„In the province of the mind, there are no limits.
The body imposes definite limits.”
(Lilly, 1972)
Numerous health conditions, such as depression or chronic pain, have been successfully treated by hypnotherapy (Hagl, 2015; Revenstorf & Hüsken-Janßen, 2008; Jensen & Patterson, 2006). A hypnotherapeutic treatment session in this context consists of an induction, clinical suggestions, and reorientation. During a hypnotherapeutic session, patients are invited to enter a trance state through what is called induction. Induction could also be described as an introduction to hypnosis, because its goal is to help the patient or client make a shift from the external perception of the environment to the internal perception of thier own experience. A trance state is thought to be associated with an increased openness to suggestions and characterized by an awakened, focused, and attentive concentration. At the same time, peripheral awareness of the external world diminishes (Spiegel, 1991; Spiegel & Moore, 1997). The hypnotic trance is distinguished by the following three characteristics: (1) absorption, (2) dissociation, and (3) increased suggestibility (Spiegel, 1991; Vanhaudenhuyse et al., 2013).
In the context of formal hypnotherapy, these three concepts might be as follows: A patient focuses intensely on a single experience and becomes absorbed (absorption). Because the patient is completely taken up by this experience, they partially excludes concurrently processed components. In our example, let us assume that the patient imagines walking through a forest. Instead of reliving the entire experience with all its impressions, that patient focuses exclusively on how the earth feels under their feet, thus diminishing perception through other sensory channels. This exclusion of certain components is described as dissociation. Dissociation is thus the conscious focusing on one partial aspect in one's experience (Vanhaudenhuyse et al., 2013). At this point, the third characteristic of the trance state comes into play, namely the increased suggestibility. This enables the patient in trance to accept the therapist’s suggestions with a greater probability without critical defensiveness. The increased suggestibility is often manifested in a person's response to the externally given hypnotic suggestions.
As hypnotherapists, our goal is to pave the way to trance for our patients. We remain with the patient for the duration of the therapy to weave in suggestions that promote healing. Finally, we end the session with a reorientation, which concludes the trance state and brings the patient back to the here and now. Both induction and reorientation are skills of the therapist that can be learned and trained. Ideally, the patient learns the skills of induction and reorientation during the course of therapy. The crucial point here is that the process of transition into trance is primarily a characteristic of the patient, the expression of which is thus subject to interindividual differences.
In a clinical context, patients have been shown to respond differently to hypnotherapeutic interventions depending on their individual level of hypnotizability, and thus to report different levels of trance depth (Patterson et al., 2018). This limitation to the successful application of hypnotherapy due to low hypnotizability is among the greatest challenges to the wider dissemination and application of hypnotherapy in healthcare (Patterson et al., 2018). At the same time, great clinical success has been achieved in a wide variety of settings with patients who report high levels of individual hypnotizability (Nash & Barnier, 2008). This raises the question of whether, and how, individual hypnotizability can be increased if needed for a particular patient. In no small part, the ability to increase hypnotizability will determine whether a greater number of patients can benefit from the promising research and treatment successes of hypnotherapy (Byrant, 2012). Whether and how hypnotizability can be increased has long been the subject of scientific investigation (e.g., Perry, 1977) and had still not been conclusively answered.
In summary, hypnosis consists of the three components, namely an induction, clinical suggestions and reorientation. In a hypnotherapeutic session, induction and reorientation are initially skills of the therapist. In the context of self-hypnosis, however, both skills can be learned by the patient and then performed independently. The depth of the trance can only be influenced by individual behavior, biochemical regulation mechanisms (such as neurotransmitters), or by cognitive characteristics of the patient.
In order to be able to influence the hypnotizability from the outside and thus to open the way to treatment by hypnosis also for people with low hypnotizability, a promising approach seems to lie in the trance itself: This is because studies suggest that different substances, such as oxytocin, ethanol, or ketamine, may work to induce trance more rapildy, or increase the depth of dissociation (Bryant et al. 2012, Yo, Sokol & Bhavsar, 2009; Castle, Gray, Neehoff, & Glue, 2017; Luckenbaugh et al., 2014). Ketamine administration could lead to enhanced hypnotizability by biochemically facilitating dissociation and thus smoothing the transition into trance.
Patterson et al. (2018) examined the relationship between hypnotizability and the administration of ketamine in an initial pilot study with eleven participants, seven of whom were women and four of whom were men. The mean age of the subjects was approximately 30 years, and they ranged in age from 22 to 50 years. Participants were randomly injected with a low dose of ketamine (3.5mcg/kg/min) on one of two days and then the depth of perceived dissociation was recorded. On the other experimental day, participants were administered saline as a placebo condition instead of ketamine. There was a span of at least 48 hours between these two intervention days.
First, the subjects' individual level of hypnotizability was measured using the Stanford Hypnotic Clinical Scale for Adults SHCS (Hilgard & Hilgard, 1975). This consists of five items suggested after an induction (e. g., the observable response to the suggestion "cough"). This revealed a low level of hypnotizability in five of the eleven participants and a medium level in the remaining six.
Second, the depth of perceived dissociation was measured with the Clinician Administered Dissociative States Scale (CADSS, Bremner, 1998). This consists of 19 items, which are elicited on a four-point Likert scale (e. g., "Do things seem unreal to you, as if you were in a dream?"). Both surveys were conducted on both experimental days about 75 minutes after the the infusion had been given.
The pilot study provides preliminary evidence that hypnotizability could be increased with the administration of ketamine:
In the study participants who evidence low hypnotizability inititally, no effect on hypnotizability recorded by the SHCS score was observed by the administration of saline. When ketamine was administered, however, this group showed a significant increase in hypnotizability, in accordance with the hypotheses established a priori.
In subjects with moderate hypnotizability, administration of saline resulted in higher levels of hypnotizability, contrary to the a priori established hypotheses, whereas administration of ketamine resulted in a decrease in hypnotizability. However, the difference was descriptive and was not significant. These results suggest that ketamine is likely to increase hypnotizability in people with low levels of hypnotizability.
Both subjects who reported a low depth of dissociation as assessed by the CADSS score and subjects with an intermediate expression of depth of dissociation reported an increase in perceived depth of dissociation with the administration of ketamine. Across the subjects, the administration of ketamine was found to increase perceived depth of dissociation: In the control condition with saline, the value of the depth of dissociation was 0.91 (SD = 1.81); in the condition with ketamine, it was 7.09 (SD = 5.41). These findings indicate that the depth of dissociation could be significantly increased by the administration of ketamine.
People with low hypnotizability showed a mean hypnotizability score of 0 when saline was administered, whereas for people with moderate hypnotizability the mean was 1.16. A descriptive difference was also present when ketamine were administered. People with a low depth of dissociation showed a mean of 5.80, and people with a moderate depth of dissociation showed a mean of 8.17. These results suggest the possibility that ketamine administration significantly deepens perceived dissociation in both the low and moderate suggestibility groups.
The primary limitation of the study is the small number of subjects. Additional research is needed – ideally in studies with larger numbers of subjects – to determine the extent to which the findings are reliable and generalize to other samples. A second limitation is that the SCHS provides only a rough estimate of hypnotizability. The development of scales that capture the present individual expression of hypnotizability through more items could more finely differentiate the effects. Third, the Patterson et al. study was embedded in a large-scale pain study and began 75 minutes before the study presented here. This could have influenced the study results. On the other hand, the study used a 2-arm double-blind radomized controlled design, assessing hypnotizability before and after each infusion, and controlled for potential confounding variables in the study design.
The approach of increasing individual hypnotizability externally by the administration of stimulating substances seems promising based on the pilot study presented. The findings are consistent with the results of previous research (e. g., Castle et al., 2017; Luckenbaugh et al., 2014; Schüler et al., 2021). For example, the results of the research by Castle et al. (2017) also provide evidence of increased dissociation scores on the CADDS scale due to the administration of ketamine. This group of researchers also provides evidence that the effects on hypnotizability interact with hypnotizability at baseline. Thus, ketamine appears to have the potential for improving the success of hypnotherapeutic treatment in patients with low hypnotizability.
It can be argued that other substances, such as oxytocin or ethanol, could also increase hypnotizability via their effects on dissociation (e. g., Bryant et al. 2012; Yo, Sokol & Bhavsar, 2009). For example, Bryant et al. (2012) examined whether an increase in body oxytocin levels would increase the response to hypnotic suggestions in forty subjects with low-level hypnotizability. They found a significant increase in hypnotizability after administration of oxytocin. Thus, the authors concluded that influence by neurochemical mechanisms on the hypnotic response is likely, and are consistent with the preliminary results of the study by Patterson et al. (2018). However, the substances used are diverse and also have different molecular biochemical mechanisms of action. Thus, at this point, we have more questions than answers. If, as suggested by the Patterson et al. (2018) study, ketamine can increase response to hypnotic treatments, additional questions that would need to be addressed include: For whom are these effects greatest? What dose has the most benefit? What are the effects of patient expectancies on the hypnosis-enhancing effects of ketamine?
The current state-of-science knowledge about ketamine in hypnotherapy also shows parallels to the research of the administration of methylphenidate in AD(H)S patients. A meta-regression analysis provides evidence that successful therapy of individuals with AD(H)S by methylphenidate is related to dose, the method of preparation of the drug, and history of prior substance abuse (Castells et al., 2011). Insight could be gained from decades of experience and establishment of a new drug such as methylphenidate in a psychological field such as the treatment of AD(H)S when researching treatment with ketamine in the field of hypnotherapy. Therefore, to understand mechanisms in people with low hypnotizability compared to people with moderate hypnotizability, for example, documentation of dose, type of ketamine used, and previous substance abuse could be considered (Castells et al., 2011). Finally, similar to what research has shown with methylphenidate, depending on these three components, interactions could occur that only come to light when the dose, ketamine type used, and previous substance abuse are taken into account in the data analysis (Schüler et al., 2021).
Preclinical animal models also provide initial clues as to which aspects should be considered in translational research. In this context, there are preclinical data suggesting that glycine receptors in the brain contribute to the hypnotic state induced by ethanol (a.k.a. alcohol) (Yo, Sokol, and Bhavsar, 2009). When the glycine receptor was blocked by strychnine, the influence of ethanol on the time of onset, strength, and duration of the trance state was reduced. That is, the inhibitory influence of glycine was reduced by blocking the corresponding receptor. In a second condition, ketamine was administered instead of ethanol. In this second condition, the effects of the ketamine were not reduced even after blockade of the inhibitory glycine receptor. Thus, the strychnine had no effect on the occurrence, strength, and duration of the trance when ketamine was administered. Thus, it can be concluded that different pathways of neuronal activation are possible for achieving the trance state and thus increasing individual hypnotizability. This study, when considered in light of the study conducted by Patterson et al. (2018), underscores that the possible neural pathways are not yet understood.
Another approach that is being pursued with growing interest in this regard are studies using ketamine as a moderator of individual hypnotizability. Ketamine is known to act as an antagonist of the glutamatergic N-methyl-D-aspartate receptor (NMDA receptor). What is unique about this receptor is that activation of the NMDA receptor requires both glutamate and the coagonist glycine (Liu et al., 2018). When an antagonist of the NMDA receptor is administered, it leads to a decrease in calcium influx, which decreases stimulus conduction in the postsynapse (Liu et al., 2018). Since both glycine and glutamate appear to play a role at the NMDA receptor, this again highlights the importance of better understanding neuronal processes to achieve an optimal fit between patient characteristics and ketamine administration.
Ketamine appears to have an effect on receptors in the brain that influence the depth of dissociation or individual hypnotizability. This may benefit individuals with low trait levels of hypnotizability, reducing the time need to achieive trance, increasing the depth of dissociation, or both. However, questions remain as to what effects ketamine specifically has on hypnotizability. and whether the dissociative effect of ketamine might interfere with formal hypnosis induction in individuals with moderately marked hypnotizability. Accordingly, it would be of interest to investigate in subsequent studies how hypnotizability behaves under the administration of ketamine, depending on whether formal trance induction occurs or not. It is also important to clarify whether the influence of ketamine alters the response to clinical suggestions, as a function of basline hypnotizability level.
How it behaves in people with a high degree of individual hypnotizability remains to be clarified. The question that arises from this is what implications follow from this for people who exhibit high suggestibility. Furthermore, it must be determined to what extent the influence of ketamine on hypnotizability differs from other possibilities of influence such as alcohol, reduced environmental stimulation, neurofeedback, transcranial magnetic stimulation (TMS), nitric oxide or the concentration of oxytocin in the blood. The ideal amount and type of ketamine administered also remains to be explored.
In summary, the results of the presented pilot study provide preliminary evidence that ketamine increases subjectively perceived dissociation. Specifically, in people with low suggestibility, ketamine may increase hypnotizability, whereas it may decrease it in people with moderate hypnotizability. Further research is needed to compare the effects of ketamine with those of other approaches to find the answer to the question of ketamine's utility for hypnotherapy – especially for patients who demonstrate low levels of individual hypnotizability.