OPEN Foundation

Psychology

Oral ketamine for the treatment of pain and treatment-resistant depression

Abstract

Background

Recent studies with intravenous (i.v.) application of ketamine show remarkable but short-term success in patients with MDD. Studies in patients with chronic pain have used different ketamine applications for longer time periods. This experience may be relevant for psychiatric indications.

Aims

To review the literature about the dosing regimen, duration, effects and side-effects of oral, intravenous, intranasal and subcutaneous routes of administration of ketamine for treatment-resistant depression and pain.

Method

Searches in PubMed with the terms ‘oral ketamine’, ‘depression’, ‘chronic pain’, ‘neuropathic pain’, ‘intravenous ketamine’, ‘intranasal ketamine’ and ‘subcutaneous ketamine’ yielded 88 articles. We reviewed all papers for information about dosing regimen, number of individuals who received ketamine, number of ketamine days per study, results and side-effects, as well as study quality.

Results

Overall, the methodological strength of studies investigating the antidepressant effects of ketamine was considered low, regardless of the route of administration. The doses for depression were in the lower range compared with studies that investigated analgesic use. Studies on pain suggested that oral ketamine may be acceptable for treatment-resistant depression in terms of tolerability and side-effects.

Conclusions

Oral ketamine, given for longer time periods in the described doses, appears to be well tolerated, but few studies have systematically examined the longer-term negative consequences. The short- and longer-term depression outcomes as well as side-effects need to be studied with rigorous randomised controlled trials.

Schoevers, R. A., Chaves, T. V., Balukova, S. M., aan het Rot, M., & Kortekaas, R. (2016). Oral ketamine for the treatment of pain and treatment-resistant depression. The British Journal of Psychiatry, 208(2), 108-113. http://dx.doi.org/10.1192/bjp.bp.115.165498

Link to full text

Oxytocin receptor gene variation predicts subjective responses to MDMA

Abstract

3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) enhances desire to socialize and feelings of empathy, which are thought to be related to increased oxytocin levels. Thus, variation in the oxytocin receptor gene (OXTR) may influence responses to the drug. Here we examined the influence of a single OXTR nucleotide polymorphism (SNP) on responses to MDMA in humans. Based on findings that carriers of the A allele at rs53576 exhibit reduced sensitivity to oxytocin-induced social behavior, we hypothesized that these individuals would show reduced subjective responses to MDMA, including sociability. In this 3-session, double blind, within-subjects study, healthy volunteers with past MDMA experience (N = 68) received a MDMA (0, 0.75 mg/kg and 1.5 mg/kg) and provided self-report ratings of sociability, anxiety, and drug effects. These responses were examined in relation to rs53576. MDMA (1.5 mg/kg) did not increase sociability in individuals with the A/A genotype as it did in G allele carriers. The genotypic groups did not differ in responses at the lower MDMA dose, or in cardiovascular or other subjective responses. These findings are consistent with the idea that MDMA-induced sociability is mediated by oxytocin, and that variation in the oxytocin receptor gene may influence responses to the drug.

Bershad, A. K., Weafer, J. J., Kirkpatrick, M. G., Wardle, M. C., Miller, M. A., & de Wit, H. (2016). Oxytocin receptor gene variation predicts subjective responses to MDMA. Social neuroscience. http://dx.doi.org/10.1080/17470919.2016.1143026

Link to full text

A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

Abstract

Objective:
Ketamine, an N-methyl-d-aspartate glutamate receptor antagonist, has demonstrated a rapid-onset antidepressant effect in patients with treatment-resistant depression. This study evaluated the efficacy of twice- and thrice-weekly intravenous administration of ketamine in sustaining initial antidepressant effects in patients with treatment-resistant depression.

Method:
In a multicenter, double-blind study, adults (ages 18–64 years) with treatment-resistant depression were randomized to receive either intravenous ketamine (0.5 mg/kg of body weight) or intravenous placebo, administered over 40 minutes, either two or three times weekly, for up to 4 weeks. Patients who discontinued double-blind treatment after at least 2 weeks for lack of efficacy could enter an optional 2-week open-label phase to receive ketamine with the same frequency as in the double-blind phase. The primary outcome measure was change from baseline to day 15 in total score on the Montgomery-Åsberg Depression Rating Scale (MADRS).

