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Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults

March 28, 2017 / Mushrooms / Psilocybin, Papers, Psychology, Psychopharmacology, Publications, Safety, Toxicology / By / , , , , , ,

Abstract

INTRODUCTION: Psilocybin is a psychedelic tryptamine that has shown promise in recent clinical trials for the treatment of depression and substance use disorders. This open-label study of the pharmacokinetics of psilocybin was performed to describe the pharmacokinetics and safety profile of psilocybin in sequential, escalating oral doses of 0.3, 0.45, and 0.6 mg/kg in 12 healthy adults.

METHODS: Eligible healthy adults received 6-8 h of preparatory counseling in anticipation of the first dose of psilocybin. The escalating oral psilocybin doses were administered at approximately monthly intervals in a controlled setting and subjects were monitored for 24 h. Blood and urine samples were collected over 24 h and assayed by a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) assay for psilocybin and psilocin, the active metabolite. The pharmacokinetics of psilocin were determined using both compartmental (NONMEM) and noncompartmental (WinNonlin) methods.

RESULTS: No psilocybin was found in plasma or urine, and renal clearance of intact psilocin accounted for less than 2% of the total clearance. The pharmacokinetics of psilocin were linear within the twofold range of doses, and the elimination half-life of psilocin was 3 h (standard deviation 1.1). An extended elimination phase in some subjects suggests hydrolysis of the psilocin glucuronide metabolite. Variation in psilocin clearance was not predicted by body weight, and no serious adverse events occurred in the subjects studied.

CONCLUSIONS: The small amount of psilocin renally excreted suggests that no dose reduction is needed for subjects with mild-moderate renal impairment. Simulation of fixed doses using the pharmacokinetic parameters suggest that an oral dose of 25 mg should approximate the drug exposure of a 0.3 mg/kg oral dose of psilocybin. Although doses of 0.6 mg/kg are in excess of likely therapeutic doses, no serious physical or psychological events occurred during or within 30 days of any dose.

Brown, R. T., Nicholas, C. R., Cozzi, N. V., Gassman, M. C., Cooper, K. M., Muller, D., … & Hutson, P. R. (2017). Pharmacokinetics of Escalating Doses of Oral Psilocybin in Healthy Adults. Clinical Pharmacokinetics, 1-12. 10.1007/s40262-017-0540-6
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Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome

March 21, 2017 / Depression, Ketamine, Medicine, Papers, Psychology, Safety / By / , , , , , ,

Abstract

A subset of patients with depression have elevated levels of inflammatory cytokines, and some studies demonstrate interaction between inflammatory factors and treatment outcome. However, most studies focus on only a narrow subset of factors in a patient sample. In the current study, we analyzed broad immune profiles in blood from patients with treatment-resistant depression (TRD) at baseline and following treatment with the glutamate modulator ketamine. Serum was analyzed from 26 healthy control and 33 actively depressed TRD patients free of antidepressant medication, and matched for age, sex and body mass index. All subjects provided baseline blood samples, and TRD subjects had additional blood draw at 4 and 24 h following intravenous infusion of ketamine (0.5 mg kg−1). Samples underwent multiplex analysis of 41 cytokines, chemokines and growth factors using quantitative immunoassay technology. Our a priori hypothesis was that TRD patients would show elevations in canonical pro-inflammatory cytokines; analyses demonstrated significant elevation of the pro-inflammatory cytokine interleukin-6. Further exploratory analyses revealed significant regulation of four additional soluble factors in patients with TRD. Several cytokines showed transient changes in level after ketamine, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response. In sum, we found that patients with TRD demonstrate a unique pattern of increased inflammatory mediators, chemokines and colony-stimulating factors, providing support for the immune hypothesis of TRD. These patterns suggest novel treatment targets for the subset of patients with TRD who evidence dysregulated immune functioning.
Kiraly, D. D., Horn, S. R., Van Dam, N. T., Costi, S., Schwartz, J., Kim-Schulze, S., … & Iosifescu, D. V. (2017). Altered peripheral immune profiles in treatment-resistant depression: response to ketamine and prediction of treatment outcome. Translational psychiatry, 7(3), e1065. 10.1038/tp.2017.31
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LSD instead of 25I-NBOMe: The revival of LSD? A case report

February 27, 2017 / LSD, Medicine, New substances, Other substances, Papers, Publications, Safety, Toxicology / By / , , , , , ,

Abstract

Observation: We report a case of a 25-year-old man crushed by a train while he was returning from a rave party. The consumption of 25I-NBOMe was rapidly evoked by people who had participated at the party.

