIATRY
Learning how to make use of dissociative therapies
David S. Mathaia,b,c
aBaylor College of Medicine – Department of Psychiatry and Behavioral Sciences, Houston, TX, USA; bBaylor College of Medicine – Ethical
Legal Implications of Psychedelics in Society Program, Center for Medical Ethics and Health Policy, Houston, TX, USA; cSattva Medicine
– Psychiatry, Psychotherapy, and Consulting Practice, Miami, FL, USA
ABSTRACT
Dissociative therapies are being increasingly explored for their psychiatric applications, although
questions remain about how they work and how best to use them. In exploring these questions,
this review highlights six key areas of clinical relevance: (1) The possible contributions of functional
unblinding when interpreting efficacy data; (2) The degree to which the therapeutic effects of
dissociative therapies can be distinguished from the transient forms of relief seen with recreational
drug use; (3) Understanding the construct of dissociation as it is tasked with describing the
function of dissociative drugs; (4) The investigation of subjective drug effects as predictors of
therapeutic outcome; (5) Similarities and differences in the effects of dissociative and classic
psychedelics; and (6) The anticipated need for judicious prescribing/deprescribing resources as
dissociative therapies proliferate.
Introduction
In recent years, several dissociative drugs have
advanced through successful clinical development
programs either as isolated compounds (e.g. esket-
amine, the patented S-enantiomer of ketamine, mar-
keted as Spravato®) or in combined formulations (e.g.
dextromethorphan-bupropion, marketed as Auvelity®)
for the treatment of depression. Racemic ketamine is
available as a generic medication and is used ‘off-label’
for its antidepressant properties. These drugs can be
classified as a structurally heterogenous group of
antagonists of the N-methyl-d-aspartate (NDMA)
receptor that possess dose-dependent hallucinogenic
properties but that can be distinguished pharmacolog-
ically and clinically from classic psychedelics like
lysergic acid diethylamide (LSD) and psilocybin
(Denomme et al., 2024). Referred to hereafter as ‘dis-
sociatives’ or ‘dissociative therapies’ – these agents
might also be seen as representing a new generation
of psychiatric medications that are available today,
and are unique in their mechanism of action and
rapid-acting clinical properties when compared to
existing therapies (Anand et al., 2023; Mathai et al.,
2022; Schenberg, 2018). Despite considerable progress,
there are still key, unresolved questions about how
dissociatives work and how best to use them. Six
opportunities for conceptual development and poten-
tial evolution in this space are explored below.
Clinically relevant eects?
In only one of three short-term phase 3 trials for
esketamine submitted for U.S. Food and Drug
Administration (FDA) approval was there a statisti-
cally significant separation from placebo for the pri-
mary depression endpoint assessed (Popova et al.,
2019). Given that the size of this effect was modest
and the added limitation of saline used as a control
intervention, the true efficacy of esketamine has been
called into question (Schatzberg, 2019). The findings
of a recent meta-analyses have further suggested that
the placebo response may account for 64% of the
overall treatment response observed across trials of
patients with depression receiving esketamine
(Matsingos etal., 2024). Dextromethorphan-bupropion
was similarly approved by the FDA as an antidepres-
sant based on short-term efficacy data from just one
positive study using an inactive placebo (Iosifescu
© 2024 Institute of Psychiatry and Johns Hopkins University
CONTACT David S. Mathai d.s.mathai@gmail.com Sattva Medicine – Psychiatry, Psychotherapy, and Consulting Practice, 2121 Biscayne Blvd #1255,
Miami, FL 33137, USA
https://doi.org/10.1080/09540261.2024.2406329
ARTICLE HISTORY
Received 10 April 2024
Accepted 16 September
2024
KEYWORDS
Dissociative; ketamine;
esketamine;
dextromethorphan;
psychedelic
2 D. S. MATHAI
et al., 2022), and a second study that used bupropion
as an active comparator (Tabuteau et al., 2022). For
all these studies, it is unclear the degree to which
blinding was effective, and how functional unblinding
might account for any significant differences observed.
Clinical trials involving dissociatives are uniquely
challenged when it comes to maintaining blind integ-
rity, as has also been discussed with psychedelic trials
(Aday et al., 2022). A successful double-blind trial is
one where neither the research staff nor the partici-
pant knows their treatment assignment, allowing for
control of expectancies and other non-specific factors
related to treatment outcomes. However, for drugs
that produce significant psychoactive effects, there is
an increased likelihood that both participants and
research staff become functionally unblinded in ways
that could bias outcomes. It then becomes difficult to
know if drug-comparator differences are attributable
to a drug-specific, mechanistically identifiable effect
(Wilkinson et al., 2019).