Results:
In total, 67 (45 women) of 68 randomized patients received treatment. In the twice-weekly dosing groups, the mean change in MADRS score at day 15 was −18.4 (SD=12.0) for ketamine and −5.7 (SD=10.2) for placebo; in the thrice-weekly groups, it was −17.7 (SD=7.3) for ketamine and −3.1 (SD=5.7) for placebo. Similar observations were noted for ketamine during the open-label phase (twice-weekly, −12.2 [SD=12.8] on day 4; thrice-weekly, −14.0 [SD=12.5] on day 5). Both regimens were generally well tolerated. Headache, anxiety, dissociation, nausea, and dizziness were the most common (≥20%) treatment-emergent adverse events. Dissociative symptoms occurred transiently and attenuated with repeated dosing.

Conclusions:
Twice-weekly and thrice-weekly administration of ketamine at 0.5 mg/kg similarly maintained antidepressant efficacy over 15 days.

Singh, J. B., Fedgchin, M., Daly, E. J., De Boer, P., Cooper, K., Lim, P., … & Kurian, B. (2016). A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression. American Journal of Psychiatry. http://dx.doi.org/10.1176/appi.ajp.2016.16010037
Link to full text

Therapy with Substance – Psycholytic psychotherapy in the twenty first century

Therapy with Substance: Psycholytic psychotherapy in the twenty first century by Dr Friederike Meckel Fischer, Muswell Hill Press, 2015.

In the field where psychedelics and psychotherapy overlap, there are two main schools: the school of psychedelic therapy, most popular in the United States, which aims to give people a complete mystical experience in a very limited number of high-dose sessions, in order to help them overcome problems or reach a certain state that will help transform the person’s life for the better. The therapist generally remains silent throughout the psychedelic sessions and lets happen whatever happens. Psycholytic therapy, on the other hand, generally involves lower doses and a higher number of sessions with a psychedelic substance, and aims to bring to the surface the causes of the problems in someone’s life. By going into these, and by talking about them during the experience, insight comes and the problems dissolve. This latter approach was mainly popular in Europe and is practiced to this day in unofficial settings.

Dr Meckel Fischer is a medical doctor who went on to study many alternative modalities of healing, most notably Holotropic Breathwork under Stanislav Grof and Psycholytic Therapy with the Swiss medical society for psycholytic therapy (SAEPT) under the guidance of Samuel Widmer. She practiced psycholytic therapy (which at that point had become illegal) for some time, until one of her clients reported her to the police. She was put on trial in Switzerland and convicted. This made it possible for her to describe her experience without fearing to be convicted again. The resulting book is both a fascinating personal account of the way she learned from psycholytic therapy herself and the insights she gathered through her many years of experience in treating people.

The first three chapters deal with Dr Meckel Fischer’s personal path to healing and understanding through different types of therapy after a deep crisis in one of her relationships. She started with regular cognitive therapy, but quickly moved on to depth-psychology, and then to transpersonal psychotherapy with the help of holotropic breathwork under the guidance of Grof. At some point Grof pointed her in the direction of therapy with substance and she dove into this path, externally claiming to do it strictly for professional reasons, while at the same time discovering that it really helped her on a personal level as well.

The author then goes on to give a brief description of what psychotherapy entails in her opinion. She emphasises that there has to be a motivation for change, but that this change can only be initiated by allowing the unconscious material to come to the surface. Effective therapy and lasting change can only happen if the root cause is addressed, which means that the unconscious and pre-conscious causes, that lie in the transpersonal and perinatal domains emphasised by Grof, are allowed to be integrated into consciousness. Meckel Fischer thinks traditional psychotherapy does not work on this level and is therefore rarely effective in treating deeper issues.