Materials and methods: In this context, the post-mortem toxicological expertise was completed by a broad screening using high-resolution mass spectrometry detection (LC-HRMS). Three hundred NPS and metabolites (including 25B, 25C and 25I-NBOMes) can be found with this method. A targeted screening in MRM mode was also performed on a smaller number of hallucinogens.

Results: The toxicological analyses were performed on blood and urine samples. Amphetamines, cocaine, cannabinoids and opiates were not detected. Ethanol was measured at 0.71 g/L and 1.59 g/L in blood and urine samples, respectively. The screening by LC-HRMS did not reveal the presence of NPS, including NBOMes. The targeted screening in MRM mode revealed the presence of LSD and its metabolite, the 2-oxo-3-hydroxy-LSD. LSD was quantified at 0.2 ng/mL in blood.

Conclusion: This case alerts on the frequent confusion between NBOMes and LSD and on the renewed interest for LSD due to the popularity of NBOMes. This case therefore encourages the prudence and research of all hallucinogenic substances, even when the context is evocative.

Bodeau, S., Bennis, Y., Régnaut, O., Fabresse, N., Richeval, C., Humbert, L., … & Lemaire-Hurtel, A. S. (2017). LSD instead of 25I-NBOMe: The revival of LSD? A case report. Toxicologie Analytique et Clinique, 29(1), 139-143. 10.1016/j.toxac.2016.12.007
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Ayahuasca dimethyltryptamine, and psychosis: a systematic review of human studies

February 23, 2017 / Ayahuasca, DMT, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Safety / By / , ,

Abstract

Ayahuasca is a hallucinogen brew traditionally used for ritual and therapeutic purposes in Northwestern Amazon. It is rich in the tryptamine hallucinogens dimethyltryptamine (DMT), which acts as a serotonin 5-HT2A agonist. This mechanism of action is similar to other compounds such as lysergic acid diethylamide (LSD) and psilocybin. The controlled use of LSD and psilocybin in experimental settings is associated with a low incidence of psychotic episodes, and population studies corroborate these findings. Both the controlled use of DMT in experimental settings and the use of ayahuasca in experimental and ritual settings are not usually associated with psychotic episodes, but little is known regarding ayahuasca or DMT use outside these controlled contexts. Thus, we performed a systematic review of the published case reports describing psychotic episodes associated with ayahuasca and DMT intake. We found three case series and two case reports describing psychotic episodes associated with ayahuasca intake, and three case reports describing psychotic episodes associated with DMT. Several reports describe subjects with a personal and possibly a family history of psychosis (including schizophrenia, schizophreniform disorders, psychotic mania, psychotic depression), nonpsychotic mania, or concomitant use of other drugs. However, some cases also described psychotic episodes in subjects without these previous characteristics. Overall, the incidence of such episodes appears to be rare in both the ritual and the recreational/noncontrolled settings. Performance of a psychiatric screening before administration of these drugs, and other hallucinogens, in controlled settings seems to significantly reduce the possibility of adverse reactions with psychotic symptomatology. Individuals with a personal or family history of any psychotic illness or nonpsychotic mania should avoid hallucinogen intake.

dos Santos, R. G., Bouso, J. C., & Hallak, J. E. (2017). Ayahuasca dimethyltryptamine, and psychosis: a systematic review of human studies. Therapeutic Advances in Psychopharmacology, 2045125316689030. 10.1177/2045125316689030
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Safety pharmacology of acute MDMA administration in healthy subjects

February 21, 2017 / MDMA, Papers, Psychiatry, Psychology, Psychotherapy, Publications, Safety / By / ,

Abstract

3,4-Methylenedioxymethamphetamine (MDMA; ecstasy) is being investigated in MDMA-assisted psychotherapy. The present study characterized the safety pharmacology of single-dose administrations of MDMA (75 or 125 mg) using data from nine double-blind, placebo-controlled, crossover studies performed in the same laboratory in a total of 166 healthy subjects. The duration of the subjective effects was 4.2 ± 1.3 h (range: 1.4–8.2 h). The 125 mg dose of MDMA produced greater ‘good drug effect’ ratings than 75 mg. MDMA produced moderate and transient ‘bad drug effect’ ratings, which were greater in women than in men. MDMA increased systolic blood pressure to >160 mmHg, heart rate >100 beats/min, and body temperature >38°C in 33%, 29% and 19% of the subjects, respectively. These proportions of subjects with hypertension (>160 mmHg), tachycardia, and body temperature >38°C were all significantly greater after 125 mg MDMA compared with the 75 mg dose. Acute and subacute adverse effects of MDMA as assessed by the List of Complaints were dose-dependent and more frequent in females. MDMA did not affect liver or kidney function at EOS 29 ± 22 days after use. No serious adverse events occurred. In conclusion, MDMA produced predominantly acute positive subjective drug effects. Bad subjective drug effects and other adverse effects were significantly more common in women. MDMA administration was overall safe in physically and psychiatrically healthy subjects and in a medical setting. However, the risks of MDMA are likely higher in patients with cardiovascular disease and remain to be investigated in patients with psychiatric disorders.

Vizeli, P., & Liechti, M. E. (2017). Safety pharmacology of acute MDMA administration in healthy subjects. Journal of Psychopharmacology, 0269881117691569. 10.1177/0269881117691569
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Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine

February 9, 2017 / Iboga / Ibogaine, Medicine, Papers, Publications, Safety, Toxicology / By / , , , , ,

Abstract

BACKGROUND:
Ibogaine is an agent that has been evaluated as an unapproved anti-addictive agent for the management of drug dependence. Sudden cardiac death has been described to occur secondary to its use. We describe the clinical effects and toxicokinetics of ibogaine and noribogaine in a single patient. For this purpose, we developed a LC-MS/MS-method to measure ibogaine and noribogaine plasma-concentrations. We used two compartments with first order absorption.
CASE DETAILS:
The maximum concentration of ibogaine was 1.45 mg/L. Our patient developed markedly prolonged QTc interval of 647ms maximum, several multiple cardiac arrhythmias (i.e., atrial tachycardia and ventricular tachycardia and Torsades des Pointes). QTc-prolongation remained present until 12 days after ingestion, several days after ibogaine plasma-levels were low, implicating clinically relevant noribogaine concentrations long after ibogaine had been cleared from the plasma. The ratio k12/k21 for noribogaine was 21.5 and 4.28 for ibogaine, implicating a lower distribution of noribogaine from the peripheral compartment into the central compartment compared to ibogaine.
CONCLUSIONS:
We demonstrated a linear relationship between the concentration of the metabolite and long duration of action, rather than with parent ibogaine. Therefore, after (prolonged) ibogaine ingestion, clinicians should beware of long-term effects due to its metabolite.
Henstra, M., Wong, L., Chahbouni, A., Swart, N., Allaart, C., & Sombogaard, F. (2017). Toxicokinetics of ibogaine and noribogaine in a patient with prolonged multiple cardiac arrhythmias after ingestion of internet purchased ibogaine. Clinical Toxicology, 55(6), 600-602. 10.1080/15563650.2017.1287372
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Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects

January 20, 2017 / MDMA, Other subjects, Papers, Psychopharmacology, Publications, Safety, Toxicology / By / , , , ,

Abstract

In vitro studies showed that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of 3,4-methylenedioxymethamphetamine (MDMA, ecstasy) to 3,4-methylenedioxyamphetamine (MDA). However, the role of genetic polymorphisms in CYP2C19, CYP2B6, and CYP1A2 in the metabolism of MDMA in humans is unknown. The effects of genetic variants in these CYP enzymes on the pharmacokinetics and pharmacodynamics of MDMA were characterized in 139 healthy subjects (69 male, 70 female) in a pooled analysis of eight double-blind, placebo-controlled studies. MDMA-MDA conversion was positively associated with genotypes known to convey higher CYP2C19 or CYP2B6 activities. Additionally, CYP2C19 poor metabolizers showed greater cardiovascular responses to MDMA compared with other CYP2C19 genotypes. Furthermore, the maximum concentration of MDA was higher in tobacco smokers that harbored the inducible CYP1A2 rs762551 A/A genotype compared with the non-inducible C-allele carriers. The findings indicate that CYP2C19, CYP2B6, and CYP1A2 contribute to the metabolism of MDMA to MDA in humans. Additionally, genetic polymorphisms in CYP2C19 may moderate the cardiovascular toxicity of MDMA.

Vizeli, P., Schmid, Y., Prestin, K., zu Schwabedissen, H. E. M., & Liechti, M. E. (2017). Pharmacogenetics of ecstasy: CYP1A2, CYP2C19, and CYP2B6 polymorphisms moderate pharmacokinetics of MDMA in healthy subjects. European Neuropsychopharmacology, 27(3), 232-238. 10.1016/j.euroneuro.2017.01.008
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Tackling Harm Reduction, Human Rights and Drug Uses on Recreational Environments: Tensions, Potentialities and Learnings from the Kosmicare Project (Portugal)

January 16, 2017 / Other substances, Papers, Psychology, Safety / By / , , ,

Abstract

This paper is organized into four parts of discussion. Firstly, we present the Portuguese decriminalization law and the central role of harm reduction within this framework. The second section discusses the mainstream meanings ascribed to the ‘HR double’ mainly anchored in problematic drug uses. The third section highlights the need to take into account the specificities of recreational drug uses, users and environments. Thus, the paper highlights the experience of the Kosmicare Project at the Boom Festival, which combines principles of harm reduction, crisis intervention and Grof’s approach. The fourth section draws upon the project’s experience itself and in the idea of the normalization of drug uses to acknowledge and to discuss the potentialities, tensions and limitations of these contributions when it comes to analyzing and constructing a strong version of the ‘HR double’.
Soares, M., Carvalho, M. C., Valbom, M., & Rodrigues, T. (2017). Tackling Harm Reduction, Human Rights and Drug Uses on Recreational Environments: Tensions, Potentialities and Learnings from the Kosmicare Project (Portugal). Revista Crítica de Ciências Sociais, (112), 3-24. 10.4000/rccs.6535
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Ecstasy research: will increasing observational data aid our understanding of MDMA?

December 1, 2016 / MDMA, Neuroscience, Papers, Psychology, Psychopharmacology, Publications, Safety / By /

Abstract

Over the past three decades, millions of dollars have been spent on thousands of studies attempting to better understand the neurotoxic effects of MDMA. All of the clinical studies have recruited people who use ecstasy—a drug that does often but not always contain MDMA. Although most researchers agree that MDMA is the cause of neurocognitive deficits in ecstasy users, this consensus is based on a large body of literature with many limitations.

Amoroso, T. (2016). Ecstasy research: will increasing observational data aid our understanding of MDMA?. The Lancet Psychiatry, 3(12), 1101-1102. 10.1016/S2215-0366(16)30345-5
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Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats

November 30, 2016 / Neuroscience, New substances, Other substances, Papers, Psychopharmacology, Safety / By / , , , ,

Abstract

5-Methoxy-N,N-diisopropyltryptamine (5-MeO-DIPT, ‘foxy’) is one of the most popular tryptamine hallucinogens in the illicit drug market. It produces serious adverse effects, but its pharmacological profile is not well recognized. In vitro data have shown that 5-MeO-DIPT acts as a potent serotonin transporter (SERT) inhibitor and displays high affinity at serotonin 5-HT1A, 5-HT2A, and 5-HT2C receptors. In this study, using microdialysis in freely moving rats, we examined the effect of 5-MeO-DIPT on dopamine (DA), serotonin (5-HT), and glutamate release in the rat striatum, nucleus accumbens, and frontal cortex. In search of a possible neurotoxic effect of 5-MeO-DIPT, we measured DA and 5-HT tissue content in the above rat brain regions and also determined the oxidative DNA damage with the comet assay. Moreover, we tested drug-elicited head-twitch response and a forepaw treading induced by 8-OH-DPAT. 5-MeO-DIPT at doses of 5, 10, and 20 mg/kg increased extracellular DA, 5-HT, and glutamate level but the differences in the potency were found between brain regions. 5-MeO-DIPT increased 5-HT and decreased 5-HIAA tissue content which seems to result from SERT inhibition. On the other hand, a decrease in DA, DOPAC, and HVA tissue contents suggests possible adaptive changes in DA turnover or damage of DA terminals by 5-MeO-DIPT. DNA single and double-strand breaks persisted up to 60 days after the treatment, indicating marked neurotoxicity of 5-MeO-DIPT. The induction of head-twitch response and potentiation of forepaw treading induced by 8-OH-DPAT indicate that hallucinogenic activity seems to be mediated through the stimulation of 5-HT2A and 5-HT1A receptors by 5-MeO-DIPT.
Noworyta-Sokołowska, K., Kamińska, K., Kreiner, G., Rogóż, Z., & Gołembiowska, K. (2016). Neurotoxic Effects of 5-MeO-DIPT: A Psychoactive Tryptamine Derivative in Rats. Neurotoxicity research, 30(4), 606-619. 10.1007/s12640-016-9654-0
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