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Therapeutic Application

Capturing the different health conditions that PAP may adress

From mice to men: can ketamine enhance resilience to stress?

February 15, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By /

Abstract

The rapid antidepressant properties of intravenous ketamine have ignited high hopes from researchers, clinicians, and patients alike. While bottom-up patient demand has led some clinicians to offer repeated ketamine infusions directly to patients, academic commentators have warned against premature clinical adoption (1), at times likening the field’s enthusiasm to the misguided use of stimulants or opiates to induce short-term depression relief. The rapidity of ketamine’s antidepressant onset (2-hours post-infusion) is impressive, but effects dissipate almost as rapidly (3-7 days).

Price, R. B. (2016). From mice to men: can ketamine enhance resilience to stress?. Biological Psychiatry. http://dx.doi.org/10.1016/j.biopsych.2016.02.011
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Ascending single-dose, double-blind, placebo-controlled safety study of noribogaine in opioid-dependent patients

February 10, 2016 / Iboga / Ibogaine, Papers, Publications, Substance Use Disorder / By / , , , , , ,

Abstract

Ibogaine is a psychoactive substance that may reduce opioid withdrawal symptoms. This was the first clinical trial of noribogaine, ibogaine’s active metabolite, in patients established on methadone opioid substitution therapy (OST). In this randomized, double-blind, placebo-controlled, single ascending dose study, we evaluated the safety, tolerability, and pharmacokinetics of noribogaine in 27 patients seeking to discontinue methadone OST, who had been switched to morphine during the previous week. Noribogaine doses were 60, 120 or 180mg (n = 6/dose level) or matching placebo (n = 3/dose level). Noribogaine was well tolerated. The most frequent treatment-emergent adverse events were non-euphoric changes in light perception at ∼1h post dose, headache and nausea. Noribogaine had dose-linear increases for AUC and Cmax, and was slowly eliminated (mean t1/2 range 24–30h). There was a concentration-dependent increase in QTcI (0.17msec/ng/mL) with largest observed mean effect of ∼16msec, 28msec, and 42msec in the 60mg, 120mg, and 180mg groups, respectively. Noribogaine showed a non-statistically significant trend to decrease total scores in opioid withdrawal ratings, most notably at the 120mg dose, however the study design may have confounded evaluations of time to resumption of OST. Future exposure-controlled multiple-dose noribogaine studies are planned that will address these safety and design issues.

Glue, P., Cape, G., Tunnicliff, D., Lockhart, M., Lam, F., Hung, N., … & Howes, J. (2016). Ascending single‐dose, double‐blind, placebo‐controlled safety study of noribogaine in opioid‐dependent patients. Clinical Pharmacology in Drug Development. http://dx.doi.org/10.1002/cpdd.254
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The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization

February 8, 2016 / Ayahuasca, Papers, Psychology, Publications, Substance Use Disorder / By / , ,

Abstract

Ayahuasca is an Amazonian psychoactive brew of two main components. Its active agents are β-carboline and tryptamine derivatives. As a sacrament, ayahuasca is still a central element of many healing ceremonies in the Amazon Basin and its ritual consumption has become common among the mestizo populations of South America. Ayahuasca use amongst the indigenous people of the Amazon is a form of traditional medicine and cultural psychiatry. During the last two decades, the substance has become increasingly known among both scientists and laymen, and currently its use is spreading all over in the Western world. In the present paper we describe the chief characteristics of ayahuasca, discuss important questions raised about its use, and provide an overview of the scientific research supporting its potential therapeutic benefits. A growing number of studies indicate that the psychotherapeutic potential of ayahuasca is based mostly on the strong serotonergic effects, whereas the sigma-1 receptor agonist effect of its active ingredient dimethyltryptamine raises the possibility that the ethnomedical observations on the diversity of treated conditions can be scientifically verified. Moreover, in the right therapeutic or ritual setting with proper preparation and mindset of the user, followed by subsequent integration of the experience, ayahuasca has proven effective in the treatment of substance dependence. This article has two important take-home messages: 1) the therapeutic effects of ayahuasca are best understood from a bio-psycho-socio-spiritual model, and 2) on the biological level ayahuasca may act against chronic low grade inflammation and oxidative stress via the sigma-1 receptor which can explain its widespread therapeutic indications.

Frecska, E., Bokor, P., & Winkelman, M. (2016). The therapeutic potentials of ayahuasca: possible effects against various diseases of civilization. Frontiers in Pharmacology, 7, 35. http://dx.doi.org/10.3389/fphar.2016.00035
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Should ketamine be used for the clinical treatment of depression?

February 5, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , ,

Abstract

OBJECTIVE: There has been widespread interest from the public and media in the potential of ketamine as a novel treatment for depression. This paper reviews whether current evidence supports the use of ketamine for the clinical treatment of depression.

CONCLUSIONS: Clinical trials have investigated the use of intravenous ketamine for the treatment of depressive symptoms over the past 15 years. However, there remain many unanswered questions regarding its effectiveness, safety, and the route, dose and regimen for repeated administration. Experts have also raised concerns regarding ketamine’s adverse effects, abuse potential and the risk of addiction. At this stage, the use of ketamine in the treatment of depression remains in the realm of research settings.

Arunogiri, S., Keks, N. A., & Hope, J. (2016). Should ketamine be used for the clinical treatment of depression?. Australasian Psychiatry, http://dx.doi.org/10.1177/1039856216629839.

