Notice of Special Interest (NOSI): Synthetic Psychoactive Drugs and Strategic Approaches to Counteract Their Deleterious Effects
Notice Number:

Key Dates

Release Date:

March 25, 2021

First Available Due Date:
June 05, 2021
Expiration Date:
September 08, 2024

Related Announcements

PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)

PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)

PA-20-200 - NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)

Issued by

National Institute on Drug Abuse (NIDA)


This Notice informs potential applicants to the National Institute on Drug Abuse (NIDA) about a special interest in research on chemistry, pharmacology, biological targets and biochemical mechanisms that contribute to the effects of synthetic psychoactive substances.


Synthetic psychoactive drugs (SPDs) also known as designer drugs, new or novel psychoactive substances (NPS) are compounds that are specifically designed to mimic the actions of known drugs. SPDs can be broadly classified as follows:1) Synthetic cannabinoids (SCs) and THC-mimics that produce experiences similar to marijuana; 2) Synthetic stimulants and mimetics such as the cathinones, pyrovalerones, amphetamines and tryptamines; 3) Synthetic opioids (opioid-mimics, fentanyl and fentanyl analogs); 4) Serotonergic and atypical psychedelics that produce hallucinogenic and toxic effects; 5) Benzodiazepines, GABA analogs; and 6) Other SPDs, NPSs, and designer drugs such as those currently being used overseas and have potential for misuse in the US. In addition to their misuse potential, these synthetic psychoactive substances produce peripheral and central toxicity of varying severity. This toxicity is particularly concerning as use of these substances is on the rise. The surge of SPD use during the last 8-10 years is a major public health concern and necessitates a broad research agenda to guide prevention and treatment strategies.

There is a significant need for research aimed at investigating the receptor targets, signaling pathways, impact on circuits and neural networks and neurodevelopmental effects of SPDs. Although little is known about their detailed pharmacology, toxicology and metabolism, some of the SPDs have shown potent activity at the monoamine neurotransmitter and endocannabinoid systems. There are reports showing that rats self-administer cathinones similar to, or more robustly than, methamphetamine. SPDs can also induce intense cravings, tolerance, physical dependence, and strong withdrawal symptoms. A number of toxicological symptoms have been reported with synthetic drugs although the mechanisms underlying the toxicity remains to be fully explored. Further research is therefore needed to understand the mechanisms contributing to the toxicological profile of SPDs and to identify potential pharmacological approaches to treat SPD intoxication.

Research Objectives

The goal of this Notice is to encourage basic preclinical research to understand the chemistry, pharmacology, and molecular mechanisms of actions of the SPDs. Areas of interest include, but are not limited to:

  • Studies that determine the ligand binding properties of SPDs to receptors including off-target binding effects; functional agonism/antagonism, signaling bias, orthosteric and allosteric interactions; structure-activity studies to develop potent and selective, ultra-fast and long-acting antagonists as potential detoxifying treatment drugs;
  • Studies on neurotransmitter release and uptake following acute and chronic exposure to SPDs;
  • Development of interaction profiles of common SPD ingredients with receptors, channels, transporters, enzymes, etc. as a guide to estimate potential biological activity and toxicity;
  • Studies investigating the effects of SPDs on epigenomic modifications, non-coding RNA regulation, or gene expression in CNS cells;
  • Studies in animal behavioral models to determine addiction liability, drug interactions, and the effects of exposure to synthetic drugs on the development of vulnerability to other drugs, at various developmental stages;
  • Preclinical studies of acute and longer-term effects on processes such as sensation and perception, cognition, learning and memory, emotion and anxiety, social interactions, and the identification of novel effects that have not been observed with “traditional” drugs;
  • Comparative investigations of these SPDs versus other substances on behaviors relevant to substance use including choice behavior, relative reinforcement, and the ability to reinforce associations with environmental stimuli that serve as cues prompting drug-taking behavior;
  • Development of analytic detection methods to identify the active ingredients present in a given SPD, and to identify residual solvents, metals and reaction ingredients (cyanides, thiocyanates, diluents, herbals, etc.) that contribute to potential toxicological profiles;
  • Studies on stability, pharmacokinetic and pharmacodynamic (PK/PD) profiles (depending on route of administration), development of specific and sensitive analytical methods for in vivo and in vitro analysis including analysis of biospecimens such as urine, blood, saliva, sweat;
  • Identification of biomarkers as proxies for detecting SPDs in vitro and in vivo;
  • Studies on circadian and/or bioenergetics effects of SPDs;
  • Imaging studies to identify the general SPD effects on brain activity, blood flow and circuit connectivity;
  • Research on neurological, psychiatric, cardiovascular, or other physiological systems, pathophysiology and the time course of pathological effects;
  • Preclinical studies examining interventions to ameliorate the toxicological/ pathophysiological consequences associated with consumption of SPDs

Application and Submission Information

This notice applies to due dates on or after June 5, 2021 and subsequent receipt dates through September 7, 2024. 

Submit applications for this initiative using one of the following funding opportunity announcements (FOAs) or any reissues of these announcement through the expiration date of this notice.

  • PA-20-185 - NIH Research Project Grant (Parent R01 Clinical Trial Not Allowed)
  • PA-20-195 - NIH Exploratory/Developmental Research Grant Program (Parent R21 Clinical Trial Not Allowed)
  • PA-20-200 – NIH Small Research Grant Program (Parent R03 Clinical Trial Not Allowed)

All instructions in the SF424 (R&R) Application Guide and the funding opportunity announcement used for submission must be followed, with the following additions:

  • For funding consideration, applicants must include “NOT-DA-21-028” (without quotation marks) in the Agency Routing Identifier field (box 4B) of the SF424 R&R form. Applications without this information in box 4B will not be considered for this initiative.

Applications nonresponsive to terms of this NOSI will not be considered for the NOSI initiative.


Please direct all inquiries to the contacts in Section VII of the listed funding opportunity announcements with the following additions/substitutions:

Scientific/Research Contact(s)

Sam Ananthan, Ph.D.
National Institute on Drug Abuse (NIDA)

Telephone: 301-435-2199


Financial/Grants Management Contact(s)

Pamela G. Fleming
National Institute on Drug Abuse (NIDA)

Telephone: 301-480-1159


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