The dissociative and perceptual effects of ketamine
and esketamine have now been documented in
numerous trials of these medications for depression
treatment (Mathai et al., 2022; McIntyre et al., 2021).
Dextromethorphan is known to demonstrate similar
properties (Carbonaro et al., 2018), although it is
unclear whether such effects are apparent at the 45 mg
doses used in the FDA-approved dextromethorphan-
bupropion combination. Online forums seem to con-
vey that patients are aware of alterations in mental
status attributed to the drug, particularly within the
first few weeks of initiating treatment
(Imterrifiedrightnow, 2023). The dose-dependent psy-
choactive effects of dextromethorphan have also been
demonstrated experimentally in a study of oral doses
ranging from 100 to 800 mg/70 kg, wherein even the
lowest dose examined was discernible from placebo
(Reissig et al., 2012).
Trials of esketamine and dextromethorphan-
bupropion have not assessed blind efficacy and, there-
fore, have not yet established that a clinically relevant
effect exists for these medications apart from any sub-
jective awareness of a dissociative drug being admin-
istered. There are examples of studies for racemic
ketamine that have attempted to address this problem
by assessing blinding, while also using midazolam as
an active placebo, and thus increasing the likelihood
of detecting a treatment-specific effect with ketamine
(Grunebaum et al., 2018; Murrough et al., 2013;
Wilkinson et al., 2019). However, these studies have
also yielded smaller relative effects for ketamine than
those using a saline comparator, making it difficult to
reach conclusions about the specificity of ketamine’s
antidepressant benefit. Although this might be seen as
a criticism of the efficacy of dissociatives, it is also
worth considering that this is more the norm than an
exception when it comes to antidepressant trials at
large. In fact, fewer than 10% of randomized con-
trolled trials of antidepressants have reported data on
blinding assessments, and the success of blinding has
been mixed even for well-established medications (Lin
et al., 2022; Scott et al., 2022).
Importantly, there may not be an optimal control
condition that exists for dissociative therapies
(Murrough et al., 2013). As is thought to be the case
with psychedelic therapies more broadly (Aday et al.,
2022), it may be that the interaction between
treatment-specific and nonspecific effects impacts
therapeutic outcomes with dissociatives. For example,
the potential for therapeutic benefit may depend on
how expectations of healing combine with the acute
experience of a dissociative drug. It would then be
inappropriate to describe such interactions in reduc-
tionistic terms as a process of functional unblinding,
if they are in fact central to how dissociatives produce
their clinical effects.
Rather than attempting to isolate specific from
nonspecific influences, clinicians and researchers may
be better served by learning how to optimize and
synergize them (Colloca & Barsky, 2020; Enck et al.,
2013). Such interactions could also be presumed to be
dose-dependent, as highly variable qualities of experi-
ence emerge with increasing doses (Antoniou &
Juurlink, 2014; Kolp et al., 2014; Stanciu et al., 2016).
Following this logic, lower dissociative doses adminis-
tered as a strictly biomedical intervention (Bennett,
2019) have demonstrable value but may more closely
resemble the nonspecific response of a psychoactively-
inert placebo, and thus be less likely to be separate
from control conditions in clinical trials. Therapies
involving higher doses of a dissociative drug may rep-
resent a different type of intervention altogether, par-
ticularly in treatment contexts that value drug-induced
experiences and provide psychological support for
such (Mathai et al., 2023). The potential for optimiz-
ing treatment by considering such interactions has
been inadequately explored, even though dissociative
therapies are already being used widely.
Drug ‘highs’
Dissociative therapies have been criticized for the
drug ‘highs’ they produce (Horowitz & Moncrieff,
2021). Ketamine, for example, is unique when com-
pared to conventional psychiatric medications for its
prominent subjective effects that model states of
INTERNATIONAL REVIEW OF PSYCHIATRY 3
intoxication typically attributed to recreational drugs
(Mathai etal., 2022). The quality of these experiences
can range from more pleasant to challenging
(Breeksema et al., 2022, 2023; Mollaahmetoglu et al.,
2021; Sumner et al., 2021), and experiences that are
positive may also contribute to patterns of non-medical
drug use (Carbonaro et al., 2020; Xu & Lei, 2014).
