Psychedelic‐assisted therapy for functional neurological disorders: A theoretical framework and review of prior reports

Abstract Functional neurological disorders (FNDs), which are sometimes also referred to as psychogenic neurological disorders or conversion disorder, are common disabling neuropsychiatric disorders with limited treatment options. FNDs can present with sensory and/or motor symptoms, and, though they may mimic other neurological conditions, they are thought to occur via mechanisms other than those related to identifiable structural neuropathology and, in many cases, appear to be triggered and sustained by recognizable psychological factors. There is intriguing preliminary evidence to support the use of psychedelic‐assisted therapy in a growing number of psychiatric illnesses, including FNDs. We review the theoretical arguments for and against exploring psychedelic‐assisted therapy as a treatment for FNDs. We also provide an in‐depth discussion of prior published cases detailing the use of psychedelics for psychosomatic conditions, analyzing therapeutic outcomes from a contemporary neuroscientific vantage as informed by several recent neuroimaging studies on psychedelics and FNDs.

disorders (FNDs). They describe changes in hierarchical brain dynamics and specific functional brain networks in response to 5-HT2A agonists (classical psychedelics) and compare these with alterations in brain function thought to occur in patients with FNDs. 4 In the text that follow, we explore and expand upon this theoretical framework. We also include a review of relevant case reports and case series as an empirical counterpart to these conjectural propositions.

| OVERVIE W OF FUN C TIONAL NEUROLOG IC AL DISORDER S
While FNDs are not new within the field of neurology, the conceptions of these illnesses, as well as the terminology used to describe them, have evolved substantially over the course of history.
Symptoms that would now be classified as functional have previously been attributed to causes ranging from the supernatural to the direct and indirect manifestations of uterine disease. While the term "hysteria" has persisted in modern medical parlance to some extent, by the late 17th century, uterocentric theories of these disorders began to give way to explanations implicating the brain. 5 Between the late 19th and early 20th centuries, considerable effort was devoted to classifying and understanding these disorders, with significant contributions made by prominent neurologists including Pierre Briquet and Jean Martin Charcot. 5,6 However, the insights of one of Charcot's students, Sigmund Freud, have yielded perhaps the most enduring impact on our conceptions of functional neurological symptoms. Freud coined the term "conversion" in 1894, referencing his belief that "hysterical" symptoms resulted when intrapsychic conflict was transformed into somatic manifestations. 7 While Freud's ideas are not without their detractors, the term "conversion disorder" remains listed in the most recent edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) as synonymous with the newer terminology of functional neurological symptom disorder (FNSD). 8 In contrast to the specific language of the DSM-5, the informal labels given to medically unexplained symptoms remain somewhat heterogeneous. While "psychogenic," "psychosomatic," and "nonorganic" all remain in use, there is growing preference for the word "functional". 9 Within the field of neurology, the term FND is more commonly used than FNSD or conversion disorder, and additional diagnostic labeling is often used to distinguish among different presentations. For example, functional motor disturbances can be referred to as functional movement disorders and can be further subdivided into functional gait disturbance, tremor, dystonia, myoclonus, chorea, and weakness. 10 Other presentations include functional blindness, aphonia/dysphonia, and sensory changes. Functional seizures are often referred to as psychogenic nonepileptic spells (PNES). 9 Whether or not these phenotypes represent biologically distinct entities or different manifestations of the same underlying process remains a matter of some controversy, though that individual patients often display multiple types of functional symptoms has been cited by some as evidence of the latter. 11 Historically, FNDs have carried a generally poor prognosis. [12][13][14][15] A 2014 systematic review that included over 2000 patients with functional movement disorders found that only 20% of patients experienced complete remission of symptoms, while 40% had similar or worse symptoms to their initial presentation at long-term follow-up. 16 PNES are associated with similarly poor outcomes, with more than half of patients continuing to have episodes at the time of follow-up. 12,14 The significance of the low recovery rates seen in FNDs is underscored by the impact these disorders have on patients. For example, two separate studies found patients with functional movement disorders to have similar or greater reductions in quality of life to patients with "organic" movement disorders. 17,18 A recent study also found that patients with PNES have a standardized mortality ratio that is 2.5 times higher than the general population, similar to that of patients with medically refractory epilepsy. 19 Recent research into effective treatment practices may help reshape the prognosis of functional disorders. In the case of functional movement disorders, there is increasing evidence to support modified intensive physical rehabilitation programs. 10,20,21 One such study based out of the Mayo Clinic reported that upon completion of a week-long outpatient program, nearly three quarters of patients demonstrated at least marked improvement. 20 Similarly, Lafrance et al 22 reported that a 12-week cognitive behavioral therapy (CBT)based program for PNES resulted in a reduction of spell frequency by approximately 50%.
While the results of such programs are encouraging, treatment responses are often incomplete, and many patients fail to derive any significant benefit. For example, in the aforementioned Mayo Clinic study, at long-term follow-up, over 60% of patients continued to report persistent symptoms, and 25% reported little to no improvement from baseline. 20 Furthermore, issues of access and cost of treatment associated with such programs limit their practical utility and argue the need for other interventions. While benefit has been reported with other therapeutic strategies, including sedative-hypnotics and transcranial magnetic stimulation, studies to date have been small, and further research is needed. 23

