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Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use?

October 1, 2013 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By /

Editorial

Treatment-resistant depression is a significant clinical problem with great morbidity and mortality (1). The report by Murrough et al. (2), published concurrently with this editorial, of their two-site randomized controlled clinical trial of ketamine in patients with treatment-resistant depression is an exciting and important step in evaluating a new and promising approach for these patients. Should our desire as clinicians to help these often desperate patients propel us to adopt ketamine now, or do we need to know more before proceeding? More studies, or change practice now? Let’s take a look.

The effect of ketamine on treatment-resistant depression appears to be both quick and quite substantial. Overall, two-thirds (64%) of the patients in the trial of Murrough et al. (2) responded, and about one-third (number needed to treat, or NNT, 2.8) responded specifically to ketamine, which is a large effect size. By way of comparison, the NNT in placebo-controlled phase 3 Food and Drug Administration registration trials is 6–7 in depressed outpatients who are not treatment resistant. About half of those in the Murrough et al. study who responded to ketamine relapsed over the next week—apparently without a sharp increase in suicidal ideation. Distressing adverse events were encountered on both the day of and the day following the infusion—including anxiety, which might raise the risk of suicidal thinking. Overall, eight of the 47 patients who received ketamine (17%) had significant dissociative symptoms, which could be quite disturbing to persons with borderline personality disorder. Blood pressure in the ketamine group rose from 122/72 mm Hg (pretreatment) to 141/81 (40 minutes after infusion), and two subjects required their infusions to be stopped for hemodynamic reasons. Other adverse effects were reported.

We do not know who responds to ketamine and who does not. An intriguing suggestion from Laje et al. (3), noted by Murrough et al. in their discussion, is that some of those patients who do not respond to ketamine are carriers of a Val66Met (rs6265) single-nucleotide polymorphism (SNP) that is associated with an attenuation of brain-derived neurotrophic factor (BDNF) functioning).

How certain and generalizable are the findings from this report? The internal validity of the study might be challenged since the subjective effects of midazolam are likely to be quite different than those of ketamine. If blinding was incomplete, the NNT might be larger. On the other hand, the overall study results were comparable at the two individual sites. Furthermore, as Murrough et al. note, additional studies of ketamine in treatment-resistant depression that provide similar response rates or effect sizes have been reported.

While certainty of the results is seemingly high, generalizability is much more limited since the inclusion and exclusion criteria were quite selective and properly so. Only 73 of the 116 screened participants entered the study. Those with acute suicidal risk, history of psychosis, unstable general medical conditions, substance abuse in the last 2 years, abnormal ECGs, or various other features were excluded.

In patients with nonresistant depression, we know that over three out of four who do receive antidepressant medication in practice are excluded from well-designed, internally valid randomized placebo-controlled phase 3 trials (4). The inclusion and exclusion criteria in the trial of Murrough et al. (2) were at least as, if not more, restrictive than those in the usual phase 3 trials. Perhaps only one in four patients with treatment-resistant depression in practice would have been eligible to enter this particular trial. Consequently, we do not know whether ketamine is safe or effective in a wider, more representative group of patients with treatment-resistant depression for whom ketamine is likely to be used. Potential risks in this wider group include exacerbation of prior or even concurrent psychiatric or general medical conditions—borderline personality disorder, posttraumatic stress disorder; bipolar spectrum disorders, substance abuse, cardiovascular problems, etc.

Additional practical issues loom. For example, all of the subjects in the trial of Murrough et al. were medication free for at least 7 days (28 days for fluoxetine) prior to the ketamine infusion. In practice, the acquisition of a 7-day medication-free state in patients with treatment-resistant depression is very challenging given the exigencies of practice and restrictive coverage policies. The effects of ketamine when used in patients who are taking other psychotropic agents represents an unexplored risk in ketamine treatment of patients with treatment-resistant depression.

In addition, how to manage those patients who both do and do not respond to ketamine is unknown but very important. Do the previously ineffective antidepressant medications now work in ketamine responders, so that the follow-on treatment is a return to these medications? Are repeated ketamine infusions called for in the nonresponders or responders? Do they work?

While we lack several key pieces of information that are needed before we revise practice, this study does take several important steps: 1) it provides strong clinical evidence that the pathways targeted by ketamine deserve greater investigation and should be targets for drug development; 2) it suggests that some SNPs may usefully exclude at least some patients with treatment-resistant depression from ketamine infusion, which is an important step in targeting treatment (5); and 3) it suggests that with informed consent, a wider range of patients with treatment-resistant depression should be studied under controlled circumstances to better identify those who should and should not get ketamine—whether because of lack of efficacy or because of side effects. Multisite registries using an open design or point-of-care randomized trial designs (6) could be a rapid way to move the field forward at lower costs to elaborate on the risks as well as the pretreatment predictors of ketamine treatment.

While insufficient to recommend a wholesale change in practice presently, these results certainly provide substantial hope for patients with treatment-resistant depression, insight into the biology of this condition, and a major obligation by clinician scientists and funding agencies to answer this next set of important clinical questions for our patients with refractory depression.

Rush, A. J. (2013) Ketamine for Treatment-Resistant Depression: Ready or Not for Clinical Use? American Journal of Psychiatry, 170(10), 1079-1081. http://dx.doi.org/10.1176/appi.focus.12.2.244
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Crowdfunding: Ayahuasca Treatment Outcome Project

December 6, 2021 / Ayahuasca, Publications / By

An international scientific team – consisting of clinical psychiatrists and neuroscientists, medical doctors and anthropologists, epidemiologists and curanderos – is trying to set up an ambitious research project to study the effects of ayahuasca and how it affects addiction and other mental health issues. They have only 12 days left to reach their first funding goal of C$25.000, so please consider making a donation.

Since it can be a big challenge indeed to receive funding through traditional channels, OPEN supports funding serious research via other means. Donating means you are funding an interdisciplinary research design meeting contemporary high quality scientific standards, which involves thorough follow-up and a longitudinal assessment of treatment efficacy.

The team is being led by Dr. Brian Rush, Professor, Dept. of Psychiatry, University of Toronto, Canada and Scientist Emeritus at the Centre for Addiction and Mental Health, Toronto, Canada.

For more information and a video about this project have a look at their Indiegogo page.

Survey: Quit smoking after a psychedelic experience?

December 6, 2021 / Publications, Substance Use Disorder / By

Researchers from the Johns Hopkins University School of Medicine are currently recruiting individuals who have quit smoking cigarettes or reduced their smoking (even temporarily) after an experience with a psychedelic, for participation in an online survey. Their team has previously conducted innovative research on the effects of compounds including psilocybin, dextromethorphan, and salvinorin A.

The goal of this survey is to learn more about whether psychedelic drugs are associated with reduction or cessation of cigarette smoking. The researchers want to characterize people’s experiences in non-­laboratory settings in which taking a psychedelic may have led to reducing or quitting smoking. For the purposes of this survey, the survey will be asking specifically about individuals who have quit smoking cigarettes or reduced their smoking (even temporarily) after experiences with psilocybin (magic) mushrooms, LSD, morning glory seeds, mescaline, peyote cactus, San Pedro cactus, DMT, or ayahuasca. This research study has been approved by the Institutional Review Board of Johns Hopkins Medicine.

The survey is completely anonymous (IP addresses will not be recorded) and will require 40-45 minutes to complete. If you are interested in participating, please click this link. Participation is voluntary and will not be financially compensated.

Participants must be 18+ years of age, speak/write English fluently, and have experienced a reduction or cessation of cigarette smoking after an experience with one of the psychedelic substances listed above. For more information, please contact the researchers via the site’s private messaging system.