Distinguishing between a subjective drug ‘high’ and
reliable antidepressant effect is no straightforward
task. In the medical literature, feeling ‘high’ is often
used pejoratively to convey drug or alcohol intoxica-
tion associated with altered sensorimotor functioning
(Stith et al., 2023). This definition does not capture
the variety of psychological experiences that are pos-
sible during intoxication and that may also predict
subsequent health benefits. At the same time,
drug-induced states of euphoria, relaxation, or other
temporary disruptions in symptomatology can be
mistaken for psychiatric relief.
A more fitting question might be: when is a sub-
jective drug ‘high’ only that, and not also indicative of
a desirable therapeutic effect (Mathai etal., 2022)? In
addition to a general risk-benefit analysis, one should
consider the durability of effect. Drug intoxication
that is not accompanied by a reliable antidepressant
effect would not be expected to last significantly
beyond the period of acute intoxication. This con-
trasts in an obvious way with classic psychedelic
agents, such as psilocybin, which can elicit positive
feelings acutely but also therapeutic benefits lasting
for months and, in some cases, years following drug
administration (Aday etal., 2020; Nayak et al., 2023).
For dissociatives, this data is less certain. The anti-
depressant benefits for a single dose of ketamine peak
within 24 hours (Corriger & Pickering, 2019) and are
virtually undetectable by two weeks; even after
repeated dosing, symptom relapse occurs at high rates
within the first month of treatment cessation (Daly
et al., 2019; Smith-Apeldoorn et al., 2022). The
dextromethorphan-bupropion combination is intended
for daily use, so comparable data is limited. However,
preliminary data suggest that rates of relapse are rel-
atively lower when dextromethorphan-bupropion,
administered twice daily, is switched to placebo in
relapse prevention studies (BioSpace, 2024). It is
worth noting that placebo administered twice daily
may still sustain a significant clinical response, as
these findings seem to indicate.
Other lines of research may help inform this dis-
cussion in time. Preclinical data show that ketamine,
psilocybin, MDMA, LSD and ibogaine – but not
cocaine – reopen critical periods of social reward
learning in mice (Nardou et al., 2023). This type of
learning consists of increased responsiveness to social
influence, demonstrating the potential for ketamine
and related agents to shift behaviors marked by social
impairment or injury (Nardou et al., 2019). These
data also suggest that not all positively experienced
‘highs’ are equal, and that some may be optimized for
use in specific learning contexts. In humans, similar
capacities could help identify drugs that have some
abuse liability but also merit further clinical develop-
ment as interventions within relational,
therapeutically-oriented frameworks (Lepow et al.,
2021). It may even be the case that the greatest utility
of any dissociative intervention has less to do with
the drug itself, and more with how the drug is used.
Dissociatives and dissociation
Historically, dissociatives were first named for charac-
teristic experiences they elicited in dose-dependent
fashion when used, typically involving feelings of
detachment from one’s sense of self or reality (Petersen
et al., 2020). The origins of this convention can be
traced to Antoinette (Toni) Domino, the wife of Dr.
Edward (Ed) Domino, a neuropharmacologist who
pioneered the earliest studies of phencyclidine and
ketamine with The Parke Davis Company in the
1950s and 1960s. As Ed conveyed the dreamlike and
hallucinogenic properties of ketamine to his wife,
experienced by patients as feeling disconnected from
their environments, Toni described this process as
one of ‘dissociation,’ and invented the term ‘dissocia-
tive anesthetic’ to label ketamine and the unusual
actions of this drug class (Denomme, 2018;
Domino, 2010).
The construct of dissociation in psychiatry has a long
and complex history, which has been reviewed in detail
elsewhere (Mathai et al., 2023). Early theorists, such as
Pierre Janet, proposed dissociation as a breakdown of the
unified psychological functioning necessary for health –
reflective of nondrug states and often precipitated by
traumatic or overwhelming experiences in at-risk patients
(Scalabrini et al., 2020; Van der Hart & Horst, 1989).
This perspective is reflected in the Diagnostic and
Statistical Manual of Mental Disorders (DSM), which in
1980 first recognized dissociative disorders (e.g. psycho-
genic amnesia, psychogenic fugue, depersonalization dis-
order and ‘multiple personality disorder,’ which would
later be named dissociative identity disorder) as those
involving ‘sudden, temporary alteration in the normally
integrative functions of consciousness, identity, or motor
behavior’ (American Psychiatric Association, 1980).
This view is also consistent with how ketamine was
researched as a tool for modeling dissociative
4 D. S. MATHAI
symptomatology in the 1990s, prior to recognition of
its antidepressant effects in the early 2000s (Krystal
et al., 1994, 2019). As ketamine was repurposed, the
dissociation it produced was classified as an undesir-
able side effect of antidepressant treatment and
assessed using the same scales that had been designed
with pathology in mind (Mathai et al., 2023). It is
unclear if Toni Domino knew that she would be
invoking all this with a name – and all subsequent
associations of ketamine-induced subjective effects
with psychiatric disorder. Personal communications
suggest that this was not the case, as she and Ed
thought of such effects as ‘beautiful’ and as a ‘high
that (patients) like (Denomme, 2018).’ In any case, a
growing body of evidence points to the need for clar-
ification and improved terminology around the disso-
ciative qualities of ketamine and related compounds
(Marguilho et al., 2023; Mathai et al., 2022, 2023).
Dissociative-type phenomena have also been con-
sidered historically in terms of their non-pathologic,
and even therapeutic value (Bowins, 2012; Dell &
O’Neil, 2010; Hilgard, 1977; Seligman & Kirmayer,
2008). Normative dissociation can be more broadly
defined as qualitative departures from ordinary modes
of experiencing, including processes such as absorp-
tion in daily activities, daydreaming, and fantasy
(Butler, 2006). Such states can involve alterations of
self as an experiential context, and may be reminis-
cent of depersonalization or derealization but with a
positive affective tone (Butler, 2006). Clinical hypnosis
has also been considered by these terms, described by
some to be a ‘form of structured and controlled dis-
sociation’ (Spiegel, 1988), and perhaps more closely
resembling the actions of dissociative therapies.
Dissociation can be further examined from an
anthropological perspective that places focus on the
social meaning and discursive function of dissociation
rather than its mechanism of action. From this van-
tage point, cultural systems (including that of bio-
medicine) can be seen as allowing for dissociative
experiences to create new opportunities for talking
about identity, and facilitating shifts in narrative self
that might empower individuals to overcome per-
ceived constraints (Seligman & Kirmayer, 2008). As
before, whether dissociation functions adaptively or
not depends fundamentally on context and the atti-
tudes surrounding such phenomena. Based on this
cultural approach, dissociative therapies may be espe-
cially dependent on symbolic ritual frameworks that
constrain drug-induced experiences and emphasize
the usefulness of these experiences for moving from
states of illness to health (Kirmayer & Lifshitz, 2018).
Given this multitude of views regarding ‘dissocia-
tion,’ it is recommended that individuals establish a
shared working definition of how this term is being
used in reference to the effects of dissociative thera-
pies within a given context. While dissociative drugs
were originally named for how they were subjectively
(and often positively) experienced by users, such
qualities have not been a major focus for clinical
applications of ketamine, esketamine, or dextrometho-
rphan in modern psychiatry. Drug-induced dissocia-
tion has more commonly been viewed as an adverse
event, akin to the pathological forms of dissociation
that might be seen in response to psychological
trauma. Finally, phenomenological and narrative
frameworks can offer additional insight into how dis-
sociative therapies work and are compatible with
present-day science, including neurocomputational
accounts of how dissociatives, like psychedelic thera-
pies, alter predictive processing and mechanisms of
learning in context-dependent ways (Bottemanne
et al., 2023; Hipólito et al., 2023; Nardou et al., 2023).
With time, we may better learn how these different
levels of understanding converge.
Drug experiences as predictive of outcome
Esketamine and dextromethorphan-bupropion are
FDA-approved for the treatment of depression and
have been shown to produce improvements within
just one week of administration (Khabir et al., 2022;
Salahudeen et al., 2020). Ketamine demonstrates sim-
ilar properties as a rapid-acting antidepressant
(Corriger & Pickering, 2019). On a pharmacological
level, these effects have been attributed to NMDA
receptor antagonism and glutamate-driven changes in
neuroplasticity (Aleksandrova & Phillips, 2021;
Johnston et al., 2023; Vollenweider & Preller, 2020).
Here, it has also been considered how, at a different
level of explanation, the prominent subjective effects
of these drugs may be relevant to their demonstrated
efficacy.
Notably, the drug research programs responsible
for dose optimization of these compounds have largely
viewed such psychoactive effects as undesirable and
attempted to mitigate these. However, this pharmaco-
logical strategy could have the unintentional effect of
reducing therapeutic activity that is similarly mediated
(Morris & Wallach, 2014). Currently, the applications
of ketamine, esketamine, and dextromethorphan-
bupropion in psychiatric settings do not routinely pri-
oritize positive drug experiences, as these treatments
have demonstrated efficacy even without this empha-
sis or accompanying forms of psychological support.
INTERNATIONAL REVIEW OF PSYCHIATRY 5
Another perspective, informed by psychedelic research,
is that the subjective experiences of hallucinogen-based
therapies are central to therapeutic procedures and
outcomes (Yaden & Griffiths, 2021).
There has been limited research to date exploring
the clinical significance of how dissociative therapies
are experienced by patients. The most compelling evi-
dence in this area comes from qualitative studies,
which show that dissociatives produce non-ordinary
states of consciousness that are described as meaning-
ful and therapeutic by research participants (Breeksema
et al., 2023; Krupitsky et al., 2002; Mathai et al., 2023;
Mollaahmetoglu et al., 2021; Sumner et al., 2021; van
Schalkwyk et al., 2018). Some have even theorized
that dissociative therapies fundamentally leverage
attentional processes to alter self-experience (Clingo,
2024). Feelings of ‘happiness’ (Chen et al., 2020) or
‘lightness’ (Stocker et al., 2019) during drug adminis-
tration have also been associated with subsequent
antidepressant benefit, hinting at the value of patients
getting to experience what it is like to not be
depressed, even if transiently. Conceptually, there may
be similarities between these effects for dissociatives
and the way that stimulants rapidly induce mental
states of alertness and are highly effective for the
treatment of attention deficit hyperactivity disorder
(ADHD) (Chapter 2—How Stimulants Affect the
Brain and Behavior, 1999; Pittelkow et al., 2021).
Formal quantitative analyses of the subjective
effects of dissociatives have suffered from a lack of
clarity about which effects to measure and the poor
validity of instruments used to measure such (Mathai
et al., 2022). One conspicuous example is the
Clinician-Administered Dissociative States Scale
(CADSS), which has been used to assess drug-induced
dissociation and has been predictive of antidepressant
benefit in some but not all studies of patients receiv-
ing ketamine derivatives (Ballard & Zarate, 2020;
Mathai et al., 2020, 2023). However, as previously
alluded, the CADSS was developed primarily to cap-
ture pathological and trauma-related forms of dissoci-
ation (Mathai etal., 2023) and not different, potentially
therapeutic forms of drug experience (Butler, 2006;
Seligman & Kirmayer, 2008).
Other experiential scales that have been shown to
be predictive of clinical outcomes with ketamine
include the multi-dimensional Altered State of
Consciousness questionnaires (5D- and 11D-ASC)
(Aust et al., 2019; Sumner et al., 2021) the Hood
Mysticism Scale (HMS) (Dakwar etal., 2018; Rothberg
et al., 2021), and the AWE-scale (Aepfelbacher et al.,
2024). Among these, the disembodiment subscale of
the 5D-ASC questionnaire (marked by the following
items: ‘I felt as if I no longer had a body,’ ‘I had the
impression I was out of my body,’ and ‘I felt as if I
was floating’) strongly correlates with patient-reported
dissociation and phenomena that are thought to be
relatively specific to the effects of dissociatives (Fabus,
2023; Marguilho et al., 2023). However, these scales
overall may be limited by their relative emphasis on
mystical-type effects, which appear to be more char-
acteristic of psychedelic rather than dissociative ther-
apies (Mathai et al., 2023; Studerus et al., 2010).
Ongoing work is needed to merge qualitative and
quantitative research, toward the goal of better char-
acterizing and measuring experiences that are
drug-specific and therapeutically valuable for patients.
Despite the need for further research in this area,
there is evidence that clinicians are already titrating
dissociatives like ketamine to target specific, altered
states of consciousness in patients to achieve efficacy
(Dore et al., 2019; Mathai et al., 2024; McInnes et al.,
2022; O’Brien et al., 2021; Ross et al., 2019). Several
of these studies have shown a concerning trend for
administered doses to increase over time with this
strategy (Mathai et al., 2024; McInnes et al., 2022). It
is not yet clear how much additional benefit (if any)
could come from increasing dose in this manner. It is
also possible that any conceivable benefit of dose
escalation might be offset by proportional increases in
toxicity, including risks that have not yet been char-
acterized. While there is a compelling argument for
prioritizing subjective experiences with dissociatives,
it is also recommended that clinicians exercise cau-
tion in doing so and follow the best available evi-
dence for safe dosing.
Distinguishing the eects of dissociatives and
classic psychedelics
Dissociatives and classic psychedelics have been shown to
elicit similar phenomenological effects. This has been
most clearly demonstrated through score overlap for a
variety of global hallucinogen and subjective rating scales
in human trials comparing the acute effects of dextro-
methorphan to psilocybin (Carbonaro et al., 2018, 2020;
Mathai et al., 2023), esketamine to psilocybin (Schmidt
et al., 2013), ketamine to psilocybin (Studerus et al.,
2010), ketamine to psilocybin and LSD (Schartner et al.,
2017), esketamine to N,N-dimethlytryptamine (DMT)
(Gouzoulis-Mayfrank etal., 2005) and ketamine to DMT
(Bowdle et al., 1998).
Interestingly, in one laboratory study of the effects
of dextromethorphan and midazolam at varying doses,
12 hallucinogen-experienced participants were
unaware of the drug conditions they were assigned to,
6 D. S. MATHAI
and later asked to guess what drug they had received
from 18 different pharmacological classes (Reissig
et al., 2012). Even though all volunteers reported
extensive experience with classic psychedelics (mean
lifetime uses of LSD = 58.2; mean lifetime uses of psi-
locybin = 21), and a majority of this sample reported
previous experiences with dissociatives (mean lifetime
uses of dextromethorphan = 4.8), 92% of individuals
mistakenly identified a high dose (i.e. 400 mg/70 kg)
of dextromethorphan as a classic psychedelic, on aver-
age rating the similarity to a classic psychedelic as
93/100 on a visual analog scale. These findings illus-
trate how these drugs are similarly experienced but
may also reflect the design of this specific trial, as
individuals appear better able to discriminate between
dissociatives and classic psychedelics when both are
administered in the same trial context (Carbonaro
et al., 2018).
Thus, the effects of dissociatives can also be distin-
guished from classic psychedelics despite their analo-
gous qualities (Mathai et al., 2023). Categorically,
dissociatives have been described as possessing a dif-
ferent clinical syndrome of intoxication from the
5-HT2A receptor-dominant effects of classic psychedel-
ics, such that dissociation or impaired reality testing
is more typically evident and visual hallucinations are
less commonly featured (Denomme et al., 2024). This
is evident from comparative data showing that ket-
amine (Studerus etal., 2010) and esketamine (Schmidt
et al., 2013) produce greater disembodiment and
impaired control and cognition relative to psilocybin,
with fewer visual alterations and less elementary
imagery. A linguistic analysis of online ‘trip’ reports
also found that accounts of ketamine experiences
tended to be less emotionally charged than those
reported for psilocybin or LSD, perhaps due to a rel-
ative blunting of affective experience with dissocia-
tives (Hase et al., 2022).
Another notable trial examined the effects of pla-
cebo, dextromethorphan 400 mg/70 kg, and three
doses of psilocybin (10, 20, and 30 mg/70 kg) in 20
hallucinogen-experienced, healthy volunteers using a
double blind, within-subjects, crossover experimental
design. Almost universally and in dose-dependent
fashion, psilocybin was found to have more pro-
nounced effects than dextromethorphan, including
higher ratings of personal meaning, psychological
insight, positive mood, mystical experience, awareness
of beauty, awe/amazement, visual imagery, and user
preference attributed to acute drug administration
(Barrett et al., 2018; Carbonaro et al., 2018, 2020;
Mathai et al., 2023). Compared to psilocybin, dextro-
methorphan was associated with higher ratings of
disembodiment, physical discomfort and impairment
of balance, episodic memory, and executive control.
While volunteers in this study endorsed feeling
substantial changes in their normal experiences of
reality with both dextromethorphan and psilocybin,
50% of participants rated their experiences with dex-
tromethorphan as ‘less real’ than everyday reality
compared to only 11% who felt this way with the
30 mg/70 kg dose of psilocybin (Mathai, 2024).
Conversely, only 19% of participants felt that the
acute effects of dextromethorphan were ‘more real’
than everyday reality, compared to 42% for the same
dose of psilocybin. The remaining participants felt
that drug experiences were both more and less real
than ordinary reality. These data exemplify other spe-
cific differences in drug experiences that could be rel-
evant to subsequent outcomes.
For the volunteers receiving psilocybin, ratings of
drug experiences as personally meaningful, psycholog-
ically insightful, and spiritually significant were asso-
ciated with positive, enduring psychological effects
after one week; however, for dextromethorphan, only
ratings of drug experiences as personally meaningful
were likely to predict enduring positive changes
(Mathai etal., 2023). The study did not further assess
how specific drug experiences may have contributed
to positive changes, or why these effects differed for
psilocybin and dextromethorphan, although these
questions merit further research.
One final, seemingly unique feature of dissociative
drugs is their tendency to produce phenomenologically
distinct ‘plateaus’ of subjective experience at dosing incre-
ments (Antoniou & Juurlink, 2014; Kolp et al., 2014;
Stanciu etal., 2016). In contrast, classic psychedelics pos-
sess more gradual and linear dose-dependent effects
(Barrett et al., 2018; Carbonaro et al., 2018, 2020; Mathai
et al., 2023). William E. White, a researcher of recre-
ational dextromethorphan experiences, has famously
written, ‘DXM [Dextromethorphan], probably more than
most drugs, tends to exert its (recreational) effects in
separate stages or "plateaus", rather than being linearly
dose-dependent. Within a given plateau, a given set of
effects will occur (at a roughly dose-dependent strength).
On the other hand, once the next plateau is reached, the
feeling may change entirely. A reasonable analogy is
water – it exists in three states (solid, liquid, and gas)
which all can exist at varying temperatures (e.g. hot
water and cold water), but which have different charac-
teristics (White, 2002) .’
Taken together, these differences between drug
classes may call for different processes for optimizing
their therapeutic use, particularly when considering
the forms of psychological support that might
INTERNATIONAL REVIEW OF PSYCHIATRY 7
accompany and enhance treatment. As dissociative
therapies induce highly variable states of conscious-
ness at different doses, they may be more clearly
suited for different paradigms for therapeutic enrich-
ment (Mathai et al., 2022). For instance, lower doses
of drug may be appropriate for ‘psycholytic therapy,’
wherein a psychoactive drug is used to facilitate the
therapeutic and relational quality of psychotherapy
that coincides with acute drug effects, and higher
doses would more closely resemble traditional ‘psy-
chedelic therapy,’ with a focus on preparation for and
integration of profound, peak-type experiences
(Garcia-Romeu & Richards, 2018). Other forms of
psychotherapeutic intervention are also possible,
which assign less value to drug experiences and
instead prioritize changes in neuroplasticity that occur
in the days following drug administration (Mathai
et al., 2022).
Based on the findings above, the relatively decreased
affective charge, lower ratings of insight, and greater
impairment in episodic memory attributed to disso-
ciatives may necessitate greater effort on the part of
supporting clinicians to structure adjunctive psycho-
therapies and facilitate therapeutic progress, when
compared to psychedelic-assisted therapies. If experi-
ences of meaning, rather than those of insight or spir-
itual significance, are more likely to be predictive of
enduring psychological changes with dissociatives,
then meaning-oriented therapeutic frameworks may
prove to be especially helpful in working with these
drugs. For example, qualitative research indicates the
value of detachment-related experiences that occur for
patients during esketamine administration and disrupt
depressive thinking, making space for healthier psy-
chological attitudes toward self and others that could
be subsequently explored and cultivated (Breeksema
et al., 2023). When further considering how dissocia-
tives seem to create a ‘less real’ sense of conscious
experience, this drug class may be particularly suited
for psychotherapeutic work that allows for the soften-
ing of illness identities, which may be otherwise held
as fixed and true. Even so, more work is needed to
clarify the ways in which dissociative effects could be
safely harnessed with synergistic psychotherapies.
Learning to prescribe, learning to deprescribe
There is no consensus for what a course of adequate
treatment with dissociative therapies looks like. It is
largely acknowledged that some form of repeated
drug administration is needed to sustain antidepres-
sant benefit for racemic ketamine, but there is limited
evidence to guide clinical decisions around
maintenance dosing, frequency, and long-term safety
(McIntyre et al., 2021). There is relatively more evi-
dence to guide maintenance treatment with esket-
amine, administered approximately weekly to biweekly
after a four-week induction phase (Daly et al., 2019;
Wajs et al., 2020). While the feasibility of long-term
maintenance dosing with esketamine administered
once every four weeks has been examined, this option
appears sufficient for only a minority of patients, with
the majority needing weekly to biweekly dosing in the
years following treatment induction (Zaki etal., 2023).
Other data suggest the need to even increase treat-
ment frequency in some patients over time because of
diminishing benefit (Castro et al., 2023; Nijs et al.,
2020). The dextromethorphan-bupropion combination
is intended for use as a daily, long-term treatment
(McCarthy et al., 2023), and no guidance currently
exists for decreasing treatment frequency or safe med-
ication discontinuation. Apart from the considerable
financial costs associated with sustained, recurrent use
of dissociative therapies as detailed above, the
long-term medical and psychiatric consequences of
such regimens are still being investigated.
There may be lessons to learn from the use of ben-
zodiazepines for psychiatric indications, which have
become largely utilized due to their potential for
rapid, short-term relief of psychiatric distress.
Benzodiazepines were first identified for these clinical
properties in the mid 20th century, were thought to
have lower medical toxicity than existing pharmaco-
therapies, and thus met with great enthusiasm among
patients and medical professionals alike (Wick, 2013).
However, in the decades following, there has been
growing recognition of the limited long-term efficacy
of these medications and their propensity for harm,
to the extent that most clinical practice guidelines
now do not recommend chronic use of benzodiaze-
pines (Horowitz et al., 2021). Even so, benzodiazepine
prescribing has become entrenched in modern medi-
cine, and is even increasing by some reports (Louie
et al., 2023).
As new evidence emerges, there has been growing
acknowledgement of the need to reduce or discon-
tinue medications for which the benefits no longer
outweigh the risks – a process known as ‘deprescrib-
ing’ in psychiatry (Gupta & Cahill, 2016; Harding
et al., 2024). There are numerous resources that cur-
rently exist for deprescribing benzodiazepines (Wang
etal., 2023), and guidance of this type may be needed
for some patients who find themselves on mainte-
nance treatment with dissociative drugs. In the mean-
time, there are still opportunities for increased
vigilance when it comes to prescribing dissociative
8 D. S. MATHAI
medications, marked by close attention to the known
risks of treatment and sensible anticipation of
unknown risks that will emerge with time (Swainson
et al., 2022). Such decision-making also requires care-
ful monitoring of psychiatric functioning and should
preferably involve clinicians with expertise in psycho-
pharmacology and the treatment of mental health
conditions (Mathai et al., 2022).
Finally, if drug-specific factors are responsible for
only a minority of benefit seen with dissociative inter-
ventions (Matsingos et al., 2024), the development of
best practice guidelines in this space will require
closer attention to other variables. Nonspecific treat-
ment factors have been explored for classic psyche-
delic therapies and other pharmacological interventions;
these studies have considered the influence of ele-
ments such as the treatment setting, therapeutic alli-
ance, focus on self-efficacy, expectations of treatment,
and shared meaning of treatment (Hartogsohn, 2017;
Mintz & Flynn, 2012). When psychological therapies
are delivered in conjunction with medication, they
can provide a rich framework for optimizing these
nonspecific aspects of drug treatment. They may also
help reduce medication requirements with dissocia-
tives in ways that are clinically and publicly desirable
(Mathai et al., 2021), and as demonstrated with other
psychiatric medications (Horowitz & Taylor, 2024;
Louie et al., 2023). These areas of optimization may
not attract the same financial resources that are com-
monly directed toward the development of novel psy-
chiatric medications, although they are likely to be
deeply consequential for patients (Mintz &
Flynn, 2012).
Conclusion
Dissociative medications are being increasingly
explored for their psychiatric applications, although
questions remain about their optimal use. The psy-
choactive effects of these drugs are sometimes viewed
as limiting their overall utility, although they might
be better understood as an opportunity for synergiz-
ing treatment-specific and nonspecific factors. When
done effectively, these synergies may allow for more
durable outcomes, compared to more transient forms
of benefit and as seen with harmful patterns of recre-
ational drug use. Ongoing work is needed to clarify
how normative dissociation and a much broader
range of subjective experiences could be relevant to
the benefits of dissociative therapies. This work may
be usefully informed by existing research involving
psychedelic therapies, although the effects of
dissociatives also diverge from classic psychedelics in
clinically relevant ways. Finally, in learning how best
to prescribe dissociatives, it is imperative that we sim-
ilarly learn how best to deprescribe them, as our col-
lective understanding evolves and for cases when the
benefits of these drugs no longer appear to outweigh
the risks of use.
Acknowledgements
Thank you to all the patients and study participants who
have been my teachers. Thank you also to Victoria Mora,
Gianni Glick, Lauren Lepow, Daniel Roberts, Raquel
Bennett, Florian Birkmayer, Garrett Deckel, Joost Breeksema,
and Reed Morrison for conversations that helped develop
the ideas here.
Disclosure statement
David S. Mathai is a paid medical advisor for West Eastern
Health. He has no other relevant commercial or nancial
relationships to disclose.
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