Nicholas V Cozzi, Ph.D.
Nicholas Vito Cozzi, Ph.D. is a scientist and educator with background and training in pharmacology, chemistry, toxicology, and neuroscience. He holds a Ph.D. in Pharmacology and a B.S. in Pharmacology and Toxicology, both from the University of Wisconsin-Madison School of Pharmacy.
Dr. Cozzi’s research involves the design, chemical synthesis, and pharmacological testing of substances with central nervous system activity, especially psychedelics, empathogens, antidepressants, and psychostimulants. He is interested in how these agents act in the brain to promote neuronal health, improve mood, enhance cognition, and increase awareness, and in their clinical value in treating addiction, depression, post-traumatic fear, neurological diseases, and other health ailments. Dr. Cozzi has published numerous articles focused on the chemistry and pharmacology of psychoactive drugs and is internationally recognized for his work.
As an educator, Dr. Cozzi taught pharmacology at the Brody School of Medicine at East Carolina University, the UW-Madison School of Medicine and Public Health, and the UW-Madison School of Pharmacy, and he is a frequent guest lecturer at other academic institutions around the United States. He has received several teaching and research awards, including a Distinguished Basic Science Teaching Award from the UW-Madison and a prestigious NARSAD Award from the Brain and Behavior Research Foundation for his work involving the serotonin uptake transporter.
Dr. Cozzi's research has been supported by grants from the National Institutes of Health, the UW-Madison, and private foundations. Outside acdemia, he serves as a scientific consultant for legal, pharmaceutical industry, and government clients. Dr. Cozzi is also Co-Founder, President, and Director of Pharmacology at the Alexander Shulgin Research Institute, a psychedelics discovery, development, and educational institute located in Lafayette, CA.
Dr. Cozzi’s research involves the design, chemical synthesis, and pharmacological testing of substances with central nervous system activity, especially psychedelics, empathogens, antidepressants, and psychostimulants. He is interested in how these agents act in the brain to promote neuronal health, improve mood, enhance cognition, and increase awareness, and in their clinical value in treating addiction, depression, post-traumatic fear, neurological diseases, and other health ailments. Dr. Cozzi has published numerous articles focused on the chemistry and pharmacology of psychoactive drugs and is internationally recognized for his work.
As an educator, Dr. Cozzi taught pharmacology at the Brody School of Medicine at East Carolina University, the UW-Madison School of Medicine and Public Health, and the UW-Madison School of Pharmacy, and he is a frequent guest lecturer at other academic institutions around the United States. He has received several teaching and research awards, including a Distinguished Basic Science Teaching Award from the UW-Madison and a prestigious NARSAD Award from the Brain and Behavior Research Foundation for his work involving the serotonin uptake transporter.
Dr. Cozzi's research has been supported by grants from the National Institutes of Health, the UW-Madison, and private foundations. Outside acdemia, he serves as a scientific consultant for legal, pharmaceutical industry, and government clients. Dr. Cozzi is also Co-Founder, President, and Director of Pharmacology at the Alexander Shulgin Research Institute, a psychedelics discovery, development, and educational institute located in Lafayette, CA.
less
Interests
Uploads
Papers by Nicholas V Cozzi, Ph.D.
olanzapine, and mood-stabilizing voltage-gated sodium channel (VGSC) blockers, such as lamotrigine, carbamazepine, and valproate, show therapeutic synergy and are often prescribed in combination for the treatment of bipolar disorder. Combination therapy is a complex task for clinicians and patients, often resulting in unexpected difficulties with dosing, drug tolerances, and decreased patient compliance. Thus, an unmet need for bipolar disorder treatment is to develop a therapeutic agent that targets both 5-HT2A receptors and VGSCs. Toward this goal, we developed a novel small molecule that simultaneously antagonizes 5-HT2A receptors and blocks sodium current. The new compound, N-(4-bromo-2,5-dimethoxyphenethyl)-6-(4-phenylbutoxy)hexan-1-amine (XOB) antagonizes 5-HT-stimulated, Gq-mediated, calcium flux at 5-HT2A receptors at low micromolar concentrations while displaying negligible affinity and activity at 5-HT1A, 5-HT2B, and 5-HT2C receptors. At similar concentrations, XOB administration inhibits sodium current in heterologous cells and results in reduced action potential (AP) firing and VGSC-related AP properties in mouse prefrontal cortex
layer V pyramidal neurons. Thus, XOB represents a new, proof-of-principle tool that can be used for future preclinical investigations and therapeutic development. This polypharmacology approach of developing a single molecule to act upon two targets, which are currently independently targeted by combination therapies, may lead to safer alternatives for the treatment of psychiatric disorders that are increasingly being
found to benefit from the simultaneous targeting of multiple receptors.
SIGNIFICANCE STATEMENT: The authors synthesized a novel small molecule (XOB) that simultaneously antagonizes two key therapeutic targets of bipolar disorder, 5-HT2A receptors and voltage-gated sodium channels, in heterologous cells, and inhibits the intrinsic excitability of mouse prefrontal cortex layer V pyramidal neurons in brain slices. XOB represents a valuable new proof-of-principle tool for future preclinical
investigations and provides a novel molecular approach to the pharmacological treatment of complex neuropsychiatric disease, which often requires a combination of therapeutics for sufficient patient benefit.
Background: Sustained reductions in cluster headache burden after limited quantities of psilocybin-containing mushrooms are anecdotally reported, though there are no controlled studies investigating these effects.
Methods: Subjects were randomized to receive psilocybin (0.143 mg/kg) or placebo (microcrystalline cellulose) in a pulse of 3 doses approximately 5 days apart each. Subjects maintained headache diaries starting two weeks before and continuing through eight weeks after the first drug session. Fourteen subjects were included in the final analysis.
Results: In the three weeks after the start of the pulse regimen, cluster attack frequency was +0.03 (95% Confidence Interval: -2.6 to 2.6) attacks/week with placebo and -3.2 (-8.3 to 1.9) attacks/week with psilocybin (p = 0.251). Group difference in change from baseline had a moderate effect size (d = 0.69), though was not statistically significant (p = 0.251). The effect size in episodic subjects was small (d = 0.35), but large in chronic subjects (d = 1.25), which remained over the entire 8-week period measured (d = 0.81). Changes in cluster attack frequency were not correlated with the intensity of acute psychotropic effects during psilocybin administration. Psilocybin was well-tolerated without any unexpected or serious adverse events.
Conclusions: Findings from this initial, exploratory study provide valuable information for the development of larger, more definitive studies. The separation of acute psychotropic effects and lasting therapeutic effects underscores the need for further investigation into the mechanism(s) of action of psilocybin in headache disorders. Clinicaltrials.gov: NCT02981173
• MCAT and para-CF3-MCAT are partial releasers of SERT.
• The partial release evoked by para-CF3-MCAT involves the allosteric site of SERT.
• The substrate permeation pathway of SERT affords different binding modes.
The transporters for dopamine (DAT) and serotonin (SERT) are important targets in the treatment of psychiatric disorders including major depression, anxiety and attention-deficit hyperactivity disorder. Drugs acting at these transporters can act as inhibitors or as releasers. In addition, it has been recently appreciated that some compounds are less efficacious releasers than amphetamine. Thus, they are classified as partial releasers. Compounds can act on both SERT and DAT or display exquisite selectivity for either SERT or DAT, but the structural basis for selectivity is poorly understood. The trifluoromethyl-substitution of methcathinone in the para-position has been shown to dramatically shift the selectivity of methcathinone (MCAT) towards SERT. Here, we examined MCAT, para-trifluoromethyl-methcathinone (p-CF3-MCAT) and other analogues to understand (i) the determinants of selectivity and (ii) the effects of the para-CF 3-substitution of MCAT on the transport cycle. We systematically tested different para-substituted MCATs by biochemical, computational and electrophysiological approaches: addition of the p-CF3-group, but not of other substituents with larger van der Waal's volume, lipophilicity or polarity, converted the DAT-selective MCAT into a SERT-selective partial releaser. Electrophysiological and superfusion experiments, together with kinetic modelling, showed that p-CF3-MCAT, but not MCAT, trapped a fraction of SERTs in an inactive state by occupying the S2-site. These findings define a new mechanism of action for partial releasers, which is distinct from the other two known binding modes underlying partial release. Our observations highlight the fact that the substrate permeation pathway of monoamine transporters supports multiple binding modes, which can be exploited for drug design.
occasioned positive subjective effects.
Methods: Healthy participants (n = 12) were given three escalating doses of oral psilocybin (0.3 mg/kg; 0.45 mg/kg; 0.6 mg/kg) or (18.8–36.6 mg;
27.1–54.0 mg; 36.3–59.2 mg) a minimum of four weeks apart in a supervised setting. Blood and urine samples, vital signs, and electrocardiograms
were obtained. Subjective effects were assessed using the Mystical Experience Questionnaire and Persisting Effects Questionnaire.
Results: There was a significant linear dose-related response in Mystical Experience Questionnaire total score and the transcendence of time and space
subscale, but not in the rate of a complete mystical experience. There was also a significant difference between dose 3 compared to dose 1 on the
transcendence of time and space subscale, while no dose-related differences were found for Mystical Experience Questionnaire total scores or rate of a
mystical experience. Persisting Effects Questionnaire positive composite scores 30 days after completion of the last dose were significantly higher than
negative composite scores. Persisting Effects Questionnaire results revealed a moderate increase in sense of well-being or life satisfaction on average
that was associated with the maximum Mystical Experience Questionnaire total score. Pharmacokinetic measures were associated with dose but not
with Mystical Experience Questionnaire total scores or rate of a mystical experience.
Conclusions: High doses of psilocybin elicited subjective effects at least as strong as the lower doses and resulted in positive persisting subjective
effects 30 days after, indicating that a complete mystical experience was not a prerequisite for positive outcomes.
Key Points:
-Psilocybin, as its active metabolite psilocin, demonstrates linear pharmacokinetics over the 0.3–0.6 mg/kg oral dose range tested.
-Less than 2% of the psilocin in plasma is excreted in urine in that form, suggesting minimal effect of renal dysfunction in elimination of the active metabolite.
-A fixed oral dose of 25 mg is expected to approximate the area under the concentration–time curve and concentration profile of the 0.3 mg/kg oral dose used in this study.
Rationale: 3,4-Methylenedioxypyrovalerone (MDPV) and 3,
4-methylenedioxy-N-methylcathinone (methylone) are synthetic
drugs found in so-called 'bath salts' products. Both
drugs exert their effects by interacting with monoamine transporter
proteins. MDPV is a potent uptake blocker at transporters
for dopamine and norepinephrine while methylone is
a non-selective releaser at transporters for dopamine, norepinephrine,
and serotonin (5-HT).
Objectives: We hypothesized that prominent 5-HT-releasing
actions of methylone would render this drug less reinforcing
than MDPV.
Methods: To test this hypothesis, we compared behavioral effects
of MDPV and methylone using intravenous (i.v.) selfadministration
on a fixed-ratio 1 schedule in male rats. Additionally,
neurochemical effects of the drugs were examined
using in vivo microdialysis in nucleus accumbens, in a separate
cohort of rats.
Results: MDPV self-administration (0.03 mg/kg/inj) was acquired
rapidly and reached 40 infusions per session, similar to
the effects of cocaine (0.5 mg/kg/inj), by the end of training. In
contrast, methylone self-administration (0.3 and 0.5 mg/kg/
inj) was acquired slowly, and response rates only reached 20
infusions per session by the end of training. In dose substitution
studies, MDPVand cocaine displayed typical inverted Ushaped
dose-effect functions, but methylone did not. In vivo
microdialysis revealed that i.v. MDPV (0.1 and 0.3 mg/kg)
increased extracellular dopamine while i.v. methylone (1 and
3 mg/kg) increased extracellular dopamine and 5-HT.
Conclusions: Our findings support the hypothesis that elevations
in extracellular 5-HT in the brain can dampen positive
reinforcing effects of cathinone-type drugs. Nevertheless,
MDPV and methylone are both self-administered by rats, suggesting
these drugs possess significant abuse liability in
humans.
Methcathinone (MCAT) is a potent monoamine releaser and parent compound to emerging drugs of abuse including mephedrone (4-CH3 MCAT), the para-methyl analogue of MCAT. This study examined quantitative structure–activity relationships (QSAR) for MCAT and six para-substituted MCAT analogues on (a) in vitro potency to promote monoamine release via dopamine and serotonin transporters (DAT and SERT, respectively), and (b) in vivo modulation of intracranial self-stimulation (ICSS), a behavioural procedure used to evaluate abuse potential. Neurochemical and behavioural effects were correlated with steric (Es), electronic (σp) and lipophilic (πp) parameters of the para substituents.
EXPERIMENTAL APPROACH
For neurochemical studies, drug effects on monoamine release through DAT and SERT were evaluated in rat brain
synaptosomes. For behavioural studies, drug effects were tested in male Sprague-Dawley rats implanted with electrodes targeting the medial forebrain bundle and trained to lever-press for electrical brain stimulation.
KEY RESULTS
MCAT and all six para-substituted analogues increased monoamine release via DAT and SERT and dose- and time-dependently modulated ICSS. In vitro selectivity for DAT versus SERT correlated with in vivo efficacy to produce abuse-related ICSS facilitation. In addition, the Es values of the para substituents correlated with both selectivity for DAT versus SERT and magnitude of ICSS facilitation.
N-[2-(1H- indol-3-yl)ethyl]-N′,N′-dimethylpropane-1,3-diamine (propyl dimethyl amino tryptamine or PDAT), was shown to inhibit rabINMT by a pure noncompetitive mechanism when measured against tryptamine with a Ki of 84 μM. No inhibition by PDAT was observed at 2 mM when it was tested against structurally similar Class 1 methyltransferases, such as human phenylethanolamine-N-methyltransferase (hPNMT) and human nicotinamide-N- methyltransferase (hNNMT), indicating selectivity for INMT. The demonstration of noncompetitive mechanisms for INMT inhibition implies the presence of an inhibitory allosteric site. In silico analyses using the computer modeling software Autodock and the rabINMT sequence threaded onto the human INMT (hINMT) structure (Protein Data Bank entry 2A14) identified an N-terminal helix−loop−helix non-active site binding region of the enzyme. The energies for binding of DMT and PDAT to this
region of rabINMT, as determined by Autodock, were −6.34 and −7.58 kcal/mol, respectively. Assessment of the allosteric control of INMT may illuminate new biochemical pathway(s) underlying the biology of INMT.