Clinical Pharmacology & Therapeutics
November 4, 2016
De Nichols, Mw Johnson, Cd Nichols
366 citations
Serotonergic psychedelics like psilocybin and LSD, which activate 5-HT2A receptors, show preliminary efficacy in treating anxiety, depression, and addiction to tobacco and alcohol when combined with psychotherapy. Recent research suggests these compounds may also combat inflammatory diseases through novel mechanisms, potentially offering advantages over existing anti-inflammatory drugs. The authors propose that psychedelics work by temporarily destabilizing brain network hubs and global connectivity via amplified neuronal avalanches, allowing the brain to reset after acute effects subside. Anti-inflammatory effects could benefit both psychiatric and nonpsychiatric inflammation-related conditions, warranting rigorous further research.
Clinical Pharmacology & Therapeutics
September 1, 2006
Graham Lappin, W. Kuhnz, R. Jochemsen et al.
242 citations
A volunteer trial compared how five drugs—warfarin, ZK253, diazepam, midazolam, and erythromycin—are handled by the body when given as a microdose (100 micrograms) versus a standard therapeutic dose. For diazepam, midazolam, and ZK253, the microdose closely matched the therapeutic dose in key measures such as half-life, clearance, volume of distribution, and oral bioavailability. Warfarin's clearance was reasonably predicted from the microdose, but its volume of distribution differed, likely due to high-affinity, low-capacity tissue binding. The oral microdose of erythromycin produced no detectable blood levels, possibly because stomach acid destroyed it. Overall, microdosing can help select promising drug candidates early, if used appropriately.
Clinical Pharmacology & Therapeutics
August 10, 2011
Kazuya Maeda, Yasumasa Ikeda, Tomoe Fujita et al.
207 citations
Atorvastatin, a cholesterol-lowering drug, is cleared from the body by being taken up into the liver via organic anion transporting polypeptides (OATPs) and then broken down by the enzyme CYP3A4. A clinical study using a microdose cocktail given to eight healthy volunteers showed that blocking OATPs with rifampicin increased atorvastatin's exposure 12-fold, while blocking CYP3A4 with itraconazole had no effect. This demonstrates that hepatic uptake via OATPs, not metabolism by CYP3A4, is the dominant process for eliminating atorvastatin at a subtherapeutic dose.
Clinical Pharmacology & Therapeutics
November 1, 1968
Leo E. Hollister, R. K. Richards, H. K. Gillespie
195 citations
A synthetic isomer of tetrahydrocannabinol (THC) was compared to a semisynthetic THC-like compound, synhexyl, in 16 volunteers. THC doses ranged from 341 to 946 µg per kilogram (median 581), while synhexyl doses ranged from 633 to 2,666 µg per kilogram (median 1,370). The clinical syndromes produced by the two drugs were similar, though synhexyl had a slower onset and was only about one third as potent. At higher doses, effects resembled those of psychotomimetics like LSD, but differed in that sedation was prominent, euphoria lasted longer, dreamlike sequences were more pronounced, and there were no sympathomimetic effects.
Clinical Pharmacology & Therapeutics
November 7, 2021
A. Becker, Friederike Holze, Tanja Grandinetti et al.
177 citations
In healthy volunteers, taking the antidepressant escitalopram for two weeks before a 25 mg dose of psilocybin did not reduce the positive mood effects of the psychedelic, but it significantly lessened bad drug effects, anxiety, adverse cardiovascular effects, and other adverse effects compared to placebo pretreatment. Escitalopram did not alter psilocin's pharmacokinetics; the half-life of free psilocin was 1.8 hours. It also did not change HTR2A or SCL6A4 gene expression, QTc intervals, or BDNF levels. Longer antidepressant pretreatment and studies in patients are needed to further define interactions between antidepressants and psilocybin.
Clinical Pharmacology & Therapeutics
June 15, 2011
C.m. Hysek, Linda D. Simmler, M. Ineichen et al.
153 citations
Blocking the norepinephrine transporter with reboxetine reduces the cardiovascular and subjective stimulant effects of MDMA (ecstasy) in humans, even though MDMA and its active metabolite reach higher concentrations in the blood. In a double-blind, placebo-controlled crossover study with 16 healthy adults, reboxetine lowered MDMA-induced increases in plasma norepinephrine, blood pressure, heart rate, drug high, stimulation, and emotional excitement. The findings indicate that transporter-mediated norepinephrine release is essential for MDMA's cardiovascular and stimulant-like effects.
Clinical Pharmacology & Therapeutics
September 1, 1964
George K. Aghajanian, O. Bing
118 citations
After intravenous administration of two micrograms per kilogram of LSD-25 to five healthy adults, the drug was detected in plasma at relatively high concentrations during the period of peak effect. The half-life of LSD-25 in human plasma was calculated to be 175 minutes.
Clinical Pharmacology & Therapeutics
December 12, 2022
Friederike Holze, Urs Duthaler, A. Becker et al.
116 citations
Psilocybin is being studied as a treatment for psychiatric and neurological disorders. After oral administration of 15, 25, or 30 mg to healthy subjects, peak psilocin concentrations averaged 11, 17, and 21 ng/mL, reached after about 2 hours, with elimination half-lives around 1.4–1.8 hours. Subjective effects lasted 5.5–6.4 hours, and maximal 'any drug' effects ranged from 58% to 80%. Psilocin showed dose-proportional pharmacokinetics, and both duration and intensity of effects were dose-dependent. Body weight did not influence pharmacokinetics or response.
Clinical Pharmacology & Therapeutics
March 1, 1965
A. Hoffer
83 citations
A prominent figure in a scientific controversy reviews the contested subject, acknowledging the difficulty of obtaining an impartial perspective. The review was published because the author is an authority actively engaged in the problem and to bring details to a wide audience. The text invites correspondence, indicating an open discussion.
Clinical Pharmacology & Therapeutics
November 10, 2016
Bb Yazar‐klosinski, Mc Mithoefer
81 citations
Phase II trials of MDMA-assisted psychotherapy show initial safety and efficacy for treating PTSD, with potential expansion to depression and anxiety disorders. In this model, single doses of MDMA are given within a psychotherapy framework, unlike daily drug administration without therapy. This approach could benefit from accelerated regulatory pathways like the FDA Breakthrough Therapy Designation to efficiently test these novel treatments.
Clinical Pharmacology & Therapeutics
September 25, 2020
Friederike Holze, Matthias E. Liechti, Nadia R. P. W. Hutten et al.
63 citations
Very low doses of LSD (5, 10, and 20 µg) were given to 23 healthy participants in a double-blind, placebo-controlled crossover trial. LSD concentrations in the blood increased in proportion to dose, with maximal levels reached after about 1.1 hours and an average elimination half-life of 2.7 hours. The 5 µg dose produced no significant subjective effects. The 10 µg dose significantly increased feelings of being under the influence and good drug effect, starting at 1.1 hours, peaking at 2.5 hours, and lasting until 5.1 hours. The 20 µg dose also increased bad drug effects. The threshold for psychotropic effects was 10 µg.
Clinical Pharmacology & Therapeutics
June 29, 2011
Kazuya Maeda, Junichi Takano, Yasumasa Ikeda et al.
50 citations
Microdosing studies help identify early pharmacokinetic properties of drugs in humans, but nonlinearity between microdose and therapeutic dose due to saturation of metabolic enzymes and transporters is a concern. In healthy subjects, verapamil and quinidine, substrates of MDR1 and CYP3A4, showed dose-dependent pharmacokinetics. Dose-normalized AUC values increased 2.6-fold for quinidine and 2.3-fold for verapamil at therapeutic doses compared to microdoses, suggesting saturation of MDR1 and/or CYP3A4 in the small intestine causes nonlinearity.
Clinical Pharmacology & Therapeutics
December 19, 2007
37 citations
Regulatory agencies like the FDA and European Medicines Agency seek more efficient drug development. One resulting initiative is the creation of guidance documents for exploratory investigational new drugs (INDs) and clinical trial applications (CTAs). This article reviews the history of those guidances and the industry's experience using them so far.
Clinical Pharmacology & Therapeutics
May 30, 2023
Pablo Mallaroni, Riccardo Paci, Sabrina Ritscher et al.
34 citations
2,5‐dimethoxy‐4‐bromophenethylamine (2C‐B), a hallucinogen derived from mescaline, produces psychedelic effects of moderate depth, shorter in duration than psilocybin. In a double‐blind, placebo‐controlled study of 22 healthy participants with prior psychedelic experience, 20 mg of 2C‐B elicited alterations of waking consciousness, though psilocybin (15 mg) caused greater dysphoria, subjective impairment, auditory alterations, and ego dissolution. Both compounds equally slowed psychomotor performance and impaired spatial memory compared with placebo, and neither produced empathogenic effects on the Multifaceted Empathy Test. 2C‐B raised blood pressure transiently, similar to psilocybin, and its effects largely resolved within six hours.
Clinical Pharmacology & Therapeutics
August 24, 2017
Edward M. Sellers, Deborah B. Leiderman
27 citations
Interest in the potential therapeutic benefits of psychedelic agents has recently increased. Besides psilocybin, many other agents with psychedelic properties have been proposed and partially tested. However, obtaining approval to market a restricted psychotomimetic agent faces formidable challenges.
Clinical Pharmacology & Therapeutics
May 26, 2017
EM Sellers
18 citations
Psychedelic drugs, once used in religious ceremonies and known for distorting perception, are being rediscovered for potential therapeutic uses, continuing a long tradition of finding new applications for old drugs.
Clinical Pharmacology & Therapeutics
October 5, 2023
Robert H. Dworkin, Michael Mcdermott, Sandeep M. Nayak et al.
16 citations
Combining a classic psychedelic (e.g., psilocybin) with psychotherapy may produce benefits that are synergistic—greater than the sum of each treatment alone—but current trials have not tested this directly. Most studies pair the drug with some form of psychological support, yet providing full psychotherapy is more costly and harder to scale than basic harm-reduction support. Factorial designs, in which patients are randomly assigned to drug plus psychotherapy, drug alone, psychotherapy alone, or double placebo, can isolate the separate contributions of each component and detect true synergy. Such trials require large sample sizes but could determine whether the added expense of psychotherapy is worthwhile for improving outcomes in conditions like depression, anxiety, and chronic pain.
Clinical Pharmacology & Therapeutics
February 28, 2025
Lorenz Mueller, Alen Jelušić, Avram Tolev et al.
15 citations
In a double-blind, placebo-controlled crossover study with 23 healthy participants, daily paroxetine (an SSRI antidepressant) did not reduce the pleasant subjective effects of a single 100 μg dose of LSD, but it significantly lessened negative effects such as 'bad drug effect,' anxiety, and nausea. Paroxetine increased LSD's peak concentration and total exposure by 40% and 50%, respectively, by inhibiting the CYP2D6 enzyme, indicating this enzyme is involved in LSD metabolism. The interaction was strongest in normal CYP2D6 metabolizers and weakest in poor metabolizers. The findings suggest LSD can be safely added to SSRI treatment without dose adjustment when the SSRI inhibits CYP2D6, but no definitive recommendation can be made for other SSRIs.
Clinical Pharmacology & Therapeutics
September 30, 2024
Andreas Halman, Rachel Conyers, Claire Moore et al.
13 citations
Genetic variations in drug-metabolizing enzymes, particularly cytochrome P450, can influence the intensity of acute effects from psychedelics like LSD and ibogaine, suggesting that dose reductions may be appropriate for CYP2D6 poor metabolizers. Preclinical evidence also indicates that CYP2D6 metabolizer status might alter psychedelic experiences with 5-MeO-DMT and psilocybin when combined with monoamine oxidase inhibitors. Although evidence is limited, especially for pharmacodynamics, pharmacogenomic testing warrants further investigation to potentially improve safety and personalize psychedelic-assisted therapies for psychiatric conditions.
Clinical Pharmacology & Therapeutics
January 13, 2017
M Huestis, Rachel F. Tyndale
12 citations
This special issue examines the dual nature of novel psychoactive substances and the repurposing of established psychoactive drugs. Synthetic cannabinoids, for instance, have much higher potency than Δ9-tetrahydrocannabinol at cannabinoid receptors and were initially used as research tools but are now used illicitly and tested for clinical efficacy. Established drugs like psilocybin and LSD are being repurposed for indications where current medications are ineffective. The papers address problems such as adverse events, psychosis, rapid synthesis, abuse liability testing, internet sales, and scheduling, alongside therapeutic promises in cognition enhancement, exercise-mimetics, epilepsy, multiple sclerosis, and posttraumatic stress disorder.
Clinical Pharmacology & Therapeutics
March 15, 2023
Piet H. van der Graaf
1 citation
An editorial uses the fictional drama "Nine Perfect Strangers" to illustrate real-world challenges in psilocybin research, such as small sample sizes, lack of placebo controls, and short study durations. It notes 133 psilocybin trials listed on ClinicalTrials.gov and highlights a recent phase II clinical trial in treatment-resistant major depressive disorder, whose results were both intriguing and sobering, leading to a phase III study. The editorial emphasizes the need for rigorous clinical pharmacology, citing recent studies on the pharmacokinetics-pharmacodynamics of psilocybin and LSD, and calls for more submissions in this area to convert medical hypotheses into safe, effective therapeutics.
Clinical Pharmacology & Therapeutics
May 28, 2026
Gia Han Le, Sabrina Wong, Danica E. Johnson et al.
The serotonin 5-HT2B receptor sits at a crossroads between potential antidepressant effects in the brain and serious heart valve risks when activated peripherally. This narrative review of preclinical and clinical literature finds that peripheral activation of 5-HT2B receptors causes valvular heart disease through cell proliferation and scarring, as seen with older drugs like fenfluramine and some dopamine agonists. In the brain, the receptor's effects are mixed: astrocytic activation may support metabolism and plasticity, while neuronal blockade can normalize dopamine and glutamate activity. Several approved antidepressant adjuncts (aripiprazole, brexpiprazole, cariprazine) antagonize this receptor without observed heart valve problems. The authors propose developing centrally selective, periphery-sparing 5-HT2B antagonists for treatment-resistant depression, with early cardiac monitoring to ensure safety.