| OVERVIE W OF THE HIS TORY AND PHARMACOLOGY OF PSYCHEDELIC COMP OUNDS
Grinspoon and Bakalar describe a psychedelic substance as one that, "without causing physical addiction [or] major physiological disturbances […] produces thought, mood, and perceptual changes otherwise rarely experienced except in dreams, contemplative and religious exaltation, flashes of vivid involuntary memory, and acute psychosis". 24,25 Human experiences with psychedelics long predate knowledge of their molecular nature. Among the earliest archeologically documented consumers of psychedelic agents were aboriginal communities of northeastern Mexico and Trans-Pecos Texas. 26 Radiocarbon dating demonstrates that these communities used peyote, Lophophora williamsii, the mescal bean Sophora secundiflora, and the Mexican buckeye Ungnadia speciosa as far back as circa 8500 BCE. 27 Alongside plants, fungi are also natural sources of psychedelic chemicals, psilocybin-containing mushrooms being among the best-known examples. Such mushrooms are of major significance to indigenous traditions associated with Mesoamerica. 28 The unifying pharmacological property of the classical psychedelics appears to be agonism of serotonin 2A (5-HT2A) receptors. 29 Elucidation of this mechanism began with the discovery of serotonin in the mammalian brain in the 1950s 30 and recognition of the structural similarity between serotonin and lysergic acid diethylamide (LSD). 31 While the exact interaction between psychedelics and the serotonergic system was unclear for some time, the development of subtype-specific serotonin antagonists narrowed focus on the 5-HT2A receptor, the blockade of which was found to inhibit behavioral effects of various psychedelics in rats and, in later studies, to block the effects of psilocybin and LSD on subjective perceptual experience in humans. 3,[32][33][34][35] A key step in inaugurating the study of psychedelic compounds in academic research was the synthesis of LSD by Swiss chemist Albert Hofmann in 1938. Though initially labeled as being of no particular interest by the pharmacology division at Sandoz Laboratories, Hoffman resynthesized LSD in 1943, inoculating himself with the molecule in the process by accident. This experience, along with a purposeful ingestion a few days later, revealed the mind-altering effects of LSD and provided the first hints that it may be of relevance to the study and treatment of psychiatric disease. 36 Early studies of LSD in human subjects yielded little success in treating psychotic disorders but demonstrated exciting potential for the treatment of a variety of nonpsychotic mental illnesses including mood disorders and addiction. 2,[37][38][39] Despite this promise, passage of the Controlled Substance Act of 1970 presented a legal barrier to scientific investigation involving psychedelic substances and an ongoing challenge to reintroducing their status as tools in research and therapy. 3,24,40,41 Psychedelic research stagnated for two decades until studies reporting the neurobiological correlates of psilocybin, DMT, and mescaline emerged in the 1990s, followed by new studies evaluating their therapeutic potential in certain psychiatric disorders. 2,[42][43][44][45] These initial studies, together with efforts to formally reintroduce psychedelics as instruments of science and medicine by professional organizations (eg, the Multidisciplinary Association for Psychedelic Studies), galvanized a resurgence in psychedelic research. 46,47 In recent decades, an increasingly robust body of literature has emerged supporting the safety and therapeutic value of psychedelic substances in a variety of mental health contexts. 2,3 Three separate studies of psilocybin-assisted psychotherapy demonstrated posttreatment improvement of depression and anxiety in patients with life-threatening cancer. In the two larger studies, continued benefit was seen in 60%-80% of patients at 6 months 48-50 ; a recent follow-up to one of those studies found effects to be sustained at 4.5 years. 51 Promising preliminary results have also been observed with psilocybin-assisted psychotherapy in alcoholism, 52 smoking cessation, 53 obsessive compulsive disorder, 54 and treatment-refractory major depression. 55,56 There is interest in psychedelic-assisted therapy as a potential treatment for a number of other disorders including anorexia nervosa, 57 bipolar disorder, 58