Principal Investigator of this study, Matthew W. Johnson was a speaker at our Interdisciplinary Conference on Psychedelic Research in 2012. A video on the topic of this study can be watched below.

Self-Medication of LSD and MDMA to Treat Mental Disorders: A Case Series

September 18, 2013 / Anxiety Disorders / PTSD, Depressive Disorders, LSD, MDMA, Papers, Psychology, Publications / By /

Abstract

50 years ago LSD was prescribed to treat a variety of mental illnesses. More recently LSD and MDMA (ecstasy) have become widely used outside medicine as both recreational drugs and by some patients as ‘self-medication’. These brief reports gather together five patients’ experiences using psychedelic drugs to treat their mental disorders. They are discussed in relation to the medical profession’s current growing interest in re-visiting psychedelic drugs as therapeutic treatments in psychiatry. The first case describes the successful self-treatment for depression using LSD, followed by a case in which doctors administered LSD in the 1960s and 1970s to successfully treat a case of obsessive-compulsive disorder (OCD) and chronic fatigue syndrome. The third and fourth cases describe the successful self-treatment of OCD using respectively MDMA and then LSD and the final case describes a self-treatment with LSD to manage Anorexia Nervosa. All the participants describing their use of these drugs give a positive report of self-treatment with minimal adverse effects. They also all support a resumption of more research into the therapeutic use of hallucinogens/psychedelic drugs as potential clinical therapies.

Sessa, B. (2010). Self-medication of LSD and MDMA to treat mental disorders: A case series. The Journal of Alternative Medicine Research, 2(2), 245-249.
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Broadband cortical desynchronization underlies the human psychedelic state

September 18, 2013 / Mushrooms / Psilocybin, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

Psychedelic drugs produce profound changes in consciousness, but the underlying neurobiological mechanisms for this remain unclear. Spontaneous and induced oscillatory activity was recorded in healthy human participants with magnetoencephalography after intravenous infusion of psilocybin—prodrug of the nonselective serotonin 2A receptor agonist and classic psychedelic psilocin. Psilocybin reduced spontaneous cortical oscillatory power from 1 to 50 Hz in posterior association cortices, and from 8 to 100 Hz in frontal association cortices. Large decreases in oscillatory power were seen in areas of the default-mode network. Independent component analysis was used to identify a number of resting-state networks, and activity in these was similarly decreased after psilocybin. Psilocybin had no effect on low-level visually induced and motor-induced gamma-band oscillations, suggesting that some basic elements of oscillatory brain activity are relatively preserved during the psychedelic experience. Dynamic causal modeling revealed that posterior cingulate cortex desynchronization can be explained by increased excitability of deep-layer pyramidal neurons, which are known to be rich in 5-HT2A receptors. These findings suggest that the subjective effects of psychedelics result from a desynchronization of ongoing oscillatory rhythms in the cortex, likely triggered by 5-HT2A receptor-mediated excitation of deep pyramidal cells.

Muthukumaraswamy, S. D., Carhart-Harris, R. L., Moran, R. J., Brookes, M. J., Williams, T. M., Errtizoe, D., … & Feilding, A. (2013). Broadband cortical desynchronization underlies the human psychedelic state. The Journal of Neuroscience, 33(38), 15171-15183. 10.1523/JNEUROSCI.2063-13.2013
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Psychedelics linked to lower mental health risks

December 6, 2021 / Psychology, Publications / By

The use of LSD, magic mushrooms, or peyote does not increase a person’s risk of developing mental health problems, according to an analysis of information from more than 130,000 randomly chosen people, including 22,000 people who had used psychedelics at least once.

Researcher Teri Krebs and clinical psychologist Pål-Ørjan Johansen, from the Norwegian University of Science and Technology’s (NTNU), cleverly used data from a US national health survey to study the association between psychedelic drug use and mental health problems.