She subsequently describes the different substances used in psycholytic therapy, showing how all of them have both unique and general properties. She acknowledges that people both can and have to learn how to work with these substances, and that initial sessions can lack direction and purpose. With time and experience, the sessions become more focused and people learn how to access their unconscious more intentionally. Meckel Fischer is of the opinion that any guide in a psycholytic therapy session should use the substance themselves along with the patient, as this helps them to sense what is going on within the participant: “A mountain guide cannot lead a walker through territory that they have not explored personally”. Her arguments for this point of view are convincing, although they may be considered controversial from a western medical perspective.

Meckel Fischer identifies several tools that help the guide perform psycholytic therapy. These tools are somewhat specific to her, as they resonate with her professional experience and background, but they can be somewhat generalised. Among them are the therapist, the substance, family constellation work, live-body-work, the group and music. All these aspects influence the experience and some can be utilised to initiate or deepen a process within a participant. These tools are used throughout the session. The series of sessions moves a person through different stages: from beginner to graduate, from starting out on the path of self-discovery to knowing the way and being able to continue on their own.

She furthermore shows the different stations along the path to integrating deep unconscious material, from the core therapeutic issue, through psychosomatics, epigenetic and perinatal experiences towards spiritual experiences. Meckel Fischer gives many examples and shows how many of the stories of the people she guided fit the stages and stations she enumerates. It seems to be a universal process that is similar to the hero’s journey, popularised by Joseph Campbell.

The author ends with a discussion of the dangers and side effects of using psychoactive substances in psycholytic therapy. One of the most important dangers is of course the illegality, although she believes that under certain circumstances this can help participants to take responsibility for the process they are entering. She also briefly relates the process of psycholytic therapy to shamanism, healing and spirituality, but doesn’t really go into depths with regards to these ideas. In the concluding remarks, she hints at what lies beyond psycholytic therapy: something that isn’t therapy anymore, but that heals our worldview and makes us more integral with our environment and holistic in our outlook.

At times the impression arises that the author too readily claims that her personal experiences with certain substances are universal; this is especially tangible in the explanation of the effects of the different substances. In other cases, she acknowledges that her experience is hers alone, but the general tone of the former examples makes one think that she feels otherwise. Meckel Fischer mentions one way in which to conceptualise and practice psycholytic therapy, and does not envision the possibility that other ways are possible. However, the wisdom the book embodies generally sounds genuine. There are nuggets of wisdom that make one realise a deeper truth, like: “the intention expressed on the evening before the session signals the first stage of the process of integration”. Others run contrary to the idea that one session should be enough: “The ability to be ‘on a substance’, and learn to observe the inner self under its effects in a composed, centred and disciplined way, increases with practice”.

Overall, the book offers a great look into a very promising way of using psychedelics that can be integrated into our society quite easily, as it has built-in mechanisms for minimising risks and maximising positive outcomes, as well as the idea of medical/psychological supervision. It is a timely book, which can help to institutionalise the craft of psycholytic therapy into something that can be learned, practiced and taught to others through experience. Meckel Fischer also makes a great case for experienced practitioners to help newcomers. Moreover, disorders are viewed in a more integrative and holistic manner, showing that no-one is completely sane and no-one is completely mad, but that all can benefit from deep therapeutic work on the self. It is a book for everybody who’s interested in doing serious therapeutic work with psychedelics, either by themselves or, when legal constraints are removed, in the form of individual or group therapy.

Buy this book at bookdepository.com and support the OPEN Foundation.

Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study

Abstract

Ayahuasca is an Amazonian botanical hallucinogenic brew which contains dimethyltryptamine, a 5-HT2A receptor agonist, and harmine, a monoamine-oxidase A inhibitor. Our group recently reported that ayahuasca administration was associated with fast-acting antidepressive effects in 6 depressive patients. The objective of the present work was to assess the antidepressive potentials of ayahuasca in a bigger sample and to investigate its effects on regional cerebral blood flow. In an open-label trial conducted in an inpatient psychiatric unit, 17 patients with recurrent depression received an oral dose of ayahuasca (2.2 mL/kg) and were evaluated with the Hamilton Rating Scale for Depression, the Montgomery-Asberg Depression Rating Scale, the Brief Psychiatric Rating Scale, the Young Mania Rating Scale, and the Clinician Administered Dissociative States Scale during acute ayahuasca effects and 1, 7, 14, and 21 days after drug intake. Blood perfusion was assessed eight hours after drug administration by means of single photon emission tomography. Ayahuasca administration was associated with increased psychoactivity (Clinician Administered Dissociative States Scale) and significant score decreases in depression-related scales (Hamilton Rating Scale for Depression, Montgomery-Asberg Depression Rating Scale, Brief Psychiatric Rating Scale) from 80 minutes to day 21. Increased blood perfusion in the left nucleus accumbens, right insula and left subgenual area, brain regions implicated in the regulation of mood and emotions, were observed after ayahuasca intake. Ayahuasca was well tolerated. Vomiting was the only adverse effect recorded, being reported by 47% of the volunteers. Our results suggest that ayahuasca may have fast-acting and sustained antidepressive properties. These results should be replicated in randomized, double-blind, placebo-controlled trials.
Sanches, R. F., de Lima, O. F., Dos Santos, R. G., Macedo, L. R., Maia-de-Oliveira, J. P., Wichert-Ana, L., … & Hallak, J. E. (2015). Antidepressant Effects of a Single Dose of Ayahuasca in Patients With Recurrent Depression: A SPECT Study. Journal of clinical psychopharmacology. http://dx.doi.org/10.1097/JCP.0000000000000436
Link to full text

Salvia divinorum: An overview of the usage, misuse, and addiction processes

Abstract

Salvia divinorum, a sage plant with leaves that can produce a psychoactive high, has been used for hundreds of years for its psycho-mimetic effects in religious rituals in South America. Salvia has now become popular mainly with adolescents and young adults for the short-lived relatively pleasant experiences many consider a “legal high” and its ready availability through Internet purchases. The main (psycho)active compound in salvia is Salvinorin A, a potent κ-opioid agonist and although the short and long-term effects have not been examined in sufficient detail, it is widely believed to have low addictive potential and low toxicity. Recent findings, however, seem to suggest that Salvinorin A can precipitate psychiatric symptoms and negatively affect cognition. Its ready availability and increasingly widespread use requires clinicians to have knowledge and awareness of its effects.

Mahendran, R., Lim, H. A., Tan, J., Chua, S. M., & Winslow, M. (2015). Salvia divinorum: An overview of the usage, misuse, and addiction processes. Asia‐Pacific Psychiatry. http://dx.doi.org/10.1111/appy.12225
Link to full text

Exploring the therapeutic potential of Ayahuasca: acute intake increases mindfulness-related capacities

Abstract

BACKGROUND:

Ayahuasca is a psychotropic plant tea used for ritual purposes by the indigenous populations of the Amazon. In the last two decades, its use has expanded worldwide. The tea contains the psychedelic 5-HT2A receptor agonist N,N-dimethyltryptamine (DMT), plus β-carboline alkaloids with monoamine-oxidase-inhibiting properties. Acute administration induces an introspective dream-like experience characterized by visions and autobiographic and emotional memories. Studies of long-term users have suggested its therapeutic potential, reporting that its use has helped individuals abandon the consumption of addictive drugs. Furthermore, recent open-label studies in patients with treatment-resistant depression found that a single ayahuasca dose induced a rapid antidepressant effect that was maintained weeks after administration. Here, we conducted an exploratory study of the psychological mechanisms that could underlie the beneficial effects of ayahuasca.

METHODS:

We assessed a group of 25 individuals before and 24 h after an ayahuasca session using two instruments designed to measure mindfulness capacities: The Five Facets Mindfulness Questionnaire (FFMQ) and the Experiences Questionnaire (EQ).

RESULTS:

Ayahuasca intake led to significant increases in two facets of the FFMQ indicating a reduction in judgmental processing of experiences and in inner reactivity. It also led to a significant increase in decentering ability as measured by the EQ. These changes are classic goals of conventional mindfulness training, and the scores obtained are in the range of those observed after extensive mindfulness practice.

CONCLUSIONS:

The present findings support the claim that ayahuasca has therapeutic potential and suggest that this potential is due to an increase in mindfulness capacities.

Link to full text

Dimensions of the Psyche

Abstract

In conversation with Katherine Olivetti, Stanislav Grof and Richard Tarnas, who have collaborated for over four decades, speak candidly, exploring perinatal experience, non-ordinary states of consciousness, archetypal patterns, and astrology as a transpersonal phenomenon.

Olivetti, K. (2015). Dimensions of the Psyche: A Conversation with Stanislav Grof, MD, and Richard Tarnas, PhD. Jung Journal, 9(4), 98-124. http://dx.doi.org/10.1080/19342039.2015.1086937

Link to full text

The Psychopharmacology of ±3,4 Methylenedioxymethamphetamine and its Role in the Treatment of Posttraumatic Stress Disorder

Abstract

Prior to 1985, ± 3,4-methylenedioxymethamphetamine (MDMA) was readily used as a psychotherapeutic adjunct. As MDMA became popular in treating various psychiatric illnesses by mental health professionals, the public started to abuse the MDMA-containing recreational drug “ecstasy.” This alarmed the DEA, which led to emergency scheduling of MDMA as a Schedule I drug. Due to its scheduling in 1985, human research and clinical use has been limited. The majority of research on MDMA has been focused on the drug’s potential harmful effects rather than its possible therapeutic effects. The limitations on retrospective human studies and preclinical animal models of MDMA neurotoxicity are examined in this analysis. New research has shown that MDMA, used as a catalyst in psychotherapy, is effective in treating posttraumatic stress disorder (PTSD). This review also examines the psychopharmacological basis for the efficacy of MDMA-assisted psychotherapy. Specifically, the brain regions involved with both PTSD and those activated by MDMA (i.e., amygdala, anterior cingulate cortex, and hippocampus) are examined. Also, the possible neurochemical mechanisms involved in MDMA’s efficacy in treating PTSD are reviewed.

Amoroso, T. (2015). The Psychopharmacology of±3, 4 Methylenedioxymethamphetamine and its Role in the Treatment of Posttraumatic Stress Disorder. Journal of Psychoactive Drugs, 1-8. http://dx.doi.org/10.1080/02791072.2015.1094156

Link to full text

Plant and Fungal Hallucinogens as Toxic and Therapeutic Agents

Abstract

This chapter aimed to provide an overview of the large number of hallucinogens of natural origin. Following a literature review, the following hallucinogens were selected for a detailed description that considered their essential chemical groups: indoleamines (N,N-dimethyltryptamine, 5-methoxy-N,N-dimethyltryptamine, bufotenine, psilocybin, and ibogaine), phenylethylamines (mescaline), tropane alkaloids (atropine and scopolamine), cannabinoids (Δ9-tetrahydrocannabinol), and a neoclerodane diterpenoid (salvinorin A). The following species were included as representative of each drug class: Mimosa tenuiflora, Psychotria viridis, Banisteriopsis caapi, Virola spp., Psilocybe spp., Tabernanthe iboga, Tabernaemontana spp., Lophophora spp., Trichocereus spp., Atropa belladonna, Brugmansia spp., Cannabis sativa, and Salvia divinorum, among others. In addition to psychopharmacological effects, this chapter aims to address the sociocultural and historical use of these hallucinogenic plants and mushrooms, along with the importance of both the set and the setting factors that affect the profound consciousness-altering effects of these compounds. Moreover, the use of animal models to predict the hallucinogenic properties of psychoactive plants and compounds and to investigate the mechanisms of action of psychodysleptic drugs is discussed. This chapter also attempts to establish a parallel between hallucinogens and endogenous neurotransmitters in humans, to compare the pharmacological and psychic action of these compounds, to evaluate hallucinogens’ ability to produce symptoms typical of certain mental disorders during their use, and to investigate the role of these compounds as therapeutic agents in several psychopathological conditions.

Carlini, E. A., & Maia, L. O. (2015). Plant and Fungal Hallucinogens as Toxic and Therapeutic Agents.

Link to full text

interested in becoming a trained psychedelic-assisted therapist?

Online Event - Psychedelic Care in Recreational Settings - 3 October 2024