| The default mode network and neurobiological correlates of Freudian conceptions
Among the network changes induced by psychedelics, much attention has been given to their effect on the default mode network (DMN). The DMN is comprised of functionally connected brain regions, including the ventral medial prefrontal cortex (vmPFC), dorsal medial prefrontal cortex (dmPFC), posterior cingulate cortex (PCC), precuneus, and lateral parietal cortex, 63 and is most active when individuals are not engaged in goal-directed tasks. [63][64][65][66] The DMN appears to be important in self-related processing, 4,67 and it has been argued to correspond to Freudian conceptions of the ego. [67][68][69] The 5-HT2A receptor is densely expressed throughout the DMN, 70,71 and fMRI studies have shown that psychedelic agents acutely suppress blood-oxygen-level-dependent (BOLD) signal in key nodes of this network and also suppress its within-network resting state functional connectivity (RSFC). [72][73][74] This may explain some of the subjective effects of psychedelics, including feelings of increased connectedness and, at high doses, a phenomenon known as "ego death," in which individuals describe a dissolution of sense of self. 3,67,[73][74][75] In his recently published book on psychedelics, Michael Pollan likens this experience to feeling like a pile of post-it notes scattered to the wind, going on to say, "But the 'I' taking in this seeming catastrophe had no desire to chase after the slips and pile my old self back together […]. And then I looked and saw myself out there again, but this time spread over the landscape like paint, or butter, thinly coating a wide expanse of the world […]". 76 Many of the proposed therapeutic benefits of psychedelics have been theorized to relate to their action on the DMN. 74 For example, depressive symptoms have been argued to result from the brain entering into an overly ruminative state, corresponding on a network level to pathologic increase of within-network DMN functional connectivity 67,75,77,78 . Interestingly, and in opposition to the acute effects of psychedelics on the DMN, Carhart-Harris et al 78 found enhanced DMN integrity in a cohort of patients with refractory depression the day following treatment with psilocybin. This finding has led some to liken the therapeutic action of psychedelics to pressing a reset button for the brain. 78,79 This may explain the preliminary evidence that addiction, which has been associated with decreased baseline DMN RSFC, 25 may also benefit from psychedelic-assisted psychotherapy. 52,53 These findings are of relevance to proposed studies on psyche- Given the ability of 5-HT2A agonists to suppress DMN functional connectivity, their ability to break down repressive barriers may come as no surprise. Indeed, this feature of psychedelics has long been recognized, with the pioneering psychedelic researcher Stanislov Grof calling LSD a "nonspecific amplifier of the unconscious". 3 Numerous studies describe the reemergence of unconscious material during psychedelic-induced states of altered awareness. [91][92][93][94][95][96][97][98][99][100][101][102][103][104][105] In a 1958 paper, Eisner and Cohen wrote "the recall and 'reliving' of past events is enhanced; frequently whole sequences unroll before the patient's eyes as though they had been stored on microfilm". 96 As discussed in the case reports section, such episodes of abreaction * have been described in a number of patients with FNDs treated with psychedelics. 95,97,99,103