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Psychedelics

February 3, 2016 / Depressive Disorders, LSD, Mushrooms / Psilocybin, Neuroscience, Papers, Psychology, Publications / By /

Abstract

Psychedelics (serotonergic hallucinogens) are powerful psychoactive substances that alter perception and mood and affect numerous cognitive processes. They are generally considered physiologically safe and do not lead to dependence or addiction. Their origin predates written history, and they were employed by early cultures in many sociocultural and ritual contexts. After the virtually contemporaneous discovery of (5R,8R)-(+)-lysergic acid-N,N-diethylamide (LSD)-25 and the identification of serotonin in the brain, early research focused intensively on the possibility that LSD and other psychedelics had a serotonergic basis for their action. Today there is a consensus that psychedelics are agonists or partial agonists at brain serotonin 5-hydroxytryptamine 2A receptors, with particular importance on those expressed on apical dendrites of neocortical pyramidal cells in layer V. Several useful rodent models have been developed over the years to help unravel the neurochemical correlates of serotonin 5-hydroxytryptamine 2A receptor activation in the brain, and a variety of imaging techniques have been employed to identify key brain areas that are directly affected by psychedelics. Recent and exciting developments in the field have occurred in clinical research, where several double-blind placebo-controlled phase 2 studies of psilocybin-assisted psychotherapy in patients with cancer-related psychosocial distress have demonstrated unprecedented positive relief of anxiety and depression. Two small pilot studies of psilocybin-assisted psychotherapy also have shown positive benefit in treating both alcohol and nicotine addiction. Recently, blood oxygen level-dependent functional magnetic resonance imaging and magnetoencephalography have been employed for in vivo brain imaging in humans after administration of a psychedelic, and results indicate that intravenously administered psilocybin and LSD produce decreases in oscillatory power in areas of the brain’s default mode network.

Nichols, D. E. (2016). Psychedelics. Pharmacological reviews, 68(2), 264-355. http://dx.doi.org/10.1124/pr.115.011478

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

February 1, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , ,

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

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The effects of low-dose ketamine on the prefrontal cortex and amygdala in treatment-resistant depression: A randomized controlled study

January 29, 2016 / Depressive Disorders, Ketamine, Neuroscience, Papers, Publications / By / , , , , , ,

Abstract

Background

Low-dose ketamine has been found to have robust and rapid antidepressant effects. A hypoactive prefrontal cortex (PFC) and a hyperactive amygdala have been suggested to be associated with treatment-resistant depression (TRD). However, it is unclear whether the rapid antidepressant mechanisms of ketamine on TRD involve changes in glutamatergic neurotransmission in the PFC and the amygdala.
Methods

A group of 48 TRD patients were recruited and equally randomized into three groups (A: 0.5 kg/mg-ketamine; B: 0.2 kg/mg-ketamine; and C: normal saline [fusion_builder_container hundred_percent=”yes” overflow=”visible”][fusion_builder_row][fusion_builder_column type=”1_1″ background_position=”left top” background_color=”” border_size=”” border_color=”” border_style=”solid” spacing=”yes” background_image=”” background_repeat=”no-repeat” padding=”” margin_top=”0px” margin_bottom=”0px” class=”” id=”” animation_type=”” animation_speed=”0.3″ animation_direction=”left” hide_on_mobile=”no” center_content=”no” min_height=”none”][NS]). Standardized uptake values (SUV) of glucose metabolism measured by 18F-FDG positron-emission-tomography before and immediately after a 40-min ketamine or NS infusion were used for subsequent region-of-interest (ROI) analyses (a priori regions: PFC and amygdala) and whole-brain voxel-wise analyses and were correlated with antidepressant responses, as defined by the Hamilton depression rating scale score. The 18F-FDG signals were used as a proxy measure of glutamate neurotransmission.
Results

The ROI analysis indicated that Group A and Group B, but not Group C, had increases in the SUV of the PFC (group-by-time interaction: F = 7.373, P = 0.002), whereas decreases in the SUV of the amygdala were observed in all three groups (main effect of time, P  < 0.001). The voxel-wise analysis further confirmed a significant group effect on the PFC (corrected for family-wise errors, P  < 0.05; post hoc analysis: Group A<Group C, Group B<Group C). The SUV differences in the PFC predicted the antidepressant responses at 40 and 240 min post-treatment. The PFC changes did not differ between those with and without side effects.

Conclusion

Ketamine’s rapid antidepressant effects involved the facilitation of glutamatergic neurotransmission in the PFC.

Li, C. T., Chen, M. H., Lin, W. C., Hong, C. J., Yang, B. H., Liu, R. S., … & Su, T. P. (2016). The effects of low‐dose ketamine on the prefrontal cortex and amygdala in treatment‐resistant depression: A randomized controlled study. Human Brain Mapping. http://dx.doi.org/10.1002/hbm.23085
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A Double-Blind, Randomized, Placebo-Controlled, Dose-Frequency Study of Intravenous Ketamine in Patients With Treatment-Resistant Depression

January 11, 2016 / Depressive Disorders, Ketamine, Papers, Psychology, Publications / By / , , , , , ,

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

December 8, 2015 / Ayahuasca, Depressive Disorders, Papers, Psychology, Publications / By / , , , , , ,

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

November 29, 2015 / Papers, Psychology, Publications, Salvia / Salvinorin A, Substance Use Disorder / By / , , , ,

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
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