The researchers relied on data from the 2001-2004 National Survey on Drug Use and Health, in which participants were asked about mental health treatment and symptoms of a variety of mental health conditions over the past year. The specific symptoms examined were general psychological distress, anxiety disorders, mood disorders, and psychosis.

The study showed that lifetime use of psilocybin or mescaline and past year use of LSD were associated with lower rates of serious psychological distress. Lifetime use of LSD was also significantly associated with a lower rate of outpatient mental health treatment and psychiatric medicine prescription, although the nature of these relations were not demonstrated in the Norwegians’ study.

Interestingly, the results of this study confirm the outcomes of recent clinical trials that likewise do not demonstrate lasting harmful effects from the use of psychedelics in a clinical setting. It further shows that even when used non-clinically, psychedelic substances might be able to play a role in alleviating mental health issues.

The results are published in the journal PLOS One and are freely available online.

A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment

September 1, 2013 / Ayahuasca, DMT, Iboga / Ibogaine, LSD, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Psychology, Publications, Substance Use Disorder / By / ,

Abstract

Current treatments for addiction are frequently ineffective. Hallucinogenic therapy has been indicated as helpful for a range of substance use disorders, yet this approach remains understudied and publicly unavailable. It is nonetheless a promising treatment, which has significant, long-term beneficial effects with single doses and a profile characterized by general safety, low toxicity, and non-addictiveness. However, pharmacological interventions, such as hallucinogens, should not be offered if the same effects (e.g. psychological insights/mystical experiences) and outcomes (e.g. decreased drug use) could be achieved absent pharmacological intervention. To date, there have been no clinical comparisons of drug-induced altered states with non-drug-induced states for addiction treatment. We propose and then outline a clinical trial to address this gap in knowledge. The proposed design would evaluate abstinence outcomes in a population of prescription opioid abusers after exposure to one of three conditions: a drug-induced altered state using psilocybin, a non-drug-induced altered state via hyperventilation (Holotropic Breathwork), and an active placebo with niacin. The outcomes of such a study would reveal important differences in therapeutic potential by discriminating hallucinogen-dependent effects from those psychological effects resulting from altered states.

Burdick, B. V., & Adinoff, B. (2013). A proposal to evaluate mechanistic efficacy of hallucinogens in addiction treatment. The American Journal of Drug and Alcohol Abuse, 39(5), 291-297. http://dx.doi.org/10.3109/00952990.2013.811513
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Psychedelics and Mental Health: A Population Study

August 19, 2013 / MDMA, Mescaline / Cacti, Mushrooms / Psilocybin, Papers, Psychology, Publications / By / ,

Abstract

Background
The classical serotonergic psychedelics LSD, psilocybin, mescaline are not known to cause brain damage and are regarded as non-addictive. Clinical studies do not suggest that psychedelics cause long-term mental health problems. Psychedelics have been used in the Americas for thousands of years. Over 30 million people currently living in the US have used LSD, psilocybin, or mescaline.

Objective
To evaluate the association between the lifetime use of psychedelics and current mental health in the adult population.

Method
Data drawn from years 2001 to 2004 of the National Survey on Drug Use and Health consisted of 130,152 respondents, randomly selected to be representative of the adult population in the United States. Standardized screening measures for past year mental health included serious psychological distress (K6 scale), mental health treatment (inpatient, outpatient, medication, needed but did not receive), symptoms of eight psychiatric disorders (panic disorder, major depressive episode, mania, social phobia, general anxiety disorder, agoraphobia, posttraumatic stress disorder, and non-affective psychosis), and seven specific symptoms of non-affective psychosis. We calculated weighted odds ratios by multivariate logistic regression controlling for a range of sociodemographic variables, use of illicit drugs, risk taking behavior, and exposure to traumatic events.

Results
21,967 respondents (13.4% weighted) reported lifetime psychedelic use. There were no significant associations between lifetime use of any psychedelics, lifetime use of specific psychedelics (LSD, psilocybin, mescaline, peyote), or past year use of LSD and increased rate of any of the mental health outcomes. Rather, in several cases psychedelic use was associated with lower rate of mental health problems.

Conclusion
We did not find use of psychedelics to be an independent risk factor for mental health problems.

Krebs, T. S., & Johansen, P. Ø. (2013) Psychedelics and Mental Health: A Population Study. PLoS ONE, 8(8), 1-9. http://dx.doi.org/10.1371/journal.pone.0063972
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Phylogenetic inference and trait evolution of the psychedelic mushroom genus Psilocybe sensu lato (Agaricales)

August 6, 2013 / Biology & Ethnobotany, Mushrooms / Psilocybin, Papers, Publications / By / , , , , , ,

Abstract

The genus Psilocybe contains iconic species of fungi renowned for their hallucinogenic properties. Recently, Psilocybe also included non-hallucinogenic species that have since been shifted to the genus Deconica. Here, we reconstruct a multigene phylogeny for Psilocybe, Deconica, and other exemplars of the families Hymenogastraceae and Strophariaceae sensu stricto (s. str.), using three nuclear markers (nLSU-rRNA, 5.8S rRNA, and rpb1). Our results confirm the monophyly of Deconica within Strophariaceae s. str., as well as numerous robust infrageneric relationships. Psilocybe is also recovered as a monophyletic group in the Hymenogastraceae, in which two principal lineages are recognized, including several nested subgroups. Most sections of Psilocybe following classifications based on morphological features are not supported in these analyses. Ancestral character state reconstruction analyses suggest that basidiospore shape in frontal view and spore wall thickness, commonly used to characterize sections in Deconica and Psilocybe, are homoplastic. Chrysocystidia, sterile cells located in the hymenium, evolved on at least two occasions in the Strophariaceae s. str., including in a novel lineage of Deconica.

Ramírez-Cruz, V. Guzmán, G., Villalobos-Arámbula, A. R., Rodríguez, A.,  Matheny, P. B., Sánchez-García, M., & Guzmán-Dávalos, L. (2013). Phylogenetic inference and trait evolution of the psychedelic mushroom genusPsilocybesensu lato (Agaricales). Botany, 91, 573-591. http://dx.doi.org/10.1139/cjb-2013-0070
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Methoxetamine (MXE) – A Phenomenological Study of Experiences Induced by a “Legal High” from the Internet

August 2, 2013 / Papers, Publications, Substance Use Disorder / By / ,

Abstract

Methoxetamine (MXE), a ketamine analogue, is one of the new “legal highs” sold on the Internet. The aim of this qualitative study was to provide an initial understanding of what characterizes the experiences induced by MXE. Anonymously written reports (33 persons) on the effects of MXE were collected from public Internet forums and analyzed using the Empirical Phenomenological Psychological Method. The analysis generated 10 themes: (1) preparation, motivation and anticipation; (2) initial effects; (3) malfunction of cognitive processes stabilizing normal state; (4) inner personal processes and learning; (5) emotional processes; (6) altered sensory perception; (7) dissolution and transition; (8) spiritual and transcendental experiences; (9) effects and processes after the experience; (10) re-dosing and addiction.

MXE induced a heavily altered state of consciousness. The effects were similar to those induced by classic hallucinogens (such as LSD, psilocybin) and the dissociative ketamine. MXE seemed to have quite a high abuse potential. Beside the positive effects described, negative effects like fear and anxiety were also reported. Acceptance was considered the best coping strategy. Dissolution of identity and body often culminated in spiritual and transcendental experiences. More research is needed on safety issues, how to minimize harm, and the motivation for using legal highs.

Kjellgren, A., & Jonsson, K. (2013). Methoxetamine (MXE)–a phenomenological study of experiences induced by a “legal high” from the Internet. Journal of psychoactive drugs, 45(3), 276-286. http://dx.doi.org/10.1080/02791072.2013.803647

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