| The temporoparietal junction and disruptions in the agency network
In addition to their effects on the DMN, psychedelics have been shown to acutely alter functional connectivity within and between various other brain regions. 86,87,[107][108][109] The ability of psychedelics to alter connectivity between brain regions may bear particular relevance to the treatment of functional movement disorders. In these disorders, while motor symptoms may have the appearance of voluntariness, patients experience movements as outside their volitional control-stated differently, there is an apparent loss of motor agency. 110 While the agency network is broadly distributed, the right temporoparietal junction (TPJ) is thought to play a critical role. [110][111][112] Specifically, the right TPJ is thought to be involved in mismatch detection between performed and intended movements. 111 The TPJ is also thought to be important for maintenance of embodiment, and TPJ dysfunction has been implicated in the genesis of dissociative symptoms. 113,114 In a 2016 study, Mauer et al demonstrated impaired functional connectivity between the right TPJ and bilateral sensorimotor regions in patients with a variety of functional movement disorders. 111 Similar results were seen in a 2010 study of functional tremor. 112 In this way, functional movement disorders might be conceptualized as functional disconnection syndromes, in which motor networks have As for relevant changes in functional connectivity induced by psychedelic agents, and continuing with the TPJ as an example,

Tagliazucchi et al 109 found that IV infusion of LSD resulted in in-
creased global brain connectivity of the bilateral TPJ, and that this was positively correlated with ego dissolution scores. Furthermore, in a subsequent seed-based analysis, LSD infusion was found to acutely increase connectivity between the TPJ and sensorimotor cortex. Though an intriguing prospect, whether or not psychedelic agents could reliably reverse the baseline hypoconnectivity between TPJ and sensorimotor cortex in patients with functional movement disorders is unclear. It is further unclear whether such repairing of connectivity would result in symptomatic improvement.
As with functional imaging of patients with FNDs, the changes in connectivity reported to occur with administration of psychedelic agents vary significantly from study to study. For example, and in opposition to the findings of Tagliazucchi et al, Preller et al found that both LSD and psilocybin resulted in decreases in global connectivity of the TPJ. 86,87 In addition to uncertainty related to the acute alterations in functional connectivity induced by psychedelic agents, how these changes evolve over time remains largely unexplored.
While an in-depth discussion of the various changes in brain networks and functional connectivity that occur with administration of 5-HT2A agonists is beyond the scope of this paper, a recent review by Franz Vollenweider and Katrin Preller summarizes these and other neurobiological effects of psychedelic agents. The authors tie these changes to psychedelic-induced alterations in perception, cognition, and behavior, and link these effects to hypothesized therapeutic concepts in several psychiatric conditions.

