Pharmacological Overview of Calmatives
Marian Daggett, Research Attorney

Often termed interchangeably as chemical calmatives, calmative agents, calmative drugs, and chemical weapons, calmatives are a class of drugs that tend to produce a calming or sedative effect. These agents could be considered for law enforcement applications, such as dispersing a crowd, controlling a riot, or calming a non-compliant offender. This article discusses the science behind calmatives.

Before discussing the particular mechanisms of the various calmative drugs, a brief introduction into basic pharmacological concepts will provide a solid background on how any drug will act on the human body. First, drug delivery and routes of administration will be discussed, then an overview of the mechanisms of drug action within the body, including pharmacokinetic and pharmacodynamic principles, and finally, a description of how proposed drugs are researched and developed. After this introduction to pharmacology, the specific area of the human body that calmatives generally target the nervous system will be discussed, followed by a description of how calmatives drugs affect this area. Each major class of calmative will be described in terms of drug action and applicability, followed by general considerations for developing an ideal calmative drug for law enforcement purposes.

The two main categories of drug delivery, also called the routes of administration, are gastrointestinal and parenteral. In other words, these are the two main ways that a drug is put into the body. Gastrointestinal (GI), or enteral, refers to anything taken by mouth that follows the digestive path, or anything administered directly into various parts of the GI system, such as the stomach or the intestines. GI routes include oral, gastric, and rectal. Parenteral, on the other hand, means literally, anything outside the enteral, or GI, system. The parenteral routes include intravenous (injected by needle directly into the bloodstream); subcutaneous (injected into the fatty layer under the skin); transdermal or intradermal (through or directly into the skin); intramuscular (injected directly into a major muscle); topical (applied onto the skin or the mucous membranes); inhalation (absorbed through the lungs); and buccal or sublingual (absorbed directly through the side of the cheek or under the tongue). Drugs can also be formulated as systemic or local. Local drugs act on a particular organ or tissue of the body and are administered at that site. Systemic drugs enter the bloodstream and take effect throughout the whole body.

Some routes of administration are much faster acting than others, because certain delivery methods allow drugs to be more quickly absorbed into the bloodstream. If a drug hits the bloodstream, it is immediately transported throughout the circulatory system, which delivers blood to every cell in the body. As soon as the drug hits the bloodstream, it begins to take effect, so the fewer steps between administration and absorption into the bloodstream, the quicker the drug. For fastest action, the drug is placed directly into the bloodstream, through an intravenous injection. Generally, the other fast-acting drug routes include intramuscular, inhalation, buccal and sublingual. The intramuscular route is an injection into the muscles, which are highly vascular. The inhalation, or pulmonary, route involves the exchange of gases into the bloodstream from the tiny fluid-filled sacs, called alveoli, located in the lungs; this exchange also brings inhaled droplets of fluids and substances into the pulmonary capillaries, at a juncture close in proximity to the heart, allowing rapid central distribution. Finally, buccal and sublingual routes both involve absorption directly into the highly vascular lining of the mouth, at a bloodstream location conveniently close to the brain.

Other routes of administration offer comparatively slower-acting drug delivery, which may or may not be a benefit based on the purpose of the drug. Drugs administered through the gastrointestinal route have to pass through the digestive tract, and in the process, be exposed to acids in the stomach and bases in the intestines, be metabolized, and finally, be absorbed through the walls of the tract, if not already digested. Because the GI route is systemic, it is more difficult to achieve selectivity, the ability of the drug to target an exact organ or tissue without affecting any other cells. The subcutaneous route, where a drug is injected into the fatty layer below the skin, provides a slow, indirect pathway to the bloodstream as the fat in the subcutaneous layer muddles and insulates the drug. One final route, providing not necessarily fast or slow action, but a controllable route of delivery, is the transdermal route, usually a patch that adheres to the skin. This application can be designed to release certain dosage amounts of the drug at controlled intervals throughout a duration of time.

Once in the body, the drug begins to take effect, through certain procedures collectively termed the drug action. Generally, drug actions within the body can be summed up by two concepts: pharmacodynamics and pharmacokinetics. Pharmacodynamics describes what the drug does to the body, and pharmacokinetics describes what the body does to the drug.

Pharmacodynamics is the study of how a drug interacts within the body to find and affect its target organ or tissue, including the chemical interaction of the drug with its target. A drug target is the specific body part, organ, or system that the drug is aimed to affect. On the target, the drug molecules interact with receptors, on each particular cell. A receptor is the area on a cell that chemically binds with a drug to alter the activity of the cell.

Within the study of pharmacodynamics is the sub-pursuit of investigating the ability to start and stop a drug effect This is achieved by analyzing what is called the pharmacodynamic profile, or the specificity of the drug action on the body. The specificity of a drug is linked to its actions as a receptor agonist or antagonist. An agonist transmits a signal to a cell to stimulate activity, while an antagonist chemically blocks signal transmission to the cell. The study of receptor agonists and antagonists helps to determine what will start and stop drug action. For instance, an agonist will activate a receptor on the target tissue, and to stop this action, an inhibitor is used to work against the action of the agonist. Likewise, an antagonist will block the receptor on the target tissue, so an activator will work against the action of the antagonist.

Pharmacokinetics, like pharmacodynamics, describes drug action, specifically instead, how a drug is processed through the human body. In other words, it is the study of how the body handles the drug. The four main steps of pharmacokinetics are absorption, distribution, metabolism, and excretion. Absorption refers to how the drug enters the body and the rate at which it passes into the bloodstream from point of entry. Distribution refers to how quickly, and through what pathways, once in the bloodstream, the drug travels to its target. Metabolism, or biotransformation, involves the interactions with the body's systemic processes, and the transition from an agent to an effect. Excretion is the process of digestion, or the removal of dissolved waste particles from the body.

Paradoxical reactions can occur with any drug, meaning that the drug produces an atypical, opposite effect to that of the expected action. For example, instead of a calm sedation, calmative agents might produce anger, mania, or hyperactivity.

The actions of a drug may also be effected by its potential for synergistic relationships. Synergism is a combined and exponentially greater result from two drugs taken together, than either drug taken alone or even the arithmetical sum of both drugs. The benefit of synergism is that improved effects could be achieved with lower dosages of each drug.

To evaluate a proposed drug, before entry into the market, pharmacological research must be done on preclinical and clinical levels. Preclinical research occurs in the laboratory, primarily using cell cultures and brain tissue slices from animals; the purpose of this research is to explore cellular and molecular effects of the drug action and to determine dose response. Following that, clinical research is performed on human patients, to show that the drug does what it is intended to do, determining efficacy. This level of research also confirms in humans what was found in the preclinical trials, in terms of dosage and proper method of administration. In addition, clinical research identifies toxicities and side effects. A benefit of clinical trials is that the drug scientists can select specific patient populations for research.

Calmatives, as a class of drugs, are compounds that depress or inhibit the central nervous system. This action causes a calm or sedated state. The target of these drugs, the central nervous system, includes the brain and the spinal cord. It is the central control system of the peripheral nervous system, which transmits signals electrically throughout the entire body via nerve impulses. There are many components within the nervous system where a calmative drug might take effect. The neurons are the building blocks of the nervous system, and a bundle of neurons composes a nerve. Each neuron transmits signals to the next neuron across a synapse, or the connection between two neurons; this synapse is often the target of calmative drugs. Neurotransmitters transmit the nervous signals across the synapse. Dopamine, serotonin, and norepinephrine are specific types of neurotransmitters. If the actions of central nervous system are depressed, there is normally a shortage of these key neurotransmitters. major classes of calmative compounds act distinctly on the various components of the central nervous system. Generally, the classes of calmatives include sedative-hypnotic agents, anesthetic agents, antipsychotics, skeletal muscle relaxants, opioid analgesics, anxiolytics, and antidepressants.

Sedative-hypnotic agents promote sedation, or a calming effect, in small doses. Larger doses of sedatives and hypnotics promote sleep. Anesthetic agents block the sensation of pain within the nervous system. Antipsychotics work as tranquilizers and are sometimes called neuroleptics. Both anesthetics and antipsychotics activate the receptors that stop the transmission of nervous signals and trigger sedation.

Skeletal muscle relaxants inhibit the transmission of muscle movement signals across the nerves that connect the nervous system to the muscular system. This action affects the functioning of the spinal cord and brain, producing a sedative effect on the affected muscle group.

Opioid analgesics alter the perception of pain sensation. The opioid family includes such drugs as morphine, heroin, codeine, and methadone. As analgesics, opioids relieve pain or increase pain tolerance, and they are controlled as highly addictive narcotics. Normally, receptor agonists activate the opioid receptors, causing an imbalance in the transmission of nervous signals, which sometimes causes sedation, indifference, slow breathing, euphoria, and immobilization. The actions of these agents can be reversed by receptor antagonists to prevent fatal overdose.

Anxiolytics are anti-anxiety tranquilizers. These drugs increase the action of neurotransmitters that inhibit brain activity, decreasing the rate of neurons fired throughout the central nervous system. Small doses of anxiolytics reduce anxiety and promote relaxation, while larger doses promote sedation.

Antidepressants are mood elevators; these drugs promote increased activity of chemical neurotransmitters, such as dopamine, serotonin, norepinephrine, at the neuron synapse. Sometimes, anti-depressants affect this action by blocking the reabsorption of the neurotransmitters, thus helping to restore the chemical balance of the brain. This means that there is more of the neurotransmitter available at the synapse between two neurons. As mentioned earlier, dopamine, serotonin, and norepinephrine are key neurotransmitters for the proper function of the nervous system. Dopamine is a major neurotransmitter involved in the regulation of emotion, cognition, motivation, hormones, and voluntary movement. Increased levels of serotonin improve behavior, induce sleep, and are linked to the control of agitation, anxiety, and aggression. Norepinephrine is involved in the stress response, producing increased physiological activity in the brain, heart rate, and muscles, in response to a stressful stimulus.

Each calmative drug compound produces effects that span a certain range, depending on the dose, or amount, of the drug administered. Therefore, the range of drug-induced effects are dose-dependent. An ideal calmative drug dose would lead to mild sedation or anxiety relief, not deep sedation or hypnosis.

Other factors are important when selecting an ideal calmative drug. First, the drug's ability to cross the blood-brain barrier should be examined. The blood-brain barrier is a protective mechanism of the central nervous system that blocks substances from passing into the brain from the bloodstream. Certain drugs, but not all, can permeate this blood-brain barrier. Second, the pharmacodynamic profile must be studied to determine the ability to start and stop the specific drug effect.

The research to find an ideal calmative drug might benefit from current discoveries of synergism applied in medical research, with the ability to reduce dosage but increase effect. Pharmaceutical and biotechnology companies have already made great progress through clinical trials by discovering new routes of drug delivery and synergistic drug combinations. Certain drugs of abuse, or recreational drugs, which are characterized as drugs used for non-therapeutic purposes, could also be explored for calmative drug applications based on their abilities to suppress or inhibit the mechanisms of the nervous system.

Ultimately, a calmative chosen for less lethal law enforcement purposes should exhibit the following characteristics: an easy and versatile route of administration, fast onset of action, a short drug effect duration, a consistent dose response, reversible action by antidote or rapid metabolism, and no long-lasting or permanent toxicity or side effects. A few ways that a non-lethal calmative might be administered, depending on the law enforcement environment, would include a topical or transdermal skin application, an aerosol spray, an intramuscular dart, or a rubber bullet filled with an inhalable agent. However, the ability to target a specific wrongdoer or horde, while not affecting outlying innocent bystanders, through a discriminatory application, has yet to be mastered. Until the proper administration techniques for a controllable yet effective calmative drug meet the demands of public welfare, calmatives, as riot control agents, will continue to be shelved.


1Shannon L. Bartelt-Hunt, Morton A. Barlaz, Detlef R. Knappe & Peter Kjeldsen, Fate of Chemical Warfare Agents and Toxic Industrial Chemicals in Landfills, 40 Environmental Science & Technology 4219 (July 1, 2006).
2F.W. Beswick, Chemical Agents Used In Riot Control and Warfare, 2 Human Toxicology 247 (Apr. 1983).
3Michael E. Conti, Beyond Pepper Spray: The Complete Guide To Chemical Agents, Delivery Systems, and Protective Masks (Paladin Press 2002).
4Neil Davison, Biochemical Weapons: Lethality, Technology, Development, and Policy, in Neil Davison & Nick Lewer, Bradford Non-Lethal Weapons Research Project Report NO. 5, May 2004.
5Federation of American Scientists Working Group on Biological & Chemical Weapons, The Threat of Chemical Incapacitating Agents (Position Paper, Mar. 2003).
6Martin Furmanski, Military Interest in Low-Lethality Biochemical Agents: The Historical Interaction of Advocates, Experts, Pragmatists, and Politicians, (Report, Center for Arms Control and Non-Proliferation 2005).
7Douglas Holdstock, Chemical and Biological Warfare: Some Ethical Dilemmas, 15 Cambridge Quarterly of Healthcare Ethics 356 (2006).
8Howard Hu, et al., Tear Gas: Harassing Agent or Toxic Chemical Weapon?, 262 Journal of the American Medical Association 660 (Aug. 4, 1989).
9David Isenberg, Next Up: 'Non-Lethal' Chemicals That Kill, Asia Times, April 2003, at 1.
10Matt Kelley, Pentagon Discusses Ways to Use Chemicals to Calm Rioters, Sign of San Diego, Sept. 25, 2002.
11James S. Ketchum, Chemical Warfare Secrets Almost Forgotten: A Personal Story of Medical Testing of Army Vokunteers With Incapacitating Chemical Agents During The Cold War 1955-1975 (ChemBooks 2006).
12Ian Kenyon, Moderator, Open Forum On The Chemical Weapons Convention: Challenges To The Chemical Weapons Ban, May 1, 2003.
13Lynn Klotz, Marting Furmanski & Mark Wheelis, Beware The Siren's Song: Why 'Non-Lethal' Incapacitating Chemical Agents Are Lethal (Federation of American Scientists, March 2003).
14Joan M. Lakoski, W. Bosseau Murray & John M. Kenny, The Advantages And Limitations Of Calmatives For Use As A Non-Lethal Technique (Applied Research Laboratory at Penn State University Oct. 3, 2000).
15Organization For The Prohibition Of Chemical Weapons (OPCW), Convention On The Prohibition Of The Development, Production, Stockpiling And Use Of Chemical Weapons And On Their Destruction [Chemical Weapons Convention] (April 29, 1997).
16A. Pearson, Incapacitating Biochemical Weapons: Science, Technology, and Policy for the 21st Century, 13 NONPROLIFERATION REVIEW 151 (July 2006).
17Graham Pearson & Malcolm Dando, The Danger To The Chemical WEAPONS CONVENTION From Incapacitating Chemicals (CWC Review Conference Paper No. 4, March 2003).
18Press Release, Sunshine Project, Non-Lethal Weapons Research in the U.S.: Calmatives and Malodorants (July 2001) (available at
19Press Release, Sunshine Project, The MCRU Calmatives Study and JNLWD: A Summary of (Public) Facts (September 19, 2002) (available at
20David Ruppe, Pentagon Panel Suggests Chemical Calmatives, Global Security Newswire, Apr. 21, 2004.
21David Ruppe, United States I: New Research Offers Safer Incapacitating Chemicals, Global Security Newswire, Nov. 6, 2002.
22Lou Schetzer, Victorian Police Plan to Use Chemical Weapons, 6 Current Issues Criminal Justice 152 (July 1994).
23K.J. Smith, The Prevention and Treatment of Cutaneous Injury Secondary to Chemical Warfare Agents: Application Of These Finding To Other Dermatologic Conditions and Wound Healing, 17 DERMATOLOGIC CLINICS 41 (Jan. 1999).
24J. Smith & I. Greaves, The Use of Chemical Incapacitant Sprays: A Review. 52 Journal of Trauma-Injury Infection & Critical Care 595 (2002).
25Satu M. Somani & James A. Romano, Chemical Warfare Agents: Toxicity At Low Levels (CRC Press 2000).
26Yin Sun & Kwok Ong, Detection Technologies For Chemical Warfare Agents And Toxic Vapors (CRC Press 2004).
27Mark Wheelis, Biotechnology and Biochemical Weapons, 9 NonprOliferation Review (Spring 2002).
28George N. Whitbred, Offensive Use of Chemical Technologies by US Special Operations Forces in the Global War on Terrorism, AIR WAR COLLEGE MAXWELL PAPERS, July 2006.