Brian Miller, MD, PhD, MPH

Lysergic acid diethylamide (LSD) and psilocybin are serotonergic psychedelics that are candidates for the treatment of psychiatric disorders.

 Both agents stimulate serotonin 5-HT2A receptors; LSD also acts at dopamine D13-3 receptors, and the active metabolic of psilocybin (psilocin) inhibits the serotonin transporter.

 The similarities, acute effects, and dose equivalence of these agents in humans remains unclear.

 directly compared the acute subjective, autonomic, and endocrine effects of LSD and psilocybin at 2 doses and placebo within the same participants. The acute subjective effects of these agents were assessed with validated psychometric instruments, and pharmacokinetic data were obtained over 24 hours. The investigators performed a double-blind, placebo-controlled crossover study with 5 experimental test sessions (placebo, LSD 100 µg, LSD 200 µg, psilocybin 15 mg, psilocybin 30 mg), with a washout period of at least 10 days between sessions.

The authors recruited 28 healthy participants; their mean age was 35 years and 50% were male. Exclusion criteria were: age less than than 25 years or greater than 65 years, pregnancy, family history of major psychiatric disorders in first-degree relatives, current psychotropic medication use, acute or chronic physical illness, tobacco smoking of more than 10 cigarettes/day, lifetime illicit drug use exceeding 10 times (except use of tetrahydrocannabinol [THC], the principal psychoactive cannabinoid of cannabis), or illicit drug use in the past 2 months or during the study period. In terms of previous drug use, 11 participants had previously used LSD and 6 had previously used psilocybin; 13 had previously used a stimulant; and 10 participants had no history of noncannabis illicit drug use. LSD was administered as an oral solution and psilocybin as an oral capsule. A double-dummy method was used such that participants received 6 capsules and 2 solutions at each test session.

Each test session lasted 25 hours and was conducted in a calm hospital room. Abstinence from illicit drugs was verified with a urine drug screen. Outcomes were repeatedly assessed for 24 hours. Standardized meals were served. An investigator was present in the room during the acute effect phase and remained in a room next to the participant for up to 24 hours. Subjective effects were assessed repeatedly using visual analogue scales (VAS), the Adjective Mood Rating Scale (AMRS), the 5 Dimensions of Altered States of Consciousness scale (5D-ASC), and the Mystical Effects Questionnaire(MEQ). Effect durations were assessed using the classic pharmacokinetic-pharmacodynamic link module. Blood pressure, heart rate, and temperature were repeatedly measured. Adverse effects were assessed 1 hour before and 12 and 24 hours after drug administration. Plasma LSD and psilocybin concentrations, and cortisol, prolactin, oxytocin, and brain-derived neurotrophic factor (BDNF) measurements were also obtained at multiple time points. Pharmacokinetic parameters were estimated using noncompartmental methods. Peak drug effects (minimum, maximum, or change from baseline) were determined for repeated measures, then analyzed using repeated-measures analysis of variance.

Both doses of LSD and the 30-mg psilocybin dose produced comparable subjective effects, based on VAS and 5D-ASC outcomes. There was significantly greater ego dissolution and a trend toward greater anxiety with 200 µg versus 100 µg LSD. Psilocybin 15 mg had significantly lower effects than psilocybin 30 mg and both LSD doses, based on VAS and 5D-ASC outcomes. Both LSD doses had significantly increased “emotional excitation” on the AMRS compared with psilocybin. There were no differences in subjective effects of LSD or psilocybin based on sex.

Both LSD and psilocybin significantly increased systolic and diastolic blood pressure, temperature, and pupil diameter compared with placebo. Psilocybin 30 mg produced significantly greater increases in blood pressure and temperature compared with psilocybin 15 mg and both doses of LSD. By contrast, both LSD doses produced a greater increase in pulse compared with both psilocybin doses and placebo. Psilocybin produced greater impairments in pupil contraction compared with LSD. Both LSD and psilocybin increased the total acute (0-12 hours) adverse effect score compared with placebo. Subacute (12-24 hours) adverse effect scores were significantly greater with LSD 200 µg LSD and psilocybin 30 mg compared with placebo. The most common adverse effects were headaches. Five participants had 9 flashback episodes within 72 hours. No severe adverse events were observed.

Both LSD doses had significantly longer effect durations (10-11 versus 6-7 hours) and earlier onset of effects (0.4-0.6 versus 0.8 hours) compared with both psilocybin doses. The elimination half-life values were about 4 hours for LSD and 2.5 hours for psilocybin. Both LSD and psilocybin significantly increased plasma cortisol, prolactin, and oxytocin levels, but neither affected BDNF levels. Both LSD and psilocybin showed linear pharmacokinetics, which were not influenced by body weight.

In terms of blinding, no clear distinction between LSD and psilocybin could be made after the session or at study end point. Participants correctly identified the psychedelic and dose in about 60% of sessions, compared with 96% for placebo.

The authors investigated and directly compared the acute effects of LSD and psilocybin in healthy participants in a well-blinded study. They concluded that psilocybin 15 mg exerted clearly weaker subjective effects, and both agents had dose-dependent effect durations (significantly longer for LSD), stimulant autonomic effects, and increased endocrine parameters. Body weight had no influence on blood concentrations. The investigators noted the data further supported the notion that states of consciousness alteration induced by LSD and psilocybin are more likely dose-dependent rather than substance-dependent. In addition, they concluded the differences in the pharmacological profiles of LSD and psilocybin do not relevantly influence subjectively experienced effects of both psychedelics.

Study strengths included the within-subjects design and the use of well-characterized, fixed dosing. The primary study limitations were the use of a highly controlled setting and the participation of healthy participants only.

This study supports dose finding for research and psychedelic-assisted therapy. Psilocybin 20 mg is likely equivalent to LSD 100 µg. There was no evidence for qualitative differences in altered states of consciousness, except for a shorter duration of action for psilocybin.

This article originally appeared on Psychiatric Times. 

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Trial of psilocybin versus escitalopram for depression.

2. Griffiths RR, Johnson MW, Carducci MA, et al. 

Psilocybin produces substantial and sustained decreases in depression and anxiety in patients with life-threatening cancer: a randomized double-blind trial.

Effects of psilocybin-assisted therapy on major depressive disorder: a randomized clinical trial.

LSD-assisted psychotherapy for anxiety associated with a life-threatening disease: a qualitative study of acute and sustained subjective effects.

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Receptor interaction profiles of novel psychoactive tryptamines compared with classic hallucinogens.

Direct comparison of the acute effects of lysergic acid diethylamide and psilocybin in a double-blind placebo-controlled study in healthy subjects.

Articles

In a well-blinded study, researchers investigated and directly compared the acute effects of LSD and psilocybin in healthy participants.

The Effects of Psychedelics in Healthy Participants

Partial or inadequate response to antidepressants—whose mechanisms primarily involve monoamine pathways—are common.

 Multiple lines of evidence suggest that the glutamatergic system is also involved in the pathophysiology of depression. Dextromethorpahn is a N-methyl-D-aspartate receptor antagonist and a sigma-1 receptor agonist, both of which modulate glutamate neurotransmission. The clinical utility of dextromethorphan is limited by extensive CYP2D6 metabolism.

 AXS-05, an oral tablet that combines dextromethorphan and bupropion, is formulated to increase the bioavailability and half-life of dextromethorphan through inhibition of its metabolism by bupropion, and is under development for the treatment of major depressive disorder (MDD).

 performed a phase 2, 6-week randomized double-blind active-controlled trial of AXS-05 in MDD at 4 sites in the US. They specifically used confirmation of disease severity through independent assessment and comprehensive blinding of trial sites to address factors that may contribute to poor signal detection in clinical trials.

 They included patients aged 18-65 with DSM-5 MDD and a current moderate or severe major depressive episode. Subjects had a score ≥ 25 on the Montgomery-Åsberg DepressionRating Scale (MADRS) and a score ≥ 4 on the ClinicalGlobal Impressions severity scale (CGI-S). Exclusion criteria were bipolar disorder, panic disorder, OCD, treatment-resistant depression (≥ 2 failed antidepressant trials in the current episode), substance use disorder in the past year, lifetime history of psychotic disorder, clinically significant suicide risk, and history of seizure disorder. Participants were randomized 1:1 to either dextromethorphan-bupropion (45 mg/105 mg) or bupropion (105 mg) once daily for 3 days then twice daily thereafter.

The primary efficacy variable was the change from baseline to week 6 in the MADRS total score. Secondary endpoints were clinical response (≥ 50% reduction in MADRS total score) or remission (MADRS total score ≤ 10), CGI-S and CGI-Improvement scores, scores in the 16-item Quick Inventory of Depressive Symptomatology-Self-Rated (QIDS-SR), and MADRS-6 score. Study patients also tracked their mood daily with a visual analogue mood scale. The study safety population included all patients who received at least 1 dose of study medication. The efficacy population included all patients with illness severity confirmed by the independent assessor who were randomized, received at least 1 dose of study medication, and had at least 1 postbaseline assessment. Efficacy variables assessing a change from baseline were analyzed using mixed models with repeated measures. Those efficacy variables related to percentages were analyzed by chi-square tests.

The authors randomized 97 patients, of whom the independent assessment failed to confirm diagnosis or severity for 17 patients, resulting in 80 patients. Seventy-four of the 80 patients completed the trial. Mean treatment adherence was > 90% in both groups based on tablet counts. There were nonsignificantly more women, Black or African American, and Hispanic or Latino patients in the bupropion group (p > 0.15 for each). Dextromethorphan-bupropion was associated with significantly greater reduction in MADRS scores versus bupropion (-13.7 versus -8.8 points, effect size = 1.2), with statistically significant differences beginning at week 2. Response (60.5% versus 40.5%) and remission (46.5% versus 15.2%) at week 6 was significantly more likely in the dextromethorphan-bupropion group. Dextromethorphan-bupropion was also associated with significantly greater improvement on the CGI-S scale (-1.6 versus -1.0). The prevalence of any adverse events was 73% in the dextromethorphan-bupropion group and 65% in the bupropion group. The most common adverse events in the dextromethorphan-bupropion group were dizziness, nausea, dry mouth, decreased appetite, and anxiety. There were no serious adverse events in the trial. Dextromethorphan-bupropion was not associated with psychotomimetic effects, weight gain, sexual dysfunction, increased suicidality, or significant changes in laboratory parameters and vital signs.

The authors concluded that AXS-05 showed rapid, substantial, and statistically significant antidepressant efficacy compared to the active comparator on multiple clinician- and patient-reported measures of depression severity. A primary strength was the use of bupropion (at an identical dose to AXS-05) as the active comparator. Study limitations include exclusion of patients with lower levels of symptom severity and other psychiatric or medical comorbidities. Thus, findings from efficacy trials may not be mirrored in general practice. Another limitation is the short duration of the trial (6 weeks).

This study demonstrates that dextromethorphan-bupropion significantly improves depressive symptoms compared to bupropion and was generally well tolerated. This combination represents a novel pharmacologic approach to the treatment of MDD.

1. Machado-Vieira R, Henter ID, Zarate CA Jr. 

New targets for rapid antidepressant action.

Pharmacokinetics of dextromethorphan after single or multiple dosing in combination with quinidine in extensive and poor metabolizers.

4. Tabuteau H, Jones A, Anderson A, et al. 

Effect of AXS-05 (Dextromethorphan-bupropion) in major depressive disorder: a randomized double-blind controlled trial.

5. Freeman MP, Pooley J, Flynn MJ, et al. 

Guarding the gate: remote structured assessments to enhance enrollment precision in depression trials.

A new—cough, cough—combination treatment for depression. Researchers performed an RCT of dextromethorphan-bupropion in major depressive disorder.

Update on Using Dextromethorphan-Bupropion in Depression

“Mr Wallace” is a 43-year-old African-American male with an 8-year history of bipolar I disorder, who experienced depression with psychotic features in his most recent episode. He had a history of 3 previous suicide attempts via overdose, all of which were >5 years ago. He had chronic relationship stress with his parents and adult son, whom he felt did not understand his depression. He also had chronic unresolved grief regarding the death of his brother from a myocardial infarction several years ago.

Mr Wallace was obese, with a BMI of 33. He also met the criteria for metabolic syndrome, with increased waist circumference, high triglycerides, low HDL cholesterol, and elevated blood pressure. He saw his psychiatrist monthly, and was adherent with mood stabilizing medication, but reported chronic, passive suicidal ideation without plan or intent. He would often state that he wished he had died instead of his brother. One month after his last outpatient appointment, his family contacted the clinic to report his death by suicide.

Bipolar disorder is associated with increased premature mortality,

 There is an increased prevalence of the metabolic syndrome and constellation of risk factors—including abdominal obesity, hypertension, and abnormal glucose and lipid metabolism—associated with cardiovascular disease morbidity and mortality in patients with bipolar disorder.

 There is also an increased prevalence of suicide in patients with bipolar disorder, with an estimated 34% lifetime prevalence of suicide attempt.

 One previous study found that suicide attempts were more likely in patients with (versus without) metabolic syndrome and obesity.

 investigated associations between metabolic syndrome, obesity, and suicidality in 215 patients with bipolar disorder who were part of the ongoing BIPLONG longitudinal study.

 Diagnosis was made by structured clinical interview by a psychiatrist or clinical psychologist. Inclusion criteria were inpatients and outpatients aged >18 years with complete anthropometric and clinical data. Exclusion criteria were comorbid chronic obstructive pulmonary disease (COPD); autoimmune, neurodegenerative, or neuroinflammatory disease; hemodialysis; and interferon immunotherapy.

Subjects were assessed with the Beck Depression Inventory, the Hamilton Depression Rating Scale, the Young Mania Rating Scale, and lifetime suicidal ideation and suicide attempt. Subjects also had anthropometric measures, vital signs, and fasting blood samples for glucose and lipids. Metabolic syndrome was defined by the International Diabetes Federation criteria (Alberti). BMI was trichotomized as normal (18.5 to 24.9), overweight (25 to 29.9), and obesity (≥30). Data were analyzed using analysis of covariance, controlling for age, sex, and illness duration.

Of the 215 subjects, 52% were male, the mean age was 44 years, and the mean illness duration was 19 years. Sixty-six subjects (31%) met the criteria for metabolic syndrome. One-hundred seventy-four subjects (81%) had current suicidal ideation, and 76 (35%) had at least 1 suicide attempt. Sixty-six subjects (31%) were obese, and 75 (35%) were overweight.

There was no significant association between metabolic syndrome or waist-hip ratio and suicidal ideation or suicide attempt. There was also no significant association between BMI categories and suicide attempt. However, there was a significantly higher prevalence of suicidal ideation in normal weight (88%) versus overweight (71%) and obese plus overweight (77%). Suicidal ideation was positively correlated with glucose and negatively correlated with total and LDL cholesterol, although findings were no longer significant after Bonferroni correction.

The authors concluded that there was no significant association between the metabolic syndrome, lipid levels, and suicidality in the study sample. Subjects with normal weight had more lifetime suicidal ideation than the other groups. Study limitations included the cross-sectional study design and the absence of a standardized questionnaire on suicide; the authors also did not control for potential confounding effects of medications.

This study did not confirm an association between metabolic syndrome and suicidality in patients with bipolar disorder. However, BMI warrants further investigation as a potential risk marker for suicide in this population.

This article originally appeared on Psychiatric Times.

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5. Stenzel C, Dalkner N, Unterrainer HF, et al. Effects of metabolic syndrome and obesity on suicidality in individuals with bipolar disorder. 

6. Dalkner N, Bengesser SA, Birner A, et al. Metabolic syndrome impairs executive function in bipolar disorder. 

Cardiometabolic risk factors for suicide? Researchers investigated associations between obesity/metabolic syndrome and suicidality in patients with bipolar disorder.

Examining Links Between Metabolic Syndrome, Obesity, and Suicidality in Bipolar Disorder

Treatment-resistant bipolar depression (TRBD) is defined by non-remission after 2 8-week trials of recommended medications, including combination therapy, at therapeutic doses, and associated with increased psychiatric hospitalizations and disability, and poorer quality of life.

 The prevalence of type 2 diabetes and insulin resistance in patients with bipolar disorder is approximately 22% and 32%, respectively, and these conditions may worsen illness course.

“Mr Joseph” is a 60-year-old Caucasian male with a history of chronic bipolar I disorder, whose most recent episode included depression without psychotic features. He failed a previous trial of lithium due to adverse effects on renal function. He had improved mood with treatment with ziprasidone, titrated to 40 mg qAM and 80 mg qPM, although he has residual depressive symptoms. He gained weight with ziprasidone, with an increase in BMI from 28 to 32. He maintained a normal fasting glucose. He requested to continue ziprasidone, and 3 months ago was started on metformin, which was titrated to 1000 mg BID. At his most recent outpatient clinic visit, his BMI had decreased to 29.5, and he also noted mild improvements in mood and anxiety.

Calkin and colleagues hypothesized that patients with TRBD who met criteria for insulin resistance would exhibit a favorable response to metformin, which has insulin-sensitizing properties.

 They performed a randomized quadruple-masked (patient, investigator, outcomes assessor, statistician) trial of adjunctive metformin at 2 sites in Canada and the United States. They included adults aged 18 and older with DSM-5 bipolar disorder and unremitting depressive symptoms (Montgomery-Asberg Depression Rating Score [MADRS] score ≥15) for at least 4 weeks despite optimal treatment.

Subjects were screened for insulin resistance using the Homeostatic Model Assessment-Insulin Resistance (HOMA-IR) equation, which is based on fasting blood glucose and insulin. Subjects were excluded if they did not have insulin resistance (HOMA-IR <1.8), had manic symptoms (Young Mania Rating Scale score ≥15), had a suicidal ideation rating of 5 on the Columbia Suicide Severity Rating Scale, were already receiving or were allergic to metformin, or had liver function tests ≥3 times the upper limit of normal.

Subjects received metformin 500 mg (or placebo) twice daily for 1 week, then titrated to 1000 mg BID for up to 25 additional weeks. The minimum maintenance dose of metformin was 1500 mg daily. The MADRS was administered, and insulin resistance was measured at baseline, week 2, and every 4 weeks thereafter (primary outcomes). Secondary outcomes included the Clinical Global Impressions Scale (bipolar disorders version; CGI-BP) and the Global Assessment of Functioning (GAF) scale. Returned pill counts were used to determine study medication adherence. The primary hypothesis that metformin would reverse insulin resistance (conversion) was tested using Fisher’s exact test. Improvements in MADRS scores (and other outcomes) in converters were tested using mixed-effects linear models.

The authors consented and screened 88 subjects, of whom 50 were randomized. Efficacy and safety data were reported for 45 subjects (20 metformin and 25 placebo). Thirty-nine subjects (87%) completed the study to the week-14 primary outcome endpoint, and 28 subjects completed the full 26 weeks. Medication adherence was 97% in both treatment groups. Mean subject age was 48, 76% were women, and the mean illness duration was 26 years. There were no significant between-group differences in weight, BMI, glucose, insulin, or blood levels of lithium or lamotrigine.

Ten metformin-treated patients no longer met insulin resistance criteria (converters) at week 14, versus 1 placebo-treated patient (Fisher’s exact p=0.0009). Converters had a significantly greater reduction in MADRS total scores beginning at week 6 and continuing through week 26, with large effect sizes (1.04 to 1.17). There were concordant improvements in GAF, Hamilton anxiety scale, and, to a lesser extent, CGI-BP scores in converters. The most common adverse events were diarrhea and vomiting, which were expected in the metformin group. At week 14, metformin-treated patients lost 1.7 kg and placebo-treated patients gained 1.4 kg, and this difference was statistically significant.

The authors concluded that reversal of insulin resistance by metformin resulted in statistically and clinically significant sustained improvements in depression, with no changes in mania, in patients with TRBD. No serious adverse events occurred, and the most common adverse events were gastrointestinal symptoms. Study limitations included the modest sample size, and whether a higher rate of conversion from insulin resistance could be achieved with either higher doses or extended-release preparations of metformin.

Reversal of insulin resistance by metformin improves depression, anxiety, and general functioning in a large proportion of patients with TRBD. These findings warrant replication in a larger trial.

1. Fountoulakis KN, Yatham LN, Grunze H, et al. 

The CINP guidelines on the definition and evidence-based interventions for treatment-resistant bipolar disorder.

2. Calkin CV, Ruzickova M, Uher R, et al. 

Insulin resistance and outcome in bipolar disorder, 2015.

3. Calkin CV, Chengappa KNR, Cairns K, et al. 

Treating insulin resistance with metformin as a strategy to improve clinical outcomes in treatment-resistant bipolar depression (the TRIO-BD Study): a randomized, quadruple-masked, placebo-controlled clinical trial.

Adjunctive metformin in bipolar disorder. Researchers performed a randomized clinical trial of treating insulin resistance to improve clinical outcomes in treatment-resistant bipolar depression.