| Suggestibility and Bayesian remodeling
As discussed in detail in the case reports section that follows, Edward Baker published a 1967 case report of a man with functional weakness of three limbs which resolved with LSD-assisted psychotherapy. In the discussion of his report, Baker comments, "It is impossible to state how much was drama and suggestion vs how much LSD forcing of repressive barriers; we are awaiting more cases to arbitrate the point." 91 The power of suggestion has long been recognized to have both diagnostic and therapeutic value in functional disorders. This power of suggestion, combined with the poor prognosis and relative lack of other effective therapies, has led some to advocate for the ethical use of placebo in the treatment of FNDs. 116,117 Perhaps not surprisingly, there is evidence that hypnosis, a technique known for its ability to enhance suggestibility, has benefit in treating FND symptoms. 118,119 Charcot himself would often use hypnosis to induce and relieve functional symptoms in "hysteria" patients during his clinical lessons at La Salpêtrière. 120 Similarly, a 2010 meta-analysis of "drug interviews" (predominantly utilizing sedative-hypnotics) for conversion disorder found suggestibility to be a positive predictor of recovery. 90 It bears mentioning that, like psychedelics, hypnosis 121,122 and sedative-hypnotics 123 have been shown to have a suppressive effect on within-network functional connectivity of the DMN.
The ability of psychedelics to increase suggestibility has been noted at least since early clinical work with LSD began in the 1950s 124 and has been demonstrated empirically by at least three different studies. [124][125][126] Possibly related is the observation that psychedelic experiences often carry a noetic quality, 25,74,79,127,128 such that insights gained under the influence of psychedelics are sometimes perceived by subjects as more true/important than waking reality. 79 These properties at once underscore the powerful therapeutic potential of psychedelics and portend their potential for harm if used incautiously. 77 The importance of suggestibility in functional disorders may relate to the reshaping of inaccurate prior "expectations" or "beliefs." Edwards et al 11  Lorenz et al demonstrated that the perception of intensity of noxious stimuli was impacted by cuing prior to stimulus delivery. If subjects were cued that they would be receiving a strong stimulus, there was a tendency to rate the stimulus intensity higher than if they were told they would be receiving a weak stimulus; the reverse was also true. Interestingly, secondary somatosensory evoked potential amplitudes as measured by magnetoencephalography were similarly impacted by cuing. 129  Carhart-Harris and Friston provide the example of the commonly reported psychedelic-induced visual illusion of seeing the walls "breathe." They argue that under normal circumstances, the heavily weighted prior expectation that walls are static prevents the incomplete fidelity of ascending visual information from being interpreted as motion, but that, in the presence of 5-HT2A agonism, these top-down refinements are lost. 77 Another example is the hollow mask illusion in which a rotating plain mask is perceived as forward facing whether the viewer is looking at it from the front or the back. 133 Dissolution of this phenomenon has been reported to occur under psychedelic states. 134 While this review uses terminology such as "beliefs" and "expectations" in reference to high-level priors, this is not meant to imply that these are volitionally formed or maintained at a conscious level.
Conversely, in some cases, as exemplified by the hollow mask illusion, high-level priors may directly oppose conscious understanding. This is often the case in FNDs, in which patients may come to understand the nature of their symptoms on a conscious level, but that understanding does not necessarily lead to symptom amelioration. This supports the idea, as suggested by Edwards  Therefore, what has to this point been referred to as expectations and beliefs would perhaps be better described as high-level constructs encoded by neural tissue. An illustrative example of this is the phenomenon of phantom limb sensations, in which patients with amputations, despite understanding at a conscious level that a limb is gone, feel as though it is still present. Interestingly, alleviation of phantom limb pain through the use of psychedelics has been described in the literature. 135 in a psychedelic state, he experienced more substantial and longer-lasting effects and was eventually able to discontinue treatment altogether. 138 The improvement the patient experienced with psychedelic-assisted mirror therapy, as well as the unsatisfactory response with psychedelic administration alone, is explained by the REBUS model. That is to say, while psychedelics may make F I G U R E 1 The top row depicts aberrant brain dynamics in which over-weighted, high-level priors overwhelm bottom-up signalling, which is represented in the top left panel by the big and small arrows, respectively. These dynamics, thought to be common to many psychopathologies, create an overly rigid state in which the brain is relatively insensitive to ascending information. This is depicted by the ball in the top right panel landing without causing a surface perturbation. The bottom row depicts brain dynamics during psychedelic states. In the bottom left panel, the two brains are of equal size, intended to represent flattening of the Bayesian hierarchy. The increased translucence of the top-down arrow represents de-weighting of high-level priors, and the increase in thickness of the bottom-up arrow reflects increased influence of ascending information, such as from the limbic system. This increased sensitivity to bottom-up signalling is represented in the bottom right panel; the same ball now creates ripples on a less rigid surface. high-level constructs more amenable to reshaping, the appropriate bottom-up influences must be present for this reshaping to occur in a therapeutic way.
It should be noted that the Freudian framework involving the DMN and its suppression of limbic activity detailed in subsection 4.1 is concordant with the Bayesian brain model. 67,77 Carhart-Harris and Friston propose that the DMN is situated at the top of the brain's functional hierarchy and exerts top-down inhibition of ascending information including, and importantly, from intrinsic sources such as the limbic system. 77

| C A S E S ERIE S AND REP ORTS OF PSYCHEDELIC THER APY FOR FUN C TIONAL NEUROLOG IC AL DISORDER S
A number of case series from the pre-prohibition era of psychedelic research include patients labeled as "conversion," "hysteria," and "psychosomatic" 140 (Table 1). However, in the majority of these papers, no details of the patients' presentations are given, making it difficult to know whether their diagnoses would be classified as functional by modern standards. For instance, in a 1958 case series, Betty Eisner and Sidney Cohen refer to constipation and dysmenorrhea as psychosomatic illnesses, 96 with other authors applying this terminology to such varied symptoms as headache, dizziness, numbness, back pain, stomach trouble, asthma, dermatitis, and allergic rhinitis. 105,141 In a 1959 report, Margot Cutner uses the term hysteria to refer both to conversion symptoms as well as histrionic tendencies, describing one "hysteric" patient as having primary symptoms of "sporadic depressions, various fears and uncontrollable tempers." Elsewhere in the series, Cutner describes a patient with generalized stiffness, speech changes, and a feeling of "deadness" affecting the left-hemibody that resolved with LSD-assisted psychotherapy, but did not attempt to classify the symptoms as being part of a broader disorder. 94 Variability in treatment protocol-as it pertains to dose, therapist involvement, and treatment setting-further limits the strength of conclusions that can be drawn from these prior cases. While While the relative lack of details in many of these studies makes it difficult to draw conclusions from their results, there are at least four reports from the pre-prohibition literature which clearly describe functional neurological symptoms being treated with psychedelic agents and are described below. Though not a FND per se, a fifth case of psychogenic urinary urgency treated with LSD is of relevance and is included in Appendix A. 99 These cases provide potential insights into the therapeutic potential of psychedelic-assisted therapy in functional disorders.
All cases describe long-standing, treatment-refractory symptoms demonstrating rapid and sustained resolution following treatment with psychedelics. Cases 1 and 4 additionally provide some suggestion of a dose-response relationship, something also noted by the aforementioned phantom limb patient. 138 With the notable exception of case 4, all cases describe patients as developing insights into or change in connection with prior traumas, which may be of relevance to the therapeutic mechanism of these agents.

| Case 1
Perhaps the most detailed description of a psychedelic substance being used to treat a FND is from a 1961 case report written by Didier-Jacques Duché, a French child psychiatrist working out of La Salpêtrière Hospital in Paris. In part because the article is available only in French, his report will be described here in some detail.
The author describes the case of Annick B, a young girl treated for functional dystonia affecting her bilateral lower extremities.
He reports that at age 12, following an episode of minor trauma, Annick began complaining of progressive left foot pain and difficulty walking. Despite a negative medical workup, she continued to walk with a limp through age 16 when, following a second episode of minor trauma, she developed pain in her other foot and associated increased difficulty ambulating, eventually developing what is described in the paper as an equinovarus deformity of both feet.
Annick is evaluated by several doctors who, "throughout various examinations, find no joint, muscular, bony, or neurological abnormalities," and it is not until the following year when she is admitted to La Salpêtrière that she is diagnosed as having conversion disorder. There is an extremely intense muscle contracture apparently fixing the deformation. During the examination, the patient exaggerates this stiffness.
Despite endorsing a happy family environment, while undergoing narcoanalysis, ‡ she admits that she is often awoken with the fear that The series includes two patients with "conversion hysteria." No details of their presentations or treatment are provided, nor is there data available regarding response --results were presented as aggregate response rates of all 50 patients in the study. Described in paragraph format is the case of a woman with sexual dysfunction and dyspareunia who, with LSD-assisted psychotherapy, realized this to be connected with a history of childhood sexual abuse, and her symptoms eventually resolved. Includes 3 patients labeled as having "conversion," 1 of whom was rated as much better and 2 as some better. One case of a "hysterical triplegic" is discussed in detail, the patient having improvement and ultimately resolution of symptoms with LSD-assisted psychotherapy. See "Case series and reports […]" section.
Leuner ( Includes 4 patients with "conversionhysteria," 1 who is rated as recovered, 2 as greatly improved, and 1 as moderately or not improved.

TA B L E 1 (Continued) (Continues)
a man is in her bedroom, and that this man resembles her father. Apart from this, her initial hospitalization course is described as "extremely mundane." About this the author writes, "Different therapies are tried without being able to attribute one or another to a specific amelioration in symptoms with improvements being exceedingly gradual. Indeed, only towards the end of the second month does her gait return to normal." When seen initially in follow-up, Annick's gait is described as quite normal, but it is said that she "keeps a behavior of the hysterical type as well as a certain anxiety." The author goes on to say that after 3 months, she again develops progressive difficulty with gait, which is unsuccessfully treated with faradization. § Eventually, the abnormalities of her lower extremities "resume their prior intensity," at which point she is rehospitalized.
Despite 3 weeks in the hospital, Annick fails to demonstrate improvement, at which point her doctors decide to treat with psilocybin. She is first given a 3-mg IM injection, ¶ which results only in a vertiginous sensation and increased deep tendon reflexes on exam.
The following day, however, she is given a 9-mg injection after which she is described as passing through three stages: one of agitation, one of euphoria, and finally a depressive stage. It is during this last stage that she experiences an apparent breakthrough: At the end of 2 hours, she declares that she must absolutely say certain things that she has never said before […]. She confesses then that her father and mother are inveterate alcoholics […] and that the arguments and the violence of which they are both guilty create an unbearable family life.
Indeed, the apparent inner liberation which accompanies these declarations is of greater interest than their very content. Nonetheless, in six years, this is the first time she gives details about her parents, a subject she had always avoided previously; even during the narco-analyses, this problem had never been addressed.
In the following days, we very quickly witness the disappearance of the troubles and the resumption of a perfectly normal gait.
The author goes on to state that when Annick's case was last reviewed, 6 months after her hospitalization, there had been no recurrence of her symptoms. 95

| Case 2
In a 1963 article, Dietrich Heyder described the case of a 32-year-old man, who, after a job-related welding accident resulting in seconddegree burns of his right hand, developed functional paralysis of that arm. He was referred to a psychiatrist 4 months after his accident, and a diagnosis of "conversion reaction" was made, though the patient denied emotional issues, and efforts by the therapist to uncover The patient also reported that another friend had his right arm badly injured after being captured while trying to help the patient escape.
Following treatment, the patient regained mobility in his right arm but also began reporting severe muscular pains in his neck. After returning to work, the site of the welding accident, he experienced a relapse of his right arm symptoms, which did not respond to "psychotherapeutic interventions." Over a year after his symptoms first began, LSD was tried as a last resort. A dose of 300 mcg was given three times over an Includes "hysteria" as a diagnostic category and rates 6 of these patients as recovered and 3 as greatly improved. Details of the cases are not provided, but the author comments that after 6 years follow-up, only one patient experienced slight relapse, which stabilized with psychotherapy.

| Case 3
In a 1966 article, Robert Pos described his experiences treating 24 patients with LSD. Included in this is a case of "grand hysteria", ∥ a patient described as suffering for a number of years from "hallucinatory spells and seizures" which had been refractory to several interventions including intensive psychotherapy, hypnosis, ECT, and frequent hospitalizations. She was given three treatments with LSD (dose unknown) during which she "repetitively and perseveratingly states 'I can say anything I like.'" Over the course of these sessions, she is described as developing increasing detachment to her prior traumas with subsequent and sustained remission of her seizures. 103

| Case 4
In a 1967 article, Edward Baker described the case of a refractory "hysterical triplegic" who had ongoing symptoms for a number of years following a hockey accident. The full details of his treatment are not provided, but the author states that "earlier LSD psychotherapeutic interview" resulted in recovery of two of his limbs, but that he continued to experience "mental amputation" of the leg at the mid-thigh, which did not improve with escalating doses up to 1600 mcg. However, with a final dose of 2000 mcg, he regained full sensorimotor function within 10 minutes of injection after which, "he staggered down the ward, kissing whomever he saw, accepting congratulations." His remission was sustained over 2 years of followup. In addition to the tremendous doses of LSD used to treat this patient, the case is remarkable in that the patient was described as having no insight into his symptoms at the time of treatment or at any point during follow-up. 91

| E VIDEN CE AND ARG UMENTS AG AIN S T PSYCHEDELIC THER APY IN FUN C TIONAL NEUROLOG IC AL DISORDER S
In their 1963 book, "Lysergic Acid (LSD-25) and Ritalin in the Treatment of Neurosis," Ling and Buckman include a list of "unfavorable indications" for LSD psychotherapy, and listed among these is "gross hysteria, especially conversion hysteria". 100 These words of caution are repeated in Dr Buckman's 1967 article "Theoretical Aspects of LSD Therapy". 155 While the reasons for the recommendation to avoid LSD therapy in this patient population are not discussed in these works, in a published panel discussion from 1967, Buckman discusses his experience treating a "monosymptomatic conversion hysteria" patient who subsequently required hospitalization for several months for severe depression. 107 In a 1954 article, Sandison et al report that the response of the conversion hysterics to LSD therapy was "not satisfactory" but also comment that these patients were seen early in the series, and that the amount of treatment given may have not been sufficient.
Furthermore, their paper included only four patients of this type, one categorized as recovered, one as moderately improved, one as improved, and one who refused further treatment after a single session. 143 Patients with functional disorders may also be prone to medication side effects. 156 This raises some concerns about the tolerabil- In addition to general concerns about side effects, it is possible that there could be unintended consequences to the sudden unmasking of repressed material. In thinking about functional symptoms from a teleologic perspective, one wonders whether expression of intrapsychic conflicts as a physical symptom may be an adaptive response and preferable to the emotional consequences of processing these conflicts on a conscious level. While such concerns would be in alignment with the generally slow and gradual methods of psychoanalytic psychotherapy, there is evidence in the literature to suggest that a more rapid approach can be effective. For example, in the aforementioned 2010 meta-analysis of "drug interviews" for conversion disorder, in addition to suggestibility, abreaction was found to be predictive of recovery. 90

| CON CLUS I ON S AND FUTURE DIREC TIONS
Given the relevance of nascent psychedelic neurobiological models to the pathophysiology of FNDs, and the critical lack of effective therapies for these disorders, detailed investigation into the relevance of psychedelics as an attestable treatment merits further investigation.
Nevertheless, we would advocate for a measured approach which seeks to avoid extrapolation of assumptions regarding dosing and tolerability from previous trials in other medical conditions. Specifically, while relatively high doses of oral psilocybin have been found to be well tolerated in a number of conditions (eg, addiction, OCD, and cancer-related anxiety), [48][49][50]52,53,56

E THI C S APPROVAL
Ethics approval was not required for this narrative review and perspective.

ACK N OWLED G EM ENTS
This work was supported by the NeuroNEXT Fellowship Award (F053838).

D I SCLOS U R E
The authors confirm they have no relevant conflicts of interest to disclose.

N O M E N CL ATU R E O F TA RG E T S A N D LI G A N DS
Key protein targets and ligands in this article are hyperlinked to corresponding entries in http://www.guide topha rmaco logy.

PATI E NT CO N S E NT
Patient consent is not applicable for this narrative review and perspective.

DATA AVA I L A B I L I T Y S TAT E M E N T
Data sharing is not applicable to this submission as no new data or formal analysis of existing data were conducted for this article.

Benjamin Stewart
https://orcid.org/0000-0002-4376-5244 E N D N OTE S * Abreaction: As defined in Merriam-Webster, "abreaction is the expression and emotional discharge of unconscious material (such as a repressed idea or emotion) by verbalization especially in the presence of a therapist". 106 † Mirror Therapy: First introduced in 1996 as a treatment for phantom pain, mirror therapy involves placement of a mirror in front of a patient in the sagittal plane, which creates the illusion that an amputated limb is still intact. 139 ‡ Narcoanalysis: Refers to psychoanalysis conducted while patients are under the influence of sedative-hypnotic medications such as barbiturates. 151 § Faradization: refers to a form of electrotherapy in which brief faradic current is passed either throughout the body or to focal areas of dysfunction. These techniques were used to treat psychological conditions as well as physical ailments. 152  Scottish woman with frequent and severe urinary urgency which was limiting her daily activities. Her symptoms had onset suddenly 11 years prior when she found herself alone in a railway car with a young man.
While he did not threaten her in any way, she found herself in a state of panic which was accompanied by a strong urge to urinate. This urge to urinate, which the patient refers to by the euphemism "penny spending," became a frequent occurrence which persisted over the subsequent years, as did a worsened generalized anxiety-this despite counseling and attempts at treatment with "a variety of tranquilizers." In each of three sessions, she was given 50-75 mcg of LSD with 20-30 mg of methylphenidate. Over the course these sessions, both her urinary and anxiety symptoms significantly lessened, with continued improvement in the months that followed. The patient wrote the following in a progress report 4 months after completing treatment: