Drug Dependence Concept

When drugs (including medicines and other chemicals) that act on the central nervous system are repeatedly taken, persistent changes occur in the body (mainly the nervous system in the brain). The concept of drug dependence was established to describe one aspect of these changes. Until then, drug addiction, drug habituation, drug intoxication and other terms were used to describe the condition, creating confusion. However, the scientific and clear definition of drug dependence has clarified this confusion. This has led to progress in research in this field, diagnostic and therapeutic methods for drug dependence disorders, and prevention of drug abuse in the society.

At the core of drug dependence in humans is the concept of psychic dependence, which is a change in the state of the brain's nerves. The change in the brain state caused by psychic dependence is characterized by an obsessive craving for the drug. This leads to drug-seeking behavior, which is an intense pursuit of the drug, at the behavioral level. Therefore, in humans, controlling craving for drugs is the most important issue in research and treatment.

In light of the above, drug self-administration behavior as drug-seeking behavior has become the most important technique and challenge in drug dependence research using laboratory animals. The drug self-administration behaviorIf is observed by lever-pressings of the laboratory animals for the water-soluble drug via an intravenous route with an indwelling catheter and for the non water-soluble drug via  a catheter placed in the stomach with suspending the drug in a medium.

See Operant Behavior in Neuroscience and Drug Dependence and Behavioral Analysis  in this WEB site

In drug dependence research, it is also important to understand and grasp the biochemical, physiological, molecular biological, and genetic analytical aspects of the brain regarding the aforementioned sustained changes in the body. However, this is based on the premise that the essence of drug dependence is psychic dependence, and that this is manifested as drug-seeking behavior. Even if physiological, molecular biological, and genetic analytical searches of the brain are conducted on a model simply administered with a dependence producing drug, this does not unconditionally lead to an elucidation of the essence of drug dependence.

In addition to drug dependence, there are also dependences on specific things, such as gambling dependence and gaming dependence. There must be a common brain mechanism between these and drug dependence. However, unlike gambling dependence, drug dependence involves a new neural network in the brain that is complex with the pharmacological action of the ingested drug. Therefore, in this respect, there is an aspect that cannot be discussed about drug dependence in the same way as gambling dependence and gaming dependence. It is true that there may be an appealing research idea to integrate drug dependence with gambling dependence as well as gaming dependence and consider the common brain mechanism. However, this will blur the focus of drug dependence, and the concept of dependence that has been clarified in drug dependence will be mixed with the terminology used in gambling and gaming dependence, and the original concept of drug dependence will become blurred, which will be a complete waste.

In drug dependence research, it is important to recognize drug dependence as a state change of the living body (nervous system of the brain) as described above, and to conduct research from a neutral and objective scientific perspective without unilaterally assigning values ​​such as trouble or disorder. On the other hand, a separate term, drug dependence disorder, is used to describe the adverse effects and disorders on an individual's health, daily life, and social life caused by drug dependence. The goals for drug dependence include prevention, diagnosis, and treatment in psychiatric fields, as well as legal restrictions and crackdowns on the abuse of chemical substances (drugs).

Therefore, we will first explain the process by which drug dependence develops, and then provide explanations of the terms related to drug dependence. We hope that this will help to form a comprehensive understanding of drug dependence and lead to the development of targeted research on drug dependence.

Drug dependence:

The World Health Organization (WHO) has clearly defined drug dependence from a biological science perspective. In other words, drug dependence is a change in the state of the body (brain) that occurs as a result of voluntary repeated intake of a drug, and this can be divided into both psychic and physical dependence. This has helped to clarify the confusion caused by the use of various terms such as drug addiction, drug habituation, and drug abuse. Although these terms that have been used traditionally exist as everyday terms, they tend to cause confusion when discussing drug dependence scientifically, so it was thought that they should be unified under the term drug dependence.

In addition, drug dependence is merely an objective description of the state of the body, and does not describe a state in which it is good or bad, or that it has any obstacles or harmful effects. When a state of drug dependence causes problems in an individual's health, daily life, social life, and a society, it becomes a target for diagnosis and treatment in the field of psychiatry, etc. And for this, the term drug dependence syndrome or drug dedendence disorder is provided separately. In addition, when drug dependence becomes severe and drug abuse causes social problems, it becomes the subject of legal restrictions and crackdowns.

There are various definitions and ways of thinking about drug dependence, including the addiction mentioned above. Each may capture one aspect of drug dependence. However, drug dependence is extremely intricate and complex, and confusion arises when trying to include various aspects. Therefore, we believe that it is easiest to deepen our understanding from the WHO definition of drug dependence mentioned above, and that this will allow us to get to the essence of the problem of drug dependence.

Psychic dependence:

Psychic dependence, which can be said to be the main axis of drug dependence, is defined by a strong craving for drugs. Psychic dependence refers to the state of the organism (nervous system of the brain) in which such craving exists. Linked to this, at the behavioral level, compulsive drug-seeking behavior appears. In animal experiments, this part can be reproduced by self-administration of drugs (intravenous/intragastric).

See Operant Behavior in Neuroscience and Drug Dependence and Behavioral Analysis  in this WEB site

On the other hand, let us leave the issue of drug dependence aside and consider the state of hunger for food and water. This is based on neural excitation in specific related areas in the brain, and this physiological mechanism is naturally present in living organisms from birth and is a necessary condition for the organism to adapt to its environment and survive.

It is thought that psychic drug dependence is the result of repeated exposure to a specific drug, which leads to a strong neural network in the brain being formed after birth. Problems arise when this progresses to a state that causes impairment and harm to an individual's health, daily life, and social life, leading to drug dependence. For these reasons, we believe that the most important thing in preventing or treating drug dependence is to deal with psychic dependence. Here, we cannot think of intense craving for drugs simply as a matter of psychological self-control, but must consider that a biological basis has been formed behind it.

Physical dependence:

This is another aspect of drug dependence that is separate from psychic dependence. Physical dependence is a new state of neuroadaptation caused in the body by repeated drug intake, separate from the state in the brain that causes drug craving in psychic dependence. Whether or not the body is in this state of physical dependence is made clear by the appearance of physical withdrawal syndrome when the repeated drug intake is stopped (see the section below for withdrawal symptoms). When physical dependence is formed on morphine or other drugs, when the intake of the drug is stopped, not only characteristic withdrawal syndrome such as sweating but also severe pain occurs. Here, the initial morphine-seeking behavior that gives a feeling of euphoria will eventually change in nature to drug-seeking behavior as an escape or avoidance behavior from the pain. For this reason, physical dependence in drug dependence is a concept that presupposes psychic dependence. Therefore, physical dependence is shown in Figure 1 as a subset of psychic dependence.

However, the following question may arise: Isn't the craving for drugs, which is the core of psychic dependence, also one of the withdrawal symptoms that occurs when drug intake is stopped? Therefore, isn't psychic dependence also included in physical dependence? In response to this, the desire to take a drug is the starting point of drug dependence, and drug dependence is formed based on the desire and finally the craving. Therefore, the author believes that it is more convenient for the essential understanding of drug dependence to clearly distinguish between psychic dependence, which is the core and main player in the process of drug dependence, and physical dependence, which is a supporting role. The concept of drug dependence is also a conceptualization of pharmacological and physiological phenomena, and is not clearly divided like a physical structure. Of course, this is the case excluding the world of quantum physics.

Withdrawal syndrome:

A physical repulsive phenomenon that occurs when a person in a state of drug dependence suddenly stops taking the drug. Withdrawal syndromes for morphine dependence include sweating, yawning, lacrimation, nasal discharge, dilated pupils, stomach cramps, and vomiting. On the other hand, withdrawal syndromes for benzodiazepine derivative dependence include tachypnea, tachycardia, tremors, hyperreflexia, and seizures. Withdrawal syndromes from alcoholism include trembling of the hands and whole body, sweating, insomnia, vomiting, hallucinations, and disorientation.

Withdrawal sydromes were previously called abstinence symptoms. Abstinence symptoms have the nuance of being caused by the sudden discontinuation of drug use. However, even if drug use is suddenly discontinued, the blood and tissue concentrations of the drug in the body slowly disappear, so the term abstinence was considered inappropriate. Also, symptoms are subjective symptoms, such as headaches and stomachaches, that patients report to their doctors based on their subjective state of the body. On the other hand, physical changes that doctors objectively diagnose when diagnosing the patient's state are called signs. The combination of these symptoms and signs is called a syndrome, and it has come to be considered more appropriate to refer to withdrawal syndrome, including the above two aspects, as a comprehensive term rather than abstinence symptoms.

Drug dependence syndrome / drug dependence disorder:

As mentioned above, drug dependence is a scientifically objective description of the state of the living body by repeated drug intakes. Therefore, it does not mean good, bad, or troublesome. However, when it comes to drug dependence as to a pathological condition that is the subject of treatment, drug dependence comes to drug dependence syndrome or drug dependence disorder. The steps leading to this are as follows: A psychic dependent state is formed in the living body ⇨ Intense craving for drugs ⇨ Drug-seeking behavior ⇨ Drug overdose ⇨ Clear adverse effects occur in terms of health, daily life, and social life. In this final step, it becomes difficult to control the drug overdose with one's own self control. Here again, the essence of drug dependence is psychic dependence, and control or treatment targeting this will be the fundamental treatment for psychic drug dependence disorder.

To give a specific example, moderate alcohol intake is considered to be no problem. However, if the intake becomes uncontrollable and one continues to think about drinking even at work, or actually consumes alcohol, causing problems at work and in social life. In addition, when considering alcohol dependence, but controllable alcohol intake within a socially acceptable range, it is thought that alcohol dependence and alchohole dependence syndrome/disorder should be distinguished. Alcohol enjoyment, alcohol dependence, alcohol indulgence and alcoholism (alcohol dependence disorder)  are one continuous flow, and where one can stop is a matter of behavioral control against psychic dependence. However, this should not be seen as entirely a matter of individual will or reason. In drug dependence, it should be considered that a new and strong biological network foundation has been formed in the nervous system of the individual's brain. It is similar to the fact that no living organism can overcome a state of starvation from food or water by will or reason alone.

Psychotoxicity:

The toxicity of drugs and various chemical substances to various organs, such as the liver function, is understood by morphological/pathological examinations. On the other hand, the psychotoxicity of drugs cannot be understood by these examinations. However, there are some things that must be recognized as toxicity. In the case of stimulant drug (methamphetamine, etc.) dependence, addicts may experience hallucinations and delusions and commit crimes. Hallucinations and delusions caused by stimulants are called psychotoxicity caused by stimulants.

Tolerance:

As a drug is taken repeatedly, the initial effect of the drug weakens, and the drug dose must be increased to achieve the same effect. This is called drug tolerance. The term tolerance can refer to the state of the body in which tolerance occurs, or to the characteristics of the drug that cause tolerance. Some drugs cause tolerance, while others do not. However, when tolerance occurs to a drug, the state of drug dependence deepens, and the path to dependence disorder may accelerate. Drug tolerance is not an essential part of drug dependence, but it is an important aspect that occurs as drug dependence develops.

Sensitization / Reverse tolerance:

Tolerance refers to the weakening of the effect of a certain dose of a drug with repeated use, while reverse tolerance refers to the increase in the effect of a certain dose of a drug with repeated intake. Experimentally, it has been observed that repeated administration of a certain dose of methamphetamine or other stimulants to rats/mice leads to an increase in spontaneous locomotion. In addition, when addicts who have stopped using stimulants return to small amounts of stimulants after many years, they experience a different, more dramatic effect than before. These are examples of reverse tolerance, but they are also called drug hysteresis.

The author believes that there is no need to refer to reverse tolerance as the opposite of tolerance, and that it would be better to call it drug sensitization. This is because there is no guarantee that tolerance and reverse tolerance are established on the same neural mechanism, and only the direction is opposite. In physiology, there are concepts of neural inhibition and excitation, but excitation would not be called reverse inhibition. On the other hand, in neurophysiology there is the term disinhibition, which means that inhibitory neural synaptic activity is removed, so this does not seem strange to us.

Other terms related to drug dependence:

The main terms related to drug dependence are psychic dependence, physical dependence, and dependence syndrome/disorder. However, various terms other than those mentioned above have been used in the past.

Drug intoxication is a familiar term, like alcoholism. However, it is confusing whether this refers to dependence on the drug or acute alcohol poisoning caused by taking the drug. Pharmacologically, the two are completely different. Therefore, alcohol dependence and acute alcohol poisoning caused by taking large amounts of alcohol should be described separately as alcohol dependence (alcohol dependence syndrome or disorder) and alcohol acute toxicity, respectively.

Drug abuse refers to a social situation in which drugs are used illegally or excessively, rather than a concept related to a biological state, like drug dependence. In fact, terms such as abused drugs are used in legal regulations for dependence drugs.

Drug dependence potential / drug dependence liability:

Characteristics of the drug that cause dependence. As mentioned above, drug dependence is a term that describes the state of the living body. On the other hand, drug dependence is used to describe the characteristics of the drug that can cause dependence as a result of the interaction between the drug and the living body. A drug with dependence potential or dependence liability is a drug that has such characteristics.

Among the terms for drug dependence, drug dependence potential could also be used as the term drug dependence ability. As for potential, even if a drug has not yet been reported to cause dependence, there is a potential for dependence due to similarities in chemical structure with drugs that are already recognized to be dependent, and therefore the nuance is considered to include cases where drug dependence can be predicted.

As for the liability of drug dependence Liability, there is a medical term called susceptibility. Therefore, drug dependence liability has the nuance of the characteristics of a drug that is likely to cause dependence. Also, liability has the original meaning of legal responsibility. Regarding product liability for home appliances, the first page of the instruction manual provides a detailed description of liability. Therefore, even when a pharmaceutical company manufactures and sells a drug, it also has a responsibility to describe the liability for that drug's dependence potential, and in such cases, the author believes the term drug dependence liability is appropriate.

4. Classification of dependence producing drugs

Regarding general drug classification apart from dependence producing drugs, drugs are classified based on pharmacological action, chemical structure, clinical application, etc. However, dependence producing drugs are classified differently, taking into consideration the balance between the degree of dependence producing potential, the degree of harmful effects when abused, and the usefulness as a medicine. As an example of the above, the Control Substance Schedule by the US Department of Justice and the Drug Enforcement Administration is a reference for knowing the types of dependence producing drugs (compounds) and their abuse status. From the perspective of cracking down on drug use, they are classified from Schedule I to Schedule V, taking into consideration the balance between the strength of drug addictiveness and medical purposes. Schedule I is classified as extremely addictive, even though it is unlikely to be used for medical purposes. Schedule II is classified as highly addictive, but has medical usefulness. The subsequent schedules are classified by balancing the degree of addictiveness and medical purposes. We thought that this classification is easy to understand the nature of addictive drugs and how to view them. However, some of the product names of drugs distributed in the United States may be unfamiliar to us outside of US.

Schedule I:

Compounds that are the most addictive and unlikely to be used for medical purposes (only some are listed as examples, same below)

Heroin, Lysergic acid diethylamide (LSD), Marijuana (Cannabis), 3,4-Methylenedioxymethamphetamine (Ecstasy), Methaqualone, Peyote

Schedule II:

Drugs that are used for medical purposes but are highly addictive

Combination products with less than 15 milligrams of hydrocodone per dosage unit (Vicodin), Cocaine, Methamphetamine, Methadone, Hydromorphone (Dilaudid), Meperidine (Demerol), Oxycodone (OxyContin), Fentanyl, Dexedrine, Adderall, Ritalin

Schedule III:

Drugs that are used for medical purposes and are less addictive than the above two categories, but are still addictive

Products containing less than 90 milligrams of codeine per dosage unit (Tylenol with codeine), Ketamine, Anabolic steroids, testosterone

Schedule IV:

Medically used drugs that are mildly addictive

Xanax, Soma, Darvon, Darvocet, Valium, Ativan, Talwin, Ambien, Tramadol

Schedule V:

Medically used drugs for cough suppressants, diarrhea, and pain relief, which are less addictive than the above.

Cough preparations with less than 200 milligrams of codeine or per 100 milliliters (Robitussin AC), Lomotil, Motofen, Lyrica, