Majic 2015 Pe JOP

568040
research-article2015
JOP0010.1177/0269881114568040Journal of PsychopharmacologyMajić et al.
Review
Peak experiences and the afterglow

phenomenon: When and how do
therapeutic effects of hallucinogens Journal of Psychopharmacology
depend on psychedelic experiences?

1–13
© The Author(s) 2015
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DOI: 10.1177/0269881114568040
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Tomislav Majić1*, Timo T Schmidt2,3* and Jürgen Gallinat1,4
Abstract
Interest in the therapeutic potential of psychedelic substances has recently resumed. During an early phase of human psychedelic research, their
therapeutic application in different pathologies had been suggested, and the first evidence for efficacy was provided. The range of recent clinical
applications of psychedelics spans from cluster headaches and obsessive-compulsive disorder to addiction and the treatment of fear and anxiety in
patients suffering from terminal illness, indicating potentially different therapeutic mechanisms. A variety of approaches in psychotherapy emphasize
subjective experiences, such as so-called peak experiences or afterglow phenomena, as differentially mediating therapeutic action. This review aims
to re-evaluate earlier and recent concepts of how psychedelic substances may exert beneficial effects. After a short outline of neurophenomenological
aspects, we discuss different approaches to how psychedelics are used in psychotherapy. Finally, we summarize evidence for the relationship between
subjective experiences and therapeutic success. While the distinction between pharmacological and psychological action obviously cannot be clear-
cut, they do appear to contribute differently from each other when their effects are compared with regard to pathologies.
Keywords
Hallucinogens, psychedelics, serotonin, psilocybin, ketamine, LSD, substance-assisted psychotherapy, psychedelic therapy, psycholytic therapy,
obsessive-compulsive disorder, substance addiction
Introduction
In the last 15 years, hallucinogenic substances such as psilocybin been inconclusive. Since the discovery of lysergic acid diethyla-
and ketamine have been rediscovered by researchers in neurosci- mide (LSD) in 1943, three main aspects have been of major sci-
ence and psychiatry (Langlitz, 2010). With the rise of modern entific interest.
neuroimaging methods, new hypotheses regarding the mecha- First, the observation that mescaline could induce psychosis-
nism of action of these substances in the central nervous system like states (Beringer, 1927) and mescaline’s structural similarity to
have been suggested (Carhart-Harris et al., 2012; Nichols and norepinephrine led to a paradigm shift regarding the neurobiologi-
Chemel, 2006; Vollenweider and Kometer, 2010). In parallel, the cal underpinnings of schizophrenic symptoms (Osmond, 1957;
therapeutic potential of psychedelics has also been reconsidered Osmond and Hoffer, 1959). The concept of ‘model psychosis’
(Griffiths and Grob, 2010). Thus, in light of the need for new marked a turning point in modern psychopharmacology as it sug-
treatment options for psychiatric disorders, a colorful, but almost gested that states of consciousness are associated with chemical
forgotten, chapter of psychiatric history has been facing a revival processes.
(Barrau-Alonso et al., 2013; Sessa, 2012).
While modern psychopharmacologic drug development pri-
marily targets biological mechanisms, psychedelics have been
assumed to exert their therapeutic actions by facilitating different 1Clinicfor Psychiatry and Psychotherapy, Charité University Medicine,
types of therapeutically useful states of consciousness (Chandler Berlin, Germany
and Hartman, 1960; Savage et al., 1964). In contrast, some recent 2Neurocomputation and Neuroimaging Unit, Freie Universität, Berlin,
approaches have increasingly suggested other therapeutic mech- Germany

3Bernstein Center for Computational Neuroscience, Berlin, Germany
anisms of action, especially when considering ketamine treat-
4Department for Psychiatry and Psychotherapy, University Medical
ment in depression (Aan Het Rot, 2012; Zarate et al., 2006).
The current re-evaluation of clinical usage of psychedelics Center Hamburg-Eppendorf, Hamburg, Germany
includes the treatment of cluster headache (Frood, 2006), obses- *These authors contributed equally
sive-compulsive disorder (OCD) (Moreno et al., 2006), addiction Corresponding author:
(Ross, 2012), depression (Zarate et al., 2006) and anxiety in ter- Tomislav Majić, Hospital St. Hedwig, Charité University Medicine
minally ill patients (Grob et al., 2011). However, the hypotheses Berlin, Große Hamburger Str. 5-11, 10115 Berlin, Germany.
on how psychedelics might exert their therapeutic potential have Email: [email protected]
Downloaded from jop.sagepub.com at Bobst Library, New York University on February 12, 2015
2 Journal of Psychopharmacology
Secondly, psychedelic substances such as LSD-25 induce pow- assessment of qualitative experiences, additional difficulty is cre-
erful subjective experiences and altered states of consciousness ated by the fact that these experiences often go beyond the previ-
(ASCs) perceived as the ability to ‘expand consciousness’ (Watts, ously experienced epistemic range. It is not surprising that highly
1968). This triggered their use outside the scientific environment metaphoric terminology was suggested to approximate new quali-
as tools for spiritual practice, so-called self-actualization or ties of experience for which other verbal labels appear inappropri-
enhanced creativity (Harman et al., 1966; Krippner, 1964;). ate. A further limitation is that ‘online’ (while experiencing drug
Thirdly, drug-facilitated states of ‘expanded consciousness’ effects) evaluation suffers from acute drug effects, such as prob-
were found to lead to persisting changes in the perception of one- lems in verbalization or attentional and motivational fluctuations.
self, others and the environment (Savage et al., 1966). This Additionally, purposeful introspection may interfere with the
observation was one of the initial rationales for employing hal- experience as such; thus, the assessment is usually done retrospec-
lucinogens in the treatment of mental disorders in the 1950s (for tively. Appropriate operationalizations and means of quantifica-
a comprehensive bibliography, see Passie, 1997). tion form the basis for developing therapeutic approaches where
During the first period of psychedelic research, altered or non- therapeutically desirable experiences are fostered while alleviat-
ordinary states of consciousness, referred to as psychedelic experi- ing others. Finally, it has to be acknowledged that the drug-facili-
ences, were considered to be the key mechanism and the sine qua tated subjective experiences limit the validity of double-blind,
non for proclaimed therapeutic effects, often with an exclusive placebo-controlled studies as designed for drugs without obvious
emphasis on psychological aspects (Grinspoon and Bakalar, 1979, psychotropic properties (Oram, 2012).
1981; Grof, 1979; Harman et al., 1966; Savage et al., 1963, 1966; Currently, the use of questionnaires or structured interviews
Sherwood et al., 1962). In the mid-1970s, clinical psychedelic remains the method of choice to quantify between- and within-
research came to a standstill due to regulatory restrictions. After a subject differences in ASCs. Agreement on common standard
hiatus of more than 20 years, interest has re-emerged, but under dif- assessment tools is desirable, as it enables the pooling of data for
ferent conditions: methodological quality standards have improved joint analysis and fosters comparability. This is crucial, as upon
and neurobiological methods, above all, neuroimaging, have gained the administration of the same drug, psychedelic experiences
increasing importance in psychiatric research (Gallinat et al., 2012; may be markedly different when subjects undergo a positron
Hermle et al., 1992; Juckel et al., 2007; Langlitz, 2010; Vollenweider, emission tomography (PET) scan compared to a therapeutic ses-
2001). In parallel, the interest of the neurosciences in subjective sion in a comfortable atmosphere (Studerus et al., 2012).
experience was fostered, reflected in the concept of ‘neurophenom- In the 1970s, Dittrich (1985) initially designed a questionnaire
enology’ (Cardeña et al., 2012; Lloyd, 2002). for ‘Abnormal Mental States’ (in German: Abnormer psychischer
This review focuses on current clinical psychedelic research, re- Zustand (APZ)) with 158 dichotomous items and tested 11 differ-
evaluating former and recent concepts of how psychedelic sub- ent induction methods, including hallucinogens (see also Studerus
stances may exert their therapeutic effects. We focus on the classical et al., 2010). Dittrich identified three oblique primary etiology-
hallucinogens, which have been traditionally used in psychedelic- independent dimensions: ‘oceanic boundlessness’, ‘dread of ego
assisted psychotherapy, and include a special reference to keta- dissolution’ and ‘visionary restructuralization’. Meanwhile, sev-
mine. We will not discuss 3,4-methylenedioxy-methamphetamine eral refinements of Dittrich’s questionnaire were introduced,
(MDMA) here as it is not considered to be a hallucinogen in the resulting in the Altered States of Consciousness Rating Scale (5D-
narrow sense, but rather an entactogen (Nichols, 1986) or empatho- ASC), which constitutes the most frequently used questionnaire
gen (Nichols, 2004). It is of note that ibogaine has been investigated and the current gold standard (Studerus et al., 2010). As well as
in the treatment of substance addiction (Alper et al., 1999; for a the 5D-ASC, which is primarily used in Germany and Switzerland,
review, see Mash et al., 1998), but it will not be discussed here since other scales such as the Hallucinogen Rating Scale (Strassman
its complex biological mechanisms of action involve a number of et al., 1994) and the Phenomenology of Consciousness Inventory
additional pathways, making it more difficult to localize the role of (Pekala et al., 1986) are also commonly used.
psychedelic experiences in their potential anti-addictive effects.
After a short outline of methodological and neurophenomenologi-
cal aspects, we discuss different therapeutic approaches and relate Types of psychedelic experiences
them to the question of how subjective experiences contribute to the Different classification schemata have been developed in order to
therapeutic outcome. depict states of consciousness, including pathological states (for
a review, see Passie, 2007). A basic distinction of psychedelic
experiences has been suggested, to classify psychotic, psychody-
Neurophenomenology of psychedelic namic, cognitive, aesthetic and psychedelic peak/mystical
states aspects (Pahnke, 1967). In his famous ‘Good Friday Experiment’,
Pahnke (1966) administered a high dose of psilocybin (or nico-
Variable terminology has been used in the description of psyche- tinic acid as an active control) to a group of divinity students
delic experiences. Referring to phenomenological considera- before they attended a religious service. The experiment took
tions, we will discuss the temporal profiles of drug-facilitated place in a small basement chapel to which the service in the main
ASCs as they pertain to the therapeutic applications. We refer to sanctuary was transmitted. A high rate of profound mystical
conceptualizations of ASCs and finally suggest a basic operation- experiences was found in the psilocybin group when compared
alization for depicting peak or mystical type experiences in future with the control group. Consequently, the idea evolved that hal-
research. lucinogens may induce psycho-spiritual experiences with an
The study of drug-facilitated states and their subjective experi- impact on the profound belief and disbelief systems. Via this
ence is challenging. Besides general epistemic limitations on the impact, the drug leads to therapeutic or transformative effects
Majić et al. 3
Figure 1. Time course of subjective experiences induced by psychedelics.

Psychotropic effects of psychedelic substances unfold over a timescale of several hours, which is dependent on the drug and dosage. Most therapeutic approaches make
use of this window for psychotherapeutic interventions. On some occasions, subjective experiences include the so-called ‘peak experience’ (indicated by the dashed line),
which is characterized by intense states, including mystical experiences. A persisting feeling of elevated and energetic mood is termed ‘afterglow’ and may persist for
several days or even weeks. Long-term residual effects include therapeutically valuable changes of mindset as well as changes in personality traits, which have been often
reported.
(Pahnke, 1969a; Sherwood et al., 1962) wherein the temporal one subject who had sustained an acute psychotic episode during
mechanism of the drugs action contributes differently (Figure 1). the study and had difficulty integrating the experience even years
Grof’s classification largely overlapped with Pahnke’s; how- after the experiment had taken place. Several years later, a similar
ever, Grof additionally introduced the concept of ‘perinatal experiment was carried out by Griffiths et al. (2006) using a
matrices’ emphasizing the occurrence of perinatal or birth phe- sophisticated design. In this study, different doses of psilocybin
nomena in psychedelic sessions (Grof, 1979). Upon comparing or methylphenidate (as active control) were administered to 30
and integrating their nomenclature one finds that Pahnke and healthy subjects. The authors reported that in the psilocybin
Grof agree on a description of a highly intense component of the group complete mystical experiences, as measured by the
experience which only occurs on occasion. Pahnke referred to Pahnke-Richards Mystical Experience Questionnaire, occurred
this as the psychedelic peak experience. He described nine char- in 58% of the subjects (Griffiths et al., 2006). In a 14-month fol-
acteristics that psychedelic peak experiences share with non- low-up these were considered by more than 50% of subjects to be
drug-related mystical experiences (Pahnke, 1966, 1969a): (1) a one of the most personally meaningful and spiritually significant
sense of unity; (2) the transcendence of time and space; (3) a experiences of their lives, and had increased well-being or life
deeply felt positive mood; (4) a sense of sacredness; (5) the satisfaction in 64% of the subjects (Griffiths et al., 2008).
noetic quality; (6) paradoxicality; (7) alleged ineffability; (8) Furthermore, enduring increases in the personality domain of
transiency; and (9) persisting positive changes in different openness were observed among those subjects who had a com-
domains, including attitudes and behavior towards the self, oth- plete mystical experience (MacLean et al., 2011). Together these
ers, life and the experience itself. results suggest that beneficial effects of the experience had out-
After the acute effects of the drug have subsided, a psyche- lasted the afterglow phenomena.
delic afterglow has been described by several authors (Albaugh To depict psychedelic peak experiences in future research, we
and Anderson, 1974; Krupitsky and Grinenko, 1997; Metzner, propose a focus on the mystical aspect of the experience as
1998; Pahnke, 1969a; Pahnke et al., 1970a; Sherwood et al., reflected by scores on the 5D-ASC. On introducing the APZ
1962). Pahnke described this as a state of ‘elevated and energetic questionnaire, Dittrich referred to the epistemological debate that
mood with a relative freedom from concerns of the past and from one cannot ultimately clarify whether drug-facilitated ASCs are
guilt and anxiety’, furthermore, he notes that the willingness ‘to ‘real’ mystical experiences; he therefore proposed ‘Oceanic
enter into close interpersonal relationships is enhanced’ (Pahnke, Boundlessness’ (OBN) as the label for one subscale. As OBN
1969a). During the afterglow period, the effectiveness of psycho- includes changes in the sense of time, depersonalization as well
therapeutic interventions is reported to be enhanced until the as derealization and a positive basic mood (Dittrich, 1985), this
afterglow gradually subsides after a period of between two weeks subscale’s items partly overlap with items 1–3 of the psychedelic
and a month (Albaugh and Anderson, 1974; Pahnke, 1969a). peak/mystical experience as categorized by Pahnke (1966, 1967):
Interestingly, within some ritual uses of hallucinogens such as a sense of unity, the transcendence of space and time, and a
those of the União do Vegetal, religious services are separated by deeply felt positive mood. After further refinement of the
intervals of two weeks, which is often the reported duration of the 5D-ASC questionnaire, one of 11 factors is now termed ‘spiritual
afterglow phenomenon (Grob et al., 1996). experiences’ and a corresponding high cut-off score could be uti-
Whether the changes in attitude and behavior following psy- lized as an operationalization for depicting a mystical experience
chedelic experiences are limited to the timeframe of the after- (Studerus et al., 2010).
glow or result in longer-lasting effects has been controversial
(Grof, 1979; Pahnke et al., 1970a). A long-term follow-up report
from the 1990s, interviewing subjects who had participated in
Neural substrates of psychedelic experiences
Pahnke’s Good Friday Experiment, came to the conclusion that On the molecular level, the description of action of psychedelic
no persisting dysfunction and even some beneficial effects could substances has greatly progressed (for a review, see Nichols,
be observed after more than 25 years (Doblin, 1991), except for 2004). In contrast, how substances alter neuronal networks or
system behavior has not been completely understood. However, views on network interactions that might ultimately enable the
the rise of neuroimaging techniques (e.g. functional magnetic tracking of causative mechanisms in consciousness research.
resonance imaging (fMRI) electroencephalography (EEG) or The question of whether spiritual experiences facilitated by
magnetoencephalography (MEG)) has contributed new insights psychedelics are identical to those that occur spontaneously is
into the neural underpinnings of qualitative conscious experi- quite controversial, yet they have repeatedly been suggested as
ences, including mystical-type experiences. a model for religious experience (Dittrich, 1985; Griffiths
Evidence has converged that the ‘core psychedelic effects’ are et al., 2011; Maslow, 1964; Masters and Houston, 1966;
transmitted via an action on 5HT-2A receptors, while substances Nichols and Chemel, 2006; Pahnke, 1969a; Watts, 1968).
interact with multiple receptor types (Aghajanian and Marek, Nevertheless, on the level of biological research, it is difficult
1999a; Geyer and Vollenweider, 2008; Halberstadt and Geyer, to compare findings from non-drug-related mystical states to
2011; Nichols, 2004; Nichols and Chemel, 2006; Passie et al., psychedelic-facilitated states due to various confounders such
2002, 2008). This is best demonstrated by two studies in which as trait and state and pharmacological side effects, among oth-
administration of psilocybin was preceded by ketanserin, a 5HT- ers. The authors of the present review do not know of any study
2A receptor blocker, and drug effects were diminished (Kometer that specifically investigated the neural basis of peak experi-
et al., 2013; Vollenweider et al., 1998). As 5HT-2A receptors are ences. This might be for several reasons: (1) spiritual experi-
expressed on pyramidal neurons as well as on GABAergic ences have been reported to occur only sometimes, and in a
interneurons, it is challenging to distinguish which cell population subset of subjects (Grof, 1979; Nichols, 2004); (2) when con-
contributes more (Lee and Roth, 2012). A recent psilocybin study sidered as setting variables, PET, EEG, fMRI or other experi-
used dynamic causal modelling to link cell populations with mental settings may decrease the probability of experiencing
whole-brain MEG recordings and indicated that the modulation of spiritual states (Studerus et al., 2012); and (3) as mentioned
pyramidal cells best explained the given data (Muthukumaraswamy above, spiritual states are highly subjective and individual
et al., 2013). experiences (MacLean et al. 2012). Using OBN as an indicator
Despite the pivotal role of serotonergic receptors, interactions for spiritual experiences, a PET study suggested a correlation
with other transmitter systems (e.g. dopamine or norepinephrine) with changes in a fronto-limbic-striato-parietal network,
may contribute to differences in a substance’s action (Halberstadt whereas ‘Dreadful Ego Dissolution’ (DED) was associated
and Geyer, 2011; Marona-Lewicka et al., 2005; Nichols, 2004; with thalamic hyperactivity and a decrease of orbitofrontal
Passie et al., 2008). Characterization of the psychedelic effects of activity (Vollenweider, 2001, 2008).
ketamine (an N-methyl-D-aspartate (NMDA) receptor antago-
nist) points towards a shared glutamatergic pathway for seroton-
ergic psychedelics and ketamine (Aghajanian and Marek, 1999b, Concepts of hallucinogen-assisted therapy
2000; Anand et al., 2000; Deakin et al., 2008; Vollenweider and
Kometer, 2010, Vollenweider et al., 1997a, 1997b). The precise
mechanisms of interaction between the transmitter systems Psychedelic healing in the context of
remain a focus for future research.
religious rituals
The recent shift in human neuroimaging from mere activation
studies towards network analyses is also reflected in psychedelic The medical use of hallucinogenic plants has been reported for
studies. Carhart-Harris et al. (2012, 2013) investigated connec- different indigenous cultures, for example, Amazonian shamans
tivity changes of major brain networks during psychedelic-facil- (Andritzky, 1989; Naranjo, 1979) and Southern Mexican indige-
itated states. They observed distinct decreases of activity in nous people (Bruhn et al., 2002). Plant-derived serotonergic hal-
anterior and posterior cingulate cortices that related to a decreased lucinogens such as psilocybin, N,N-dimethyltryptamine (DMT)
coupling between medial prefrontal cortex and the posterior cin- and mescaline have been used safely in ritual contexts, probably
gulate cortex. A general disturbance of normal network interac- for thousands of years, and this fact has been used as an argument
tion was also indicated in an MEG study (Muthukumaraswamy for the harmlessness and safety of these substances when used in
et al., 2013). a specific setting (Bouso et al., 2012; dos Santos, 2013; Grob
The conceptualization of the Bayesian brain hypothesis’, such et al., 1996; Halpern et al., 2005, 2008). The use of mescaline-
as the predictive coding framework (Friston, 2005), has gained containing peyote cacti in the Native American Church is a cur-
prominence in neuroimaging, including in relation to psychosis rent example of such a practice (Halpern et al., 2005). In highly
and drug-facilitated ASCs. In short, it is assumed that the brain ritualized settings, peyote has been reported to increase the open-
constantly generates an implicit future model to predict sensory ness of the individual to cultural messages by enhancing suggest-
inputs. Whenever sensory input contradicts the model’s predic- ibility and inducing a state of enhanced perception of spiritual
tions, a prediction error is generated that is important to update the and self-reflective issues (Calabrese, 1997). Via this mechanism,
model for learning and for filtering sensory information. The hier- psychopharmacology and psychotherapy have been suggested to
archical ordering of the neocortex is assumed to reflect these func- become partners in a ‘tandem strategy’ (Calabrese, 2007) in
tions anatomically by means of microscopic and macroscopic which both rely highly on the other. Analogously, in the
connectivity principles (Bastos et al., 2012). Corlett et al. (2007) Amazonian basin, plant-derived concoctions containing DMT
formulated causal hypotheses for drug-facilitated states when (ayahuasca, hoasca or yage) are ingested in religious healing cer-
NMDA- and AMPA-mediated signaling is manipulated. emonies within the framework of shamanic medicine (Grob
Experimentally, mismatch paradigms were tested in combination et al., 1996; Naranjo, 1979).
with psilocybin and ketamine (Umbricht et al., 2003, Schmidt et Furthermore, syncretic churches from Brazil, such as Santo
al., 2012, Schmidt et al. 2013). Such studies contribute mechanistic Daime and the União do Vegetal, use ayahuasca in regular religious
Majić et al. 5
Table 1. Comparison of psycholytic and psychedelic therapy in terms of dosage, psychological effects, mechanism of action, number of sessions,
setting, integration to reality, goal and indications. Adapted from Leuner (1967).
Psycholytic therapy (PLT) Psychedelic therapy (PDT)
Dosage Low doses (30–200 μg LSD equivalent) High doses (200–1500 μg LSD equivalent)
Psychological effects Symbolic images, regression, transference phenomena Cosmic-mystic experiences, experiences of oneness and
ecstatic joy
Mechanism of action Activation and deepening of the psychoanalytic process No foundation in classical psychological theories. Paral-
lels to religio-psychological experiences
Number of sessions Numerous sessions The aim is to create one single ‘overwhelming’ experience
Setting Analytic discussion of material experienced in individual Extremely suggestive preparation and use of specific
and group sessions surroundings and music. No detailed discussion of the
experience
Integration into reality Reality comparison, attempt to adapt experience to Adaptation to reality not desired, but rather the fixation
everyday life of the psychedelic experience
Indications Classical indications for psychotherapy: neuroses, Alcoholism and drug addiction, anxiety and depression
psychosomatic cases; in addition, cases of psychopathy, in terminal phases of somatic illness
sexual perversion, borderline cases. Not alcoholism or
psychosis
services (Grob et al., 1996). Initial reports indicated beneficial psychotherapy, the indications of PLT were in the field of neu-
effects, however, placebo-controlled studies are lacking (Halpern rotic disorders as well as personality disorders or psychosomatic
et al., 2008; Santos et al., 2007). Moreover, when comparing the diseases (Gasser, 1995; Grinspoon and Bakalar, 1979).
use of hallucinogenic substances in indigenous rituals with use in The term psychedelic, meaning ‘mind-manifesting’, was
modern psychotherapeutic settings, it is crucial to bear in mind the introduced by Osmond (Dyck, 2008). The PLT approach was
distinct concepts of mind and illness in these cultures (Metzner, grounded in the European psychoanalytic tradition, whereas PDT
1998). In contrast to the psychedelic treatment concepts in psychia- has been practiced mostly by North American therapists and sci-
try, religious services involving hallucinogens are performed regu- entists (Dyck, 2008). The most extensively studied indications
larly, weekly or monthly (Calabrese, 1997; 2007; Halpern et al., for PDT include alcohol and drug addiction and anxiety in termi-
2005), possibly providing a state of constant afterglow. nally ill cancer patients. In PDT, high to very high doses (ranging
from 250–450 μg LSD equivalent or sometimes even higher,
Modern forms of psychedelic-assisted depending on indication, set and setting variables) were adminis-
tered to the patient in order to induce a psychedelic peak experi-
psychotherapy ence in an environment of permissiveness, friendliness and
Among the different historic concepts of psychedelic-assisted psychological safety (Blewett and Chwelos, 1959; Savage et al.,
psychotherapy, psycholytic therapy (PLT) and psychedelic (peak) 1964). Originally, the drug session was embedded within a stand-
therapy (PDT) have been most intensively practiced and studied ardized procedure that included three inter-correlated phases
(Grinspoon and Bakalar, 1979; Passie, 1997) (Table 1). (Blewett and Chwelos, 1959; MacLean et al., 1961; Sherwood
The term psycholytic, meaning ‘soul-dissolving’, or ‘mind- et al., 1962): (1) preparation; (2) the drug session; and (3) work
loosening’, was first introduced by RA Sandison. In PLT, sero- on integrating the experience. First, several interviews were car-
tonergic hallucinogens were used in low doses of 50–200 μg LSD ried out to establish a stable relationship of mutual regard and
equivalent in repeated sessions over a period of months to several trust between therapist and patient and to learn about the patient’s
years, embedded within a form of psychodynamic psychotherapy specific problems (Pahnke et al., 1970a). Special consideration
(Gasser, 1995; Leuner, 1967; Sandison, 1963). The psychedelics was given to aspects of the personality structure that may have
were used to facilitate and intensify psychodynamic psychother- emerged as barriers for a fruitful psychedelic experience
apy, with markedtly more drug-free sessions than substance- (MacLean et al., 1961). Symptoms of the underlying problems of
assisted sessions (Chandler and Hartman, 1960). In this method, the patient were regularly, but only very gently, addressed, as
the psychedelic effects were used in order to facilitate the loosen- therapeutic interventions were of second priority to the establish-
ing of defensive mechanisms, the revival and abreaction of child- ment of a solid relationship (Savage and McCabe, 1973) and to
hood experiences, the release of associated emotions and a open the possibility for a ‘significant encounter’ (Kurland et al.,
deepening of introspective insight, all of which was mediated by 1967). The drug session itself was guided by at least two thera-
the interpretation of unconscious material by the therapists pists, preferentially of both genders, who were present through-
(Eisner and Cohen, 1958; Leuner, 1963, 1981; Sandison, 1959), out the session (Blewett and Chwelos, 1959; MacLean et al.,
which would have been ‘worked through’ in a psychoanalytic 1961). A harmonious, careful, tasteful and quiet atmosphere was
manner (Sandison, 1963). Another aim of using hallucinogens in created in which the patients received ‘a heavy dose of tender,
PLT was the enhancement of the relationship between patients loving care’ (Kurland et al., 1967). Patients listened to carefully
and therapists (Eisner and Cohen, 1958), including the intensifi- selected music via headphones and wore eyeshades to facilitate
cation of transference and counter-transference phenomena release into the unfolding inner experience and intense emotional
(Abramson, 1956). Analogous to psychoanalytically oriented processes (Bonny and Pahnke, 1972). The third phase focused on
the integration of the experience and consisted of a series of treated individuals the experiences under psychedelic drugs were
drug-free interviews of variable frequency, mostly not exceeding not purely negative. This led to a different approach, in which
a few weeks (Savage and McCabe, 1973). ‘thought-provoking’ instead of frightening experiences were con-
In addition to the effects observed when using lower-dosage sidered as a means of therapeutic action (Smith, 1958).
techniques, the psychedelic peak experience has been described Traditionally, a high-dose approach with the induction of
as so ‘unique, profound, overwhelming, otherworldly and impres- mystic experience has been related to the treatment of addiction
sive’ (Sherwood et al., 1962) that it was believed to be able to (Grof et al., 1973b; Kurland et al., 1967; Ludwig et al., 1969;
change a person’s underlying system of beliefs and disbeliefs, to Pahnke et al., 1970a). It has been suggested that dysfunctional
transform his view on the self, the others and the environment. It self-concepts are made visible through the psychedelic peak
has therefore been compared to religious conversion (Pahnke, experience. The notion that one is ‘infinite in essence’, leading to
1967, 1969a, 1969b; Pritchard, 1974). Even more importantly, the a conversion-like state of self-acceptance and self-surrender, has
administration of the substances was restricted to one or only a transcended, which is in line with therapeutic approaches involv-
few times, and usually terminated when a ‘peak experience’ had ing spiritual or religious elements such as Alcoholics Anonymous
been successfully induced. (Blewett and Chwelos, 1959). Some authors reported that patients
Therefore, besides dosages and frequencies of psychedelic- with a peak experience (‘peakers’) displayed a better clinical out-
assisted sessions, the most prominent difference between the two come; however, these findings are inconclusive (Grof et al.,
concepts lies in the significance given to peak experiences, which 1973b; Kurland et al., 1967; Pahnke et al., 1970a; Richards et al.,
are considered as key mechanisms of action in PDT but as much 1977). It has also been suggested that only positive reactions to
less important and sometimes even as side effects without any LSD are of therapeutic value, whereas contrary reactions such as
therapeutic significance in PLT (Leuner, 1967). However, despite sensory distortions and negative reactions like panic and fear
several obvious differences between PLT and PDT, there are were assumed to be irrelevant. Psychotic reactions may have
many overlaps and shared positions. Integrative approaches have explicit anti-therapeutic consequences (Pahnke et al., 1970a). On
been suggested by different authors (Grof, 1979; Halpern, 2007; the other hand, painful psychodynamic reactions have also been
Strassman, 1995), and recent studies investigating the therapeutic considered integral and fruitful elements by the majority of
use of hallucinogens have mostly left behind the distinction authors when embedded within a therapeutic procedure of prepa-
between these two classical concepts (e.g. Grob et al., 2011; ration and integration of the experience. In interviews with 121
Moreno et al., 2006). In addition, the concept of ‘psychodelytic patients who had undergone PLT with LSD, several had fearful or
therapy’, introduced by Arendsen-Hein, Grof and others, com- other negative experiences, but only one considered these experi-
bined aspects of PDT and PLT, including a series of low-dose ences negative for their own therapeutic outcome (Gasser, 2008).
psycholytic sessions followed by one or more high-dose psyche- It has been repeatedly emphasized that the majority of the
delic sessions with differentially arranged settings (Grof, 1969). studies conducted before the 1970s were methodically weak and
therefore do not allow conclusions regarding therapeutic efficacy
to be drawn (Abbuzahab and Anderson, 1971; Mangini, 1998;
History and present psychiatric research with Ross, 2012). However, a recent meta-analysis (Krebs and
psychedelics Johansen, 2012) identified six randomized controlled trials (from
1966–1970) evaluating the effects of a single dose of LSD on
In the following section we review current research regarding alcohol abuse with an overall sample of 536 participants.
possible indications for the therapeutic use of psychedelic sub- Beneficial effects of LSD treatment were reported at the first
stances. Reference is given to the most investigated disorders: follow-up assessment, which ranged from 4 weeks to 12 months
substance-related addiction, treatment of depression and anxiety after treatment. All of the included studies employed dosages
in patients suffering from terminal somatic illness, major depres- between 450 and 800 μg LSD, which is considered to be a high
sion, OCD and cluster headache. or even very high dose, with sample sizes ranging from 10–132.
The authors reported that the effect size of a single dose of LSD
in a therapeutic setting was comparable to the effect of naltrex-
Treatment of substance addiction
one, acamprosate or disulfiram applied daily over the same
Alcoholism and other substance-related addictions have been period of time. However, the authors emphasized that in those
among the first and most extensively studied indications for studies that showed an effect in the treatment group, therapeutic
treatment with psychedelic agents from the 1950s to the early preparation and follow-up had been carried out, whereas in the
1970s (Grof et al., 1973b; Hoffer and Osmond, 1968; Kurland groups that showed no beneficial effects the presence of a thera-
et al., 1967; Ludwig et al., 1969; Osmond, 1969; Pahnke et al., pist was minimal. For instance, in two of the studies, participants
1970a; Savage, 1962; Savage and McCabe, 1973; Smith, 1958; had been left alone during a long period of the LSD effect.
for a review, see Mangini, 1998). The concept of using psyche- It was alternatively hypothesized that serotonergic psyche-
delics in this context originally arose from the observation that delics act via experience-independent mechanisms. It has been
LSD-facilitated states of consciousness somewhat resembled suggested that serotonergic hallucinogens exert anti-addictive
delirium tremens in alcohol withdrawal syndrome (Ditman and effects by normalizing functional connectivity in the prefrontal-
Whittlesey, 1959). Due to the highly aversive nature of the expe- limbic network through glutamate-dependent neuroplastic adap-
rience, some alcohol addicts had quit drinking after experiencing tation, as serotonergic hallucinogens increase extracellular
a first episode of delirium tremens. Thus, the initial psychedelic glutamate levels in these areas (Ross, 2012).
treatment concept in alcoholism was to induce such a highly Finally, ketamine psychedelic psychotherapy (KPT) has been
aversive but spontaneously reversible and controllable state investigated for the treatment of alcoholism and heroin addiction
(Hoffer, 1967; Osmond, 1969). Surprisingly, in many of the since the 1980s (Krupitsky and Grinenko, 1997; Krupitsky et al.,
Majić et al. 7
2002, 2007). This approach initially combined the induction of were proposed to be therapeutically crucial: (1) a reduction of the
peak experiences and afterglows with aversive elements during anticipative cognition of death and enhancement of immediate
the drug session (Krupitsky and Grinenko, 1997); however, these sensory life; and (2) the loosening of ego boundaries, which
elements were dropped in subsequent KPT studies. A standard- offers a possibility to escape from the inevitability of the antici-
ized procedure for a single session, or repeated sessions, uses pated context (Kast, 1967).
ketamine at a sub-anesthetic (= psychotomimetic) dose embedded From 1965 until the 1970s several studies on the use of LSD
within up to 15 sessions of drug-free, ‘existentially oriented’ psy- and dipropyltryptamine (DPT) for the treatment of depression
chotherapy as preparation and follow-up (Krupitsky and Grinenko, and anxiety in terminally ill cancer patients were carried out at
1997; Krupitsky et al., 2002). In a double-blind, randomized, Spring Grove Hospital in Maryland (for a summary, see Grof and
active placebo-controlled sample of 70 heroin addicts, psyche- Halifax, 1977). In contrast to the previously discussed studies by
delic experiences occurred only in the high-dose ketamine group, Kast and colleagues, more consideration was given to set and
followed by significantly higher rates of abstinence during the setting and the patients’ potential reactions to the substance. Also,
subsequent 23 months after treatment (Krupitsky et al., 2002). follow-up psychotherapy sessions were carried out and the set-
Compared to the control group, which received non-psychedelic ting of the psychedelic sessions was carefully arranged (Pahnke,
ketamine doses, longer-lasting reductions in drug craving and 1967). In an initial study, the authors found that one-third of the
improvement of the anhedonia syndrome were reported (Krupitsky patients improved dramatically in regard to fear, anxiety, worry,
et al., 2002). Patients from the high-dose group also showed depression, pain and, most importantly, fear of death, one-third
improvement in nonverbal unconscious emotional attitudes and improved moderately, and one-third did not improve (Pahnke,
appeared to be more self-confident and emotionally open. In line 1969a). The effect of psychedelics on the fear of death was
with traditional psychedelic therapy of addiction, the authors reported to be most dramatic if a psychedelic mystical experience
hypothesized that psycho-spiritual experiences had led to positive had occurred. The author reported that through this experience
changes in the patients’ attitude towards the meaning of life, life the patients had gained some sense of transcendence and security,
purposes and spiritual development (Krupitsky et al., 2007). which had diminished their fear of death and deepened their pre-
Furthermore, it has also been suggested that ketamine shares its existing interpersonal relationships and thereby enhanced the
antagonistic properties on NMDA neurotransmission with non- quality of life of the patients and their families. However, it was
psychedelic drugs that also exhibit anti-addictive properties, such emphasized that these therapeutic effects depended strongly on
as acamprosate, lamotrigine and topiramate, leading to the con- set, setting, and preparatory and follow-up sessions that allowed
clusion that more than psychological effects may at least partly the integration of the experience. Similar observations regarding
contribute to the anti-addictive effects (Ross, 2008). the relationship between the ‘peak experience variable’ and ther-
In conclusion, the data pertaining to the efficacy of psyche- apeutic effects have been reported in later studies using LSD and
delic-assisted therapy for the treatment of substance-related dis- DPT (Grof and Halifax, 1977; Grof et al., 1973a; Pahnke, 1969b;
orders are conflicting and recent research has been scarce; Richards et al., 1977). Grof emphasized mystical aspects linked
however, some current approaches are encouraging for future to the experience of (ego-) death and rebirth to be of a crucial
research. Regarding the mechanisms of action, the traditional therapeutic value for the terminally ill cancer patient (Grof, 1979;
view of hallucinogens exerting their putative anti-addictive Grof and Halifax, 1977).
effects primarily via psycho-spiritual conversions has been con- A recent study investigated psilocybin in a sample of 12
tested, however, this hypothesis still holds strong arguments. patients with advanced-stage cancer and reactive anxiety using a
within-subject, double-blind, placebo-controlled design (Grob
et al., 2011). The treatment model and setting were similar to
Terminally ill cancer patients those employed by the Spring Grove clinic in the 1960s and
The treatment of anxiety and depression in cancer patients in pre- 1970s. A low to moderate dosage of psilocybin was given only
terminal states of illness has been among those indications with once. While no direct influence on pain was found, it was reported
the most promising benefits from a treatment with serotonergic that anxiety was reduced at 1 and 3 months after treatment and
hallucinogens (Grob et al., 2011; Grof and Halifax, 1977; Grof that mood was improved even 6 months after treatment. In addi-
et al., 1973a; Kast, 1966, 1967; Pahnke, 1969a, 1970b; Richards, tion, the authors reported that the patients had gained insights
1978; Richards et al., 1979). The idea to treat patients with LSD into how their illness had changed their lives, social relationships
originated from attempts to reduce cancer-related pain (Kast and and feelings of security. The psilocybin experience had induced
Collins, 1964). Promising analgesic effects were found for LSD, feelings of strong empathic rapport and strengthened relation-
which outlasted the acute psychedelic state and the analgesic ships with close relatives and friends. The authors suggested that
effects of opioids (Kast, 1966; Kast and Collins, 1964). the experience, via the treatment, of an ‘ego-free state’ and of
Surprisingly, although these studies had focused primarily on transcendence of physical existence had led to a loss of fear of
analgesia, and psychotherapeutic preparation or follow-up had death. In line with previous reports, this study suggests that psilo-
not been conducted, they reported patients having gained pro- cybin facilitates therapeutic bonds and diminishes feelings of
found insight and a changed attitude towards the self and their hopelessness. That overall effects were only moderate was
social surroundings, which alleviated their anxiety towards dying ascribed to the cases that had used only low doses of psilocybin.
(Kast, 1966, 1967). In the first reported study, many patients’ It could be speculated that high doses, as utilized in the studies
experiences were too aversive and many of them said they would from the 1960s and 1970s, may be capable of inducing more pro-
not have agreed to use the substance again (Kast and Collins, found psycho-spiritual experiences, potentially fostering benefi-
1964). However, the results of further studies were more promis- cial effects.
ing, possibly because the patients had been better prepared (Kast, Analogously, promising effects were also found when treating
1966, 1967). Two mechanisms of the psychedelic experience anxiety in patients with life-threatening diseases in the framework
of LSD-assisted psychotherapy (Gasser et al., 2014). In this study, explains the rapid tolerance to LSD that develops with repeated
moderate doses of LSD were administered on a single occasion usage (Buckholtz et al., 1990). Furthermore, it has been reported
embedded within a series of drug-free psychotherapeutic sessions. that LSD enhances neuronal responsiveness to serotonin in the
Participants exhibited a reduction of anxiety, which remained sig- orbitofrontal cortex of rats independently from the psychedelic
nificant after 12 months. Both studies, however, were not placebo- state, which potentially relates to OCD pathology (Zghoul and
controlled due to ethical considerations. Blier, 2003). In addition, the 5HT-2 agonist psilocybin was found
to reduce marble-burying behavior in mice, an animal model of
OCD (Matsushima et al., 2009). This corroborates the idea that
OCD the effects of serotonergic hallucinogens are at least partially
Moreno and Delgado (1997) reported the case of a patient with mediated by direct pharmacological mechanisms of action.
OCD who had recreationally used psilocybin-containing mush-
rooms and realized that his OCD-symptoms were diminished.
Depression
The patient used psilocybin daily for four years and found that
his OCD symptoms improved, while he lacked ASC experiences In the past decade, a large body of research has been done on the
due to the effects of tolerance. Two years after he had discontin- use of ketamine in depression (for reviews, see Aan het Rot et al.,
ued the use of this substance, his symptoms returned to their pre- 2012; Mathews and Zarate, 2013). Strong but short-lasting
vious intensity. Moreno et al. (2006) conducted a controlled effects have been found for treatment-resistant unipolar depres-
study of psilocybin with treatment-resistant OCD patients. A sion (Zarate et al., 2006) and bipolar depression (DiazGranados
sample of nine subjects was exposed to four single-dose psilocy- et al., 2010a) as well as suicidal ideation (DiazGranados et al.,
bin sessions with low to very high doses in a standardized setting 2010b). However, in this approach, the application of ketamine
in an outpatient clinic where no specific psychotherapeutic pro- has not been connected to any specific psychotherapeutic context
cedures were performed. The authors reported a consistent reduc- or to a consciously experienced psychedelic state of mind. On the
tion of OCD core symptoms in all of the patients. In contrast to contrary, direct pharmacodynamic effects upon the neurobiologi-
the delayed effects of selective serotonin reuptake inhibitors cal correlates of depression have been suggested to explain the
(SSRIs), this effect on OCD symptoms was immediate and the observed symptom reduction, independent of any subjective
effects persisted after acute effects had subsided, but were still effects of ketamine (Zarate et al., 2006). One study found a cor-
highly transient, lasting somewhat longer than 24 hours. The relation between psychotomimetic effects of ketamine and its
authors suggest a rapid, adaptive cascade including postsynaptic effects on depression; however, these effects were found to be
serotonin receptor down-regulation or early gene expression as independent of any specific therapeutic context (Sos et al., 2013).
the underlying mechanism. However, all subjects also experi- To our knowledge, there has been no study investigating the
enced moderate to severe psychedelic states, making it difficult effects of a ketamine-assisted psychotherapy for depression that
to determine the extent to which subjective experiences may have focuses on inducing psychedelic experiences. In addition to the
contributed to the treatment effects. To our knowledge this is the treatment of depression and anxiety in patients suffering terminal
only controlled study on the effectiveness of serotonergic hallu- somatic illness, serotonergic substances have sometimes been
cinogens for OCD, with the conclusion being highly limited due mentioned for the treatment of depression, in both a psychedelic
to the small sample size and the lack of a control group. and a psycholytic approach (Grof, 1979) in the context of endog-
Studies from the first period of intensive psychedelic research enous or neurotic depression. The results of these studies were
are limited to a few anecdotal accounts of LSD and psilocybin nevertheless controversial, sometimes even mentioning negative
(Brandrup and Vanggaard, 1977; Leonard and Rapoport, 1987; effects, as the substances tended to aggravate the present mood
Savage et al., 1962) as OCD sufferers were considered to be rather than ameliorating it.
resistant to the psychological effects of LSD (Grof, 1979), with
much higher dosages of up to 1500 μg LSD equivalent being
necessary to induce the effective psychedelic responses. Other clinical applications of psychedelic
Interestingly, subjects with a highly rationalistic personality
substances
structure or those who placed a strong emphasis on structure and
control (McGlothlin et al., 1967) were also reported to be less In the 1990s, a sufferer of cluster headaches accidentally discovered
prone to psychedelic states. that the recreational use of LSD prevented expected cluster periods
Additionally, ketamine was reported to induce anti-obsessive from occurring and that magic mushrooms containing psilocybin
effects; however, these findings remain controversial. One study taken in sub-hallucinogenic dosages every 3–6 months drastically
found anti-obsessive effects that did not last any longer than the reduced the frequency of further periods (Sewell, 2008; Sewell
acute drug effects (Bloch et al., 2012), whereas another study et al., 2006). The patient shared his experience via the internet,
found that the effects of ketamine on constant intrusive thoughts resulting in the formation of a group of cluster headache patients
lasted for 7 days post-treatment (Rodriguez et al., 2013). called ‘Clusterbusters’ who promoted the use of serotonergic psych-
Converging evidence suggests that serotonergic neurotrans- edelics (Frood, 2006). In an online survey, 53 cluster headache suf-
mission plays a key role in the pathophysiology of OCD. Animal ferers who had taken LSD or psilocybin reported that both
models of OCD identified 5-HT2 receptors to be critically substances were highly effective in aborting acute attacks, terminat-
involved in OCD-like behaviors in mice (Shanahan et al., 2011), ing cluster periods and extending periods of remission, i.e. reducing
and serotonergic agents such as SSRIs or clomipramine are the the frequency of cluster headache periods (Sewell et al., 2006).
standard treatment for OCD. Studies show that LSD rapidly Thus, it appears that cluster headache is one of the most strikingly
down-regulates 5-HT2 receptors in the rat brain, which partly effective indications for serotonergic psychedelics (Sewell, 2008),
Majić et al. 9
as the relationship between efficacy and the low rate of adverse 2013) without any psychotherapeutic session. These studies lead to
effects has not been observed in any of the other treatments. the conclusion that the potential therapeutic effects of psychedelics
Interestingly, the therapeutic effects in cluster headache appear to in OCD may occur independently of psychedelic experiences.
be completely independent of the psychedelic experience (Sewell Interestingly, therapeutic effects of NMDA receptor agonists
et al., 2006). Recently, non-hallucinogenic ergoline derivatives also appear to be not directly related to subjective experiences.
such as 2-bromo-lysergic acid diethylamide (BOL-148) have been Recently, ketamine has been applied to elicit short-term anti-
investigated, with promising results (Karst et al., 2010). depressive effects in major depression and bipolar disorder.
In Switzerland, a large sample of patients was legally treated These effects appear to be for the most part independent of psy-
using a substance-assisted therapy with LSD, psilocybin and chedelic states, as the dosages used were mostly sub-psychedelic.
MDMA from 1989–1993 (Gasser, 1995). Among these patients, More studies are required to determine the relationship between
the most frequent diagnosis was narcissistic personality disorder; the psychotomimetic and antidepressant properties of ketamine.
this indication for the therapy might be explained by the ego- To date, studies on serotonergic hallucinogens in depression are
dissolving properties of hallucinogens, which have also been sparse and not too promising. Nevertheless, anecdotal reports of
referred to as ‘narcissilytic’ or as ‘humility agonists’ (Halpern, PLT or PDT with beneficial effects do exist (Baker, 1964). Thus,
2003). Other previous indications include the broad spectrum of only well-designed studies could inform future applications.
neurotic disorders, above all those with a psychosomatic compo- One of the most outstanding and unique properties of psyche-
nent, sexual dysfunctions and post-traumatic stress disorder, delic drugs resides in their ability to create states of mind that
among others (Gasser, 1995; Oehen, 2008). resemble mystical experiences. This cannot be reproduced in ani-
mal models, as these experiences are dependent on the self-
reflective abilities of humans. Importantly, these specific states
Conclusions of mind may imply the existence of therapeutic options on the
level of subjective experience, which deserve further investiga-
Systematic assessment of drug-facilitated ASCs in controlled
tion in clinical trials, as well as an opportunity for the understand-
clinical trials is required to ultimately argue what experiences
ing of psychoses. At the same time, they appear to be represented
contribute to therapeutic outcomes. Despite political hurdles,
by neurobiological correlates that deserve further investigation in
several studies have investigated neuronal correlates of psyche-
brain imaging studies.
delic-facilitated ASCs. However, it remains a goal for future
research to elucidate the relationship between subjective experi-
ences and the neuronal mechanisms that underlie long-term Pharmacotherapy or psychotherapy, or both?
therapeutic effects.
In the majority of the work mentioned in this review, classical
psychedelics such as LSD have been proposed to facilitate and
How are therapeutic effects related to intensify ongoing therapeutic processes, but not to replace them.
It has been repeatedly emphasized in both major approaches to
subjective experiences?
psychedelic-assisted therapy that set and setting are of great sig-
The most extensively studied conditions for therapy with psych- nificance for the outcome. Metzner (1998) considered the drug a
edelics – involving the induction of a psychedelic (peak) experi- ‘catalyst or trigger’, not in itself a healing entity. This is in line
ence – are addiction and the treatment of terminally ill patients. with metaphors that psychedelics work as ‘unspecific amplifiers’
For both conditions, psycho-spiritual aspects have proven helpful (Grof, 1979) or ‘microscopes’ (Watts, 1962) to assess uncon-
in drug-free treatment approaches. The idea of achieving conver- scious intra-psychic material. Given the ineffability and over-
sion to a state of permanent abstinence from addiction with a whelming intensity of some drug-facilitated states and the
‘single, overwhelming experience’ has proven to be too optimis- complex interactions between drug, set and setting, it has been
tic (Albaugh and Anderson, 1974; MacLean et al., 1961). suggested that the personal psychedelic experience of the thera-
However, indigenous use of high doses in ritualized contexts has pist is a prerequisite for all treatment approaches (Blewett and
been associated with higher abstinence rates and reduced high- Chwelos, 1959; Gasser, 1995; Masters and Houston, 1966;
risk behaviors (Albaugh and Anderson, 1974; Halpern et al., Pahnke et al., 1970a).
2008; Thomas et al., 2013). The use of psychedelics in these ritu- In contrast to traditional psychiatric drugs such as antipsychot-
als is closely intertwined with an enhancement of social interac- ics or antidepressants, psychedelic agents are not to be ingested
tions and pro-community attitudes, and this has been reported to regularly but only once or a few times. Most notably, ketamine –
be part of the more holistic understanding of treating illness. although it is not a classical psychedelic – illustrates two different
From this standpoint, the notion of mere pharmacological effects aspects of the potential mechanisms of action. In KPT, as imple-
appears controversial, especially when considering that non- mented in the treatment of substance addiction, psychedelic expe-
drug-related treatments involving spirituality are among the most riences are put at the center of the hypothesis of how symptoms
fruitful strategies for treating addiction (Galanter et al., 2013; improve (Krupitsky and Grinenko, 1997). In addition, it has been
Kelly et al.; 2011). reported that anti-addictive effects may be associated with the
Conversely, OCD has been described as highly resistant to the mystical-type effects of ketamine, independently of a therapeutic
acute psychotropic effects of serotonergic psychedelics. framework (Dakwar et al., 2014). In contrast, recent studies on
Specifically, Grof (1979) reported LSD-assisted psychotherapy in depression have suggested ketamine as a treatment option for
OCD as ‘problematic’. However, recent studies have reported a affective disorders in a genuinely pharmacological sense where
reduction of OCD symptoms in patients after administration of psychedelic effects are not considered or where they are regarded
psilocybin (Moreno et al., 2006) or ketamine (Rodriguez et al., as adverse reactions (for a review, see Aan Het Rot et al., 2012).
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Declaration of Conflicting Interests Native American church: Toward a cultural psychiatry of peyote.
Psychoanal Rev 84: 237–255.
The authors declared no potential conflicts of interest with respect to the Calabrese JD (2007) The therapeutic use of peyote in the Native Ameri-
research, authorship, and/or publication of this article. can Church. In: Winkelman M and Roberts TB (eds) Psychedelic
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Funding ments. Vol 2. Westport: Praeger, pp 29–42.
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research, authorship, and/or publication of this article: TTS is supported enology of neutral hypnosis. Cortex 49: 375–385.
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568040

Peak experiences and the afterglow

depend on psychedelic experiences?

Tomislav Majić1, Timo T Schmidt2,3 and Jürgen Gallinat1,4

approaches have increasingly suggested other therapeutic mech- Germany

Figure 1. Time course of subjective experiences induced by psychedelics.

Psycholytic therapy (PLT) Psychedelic therapy (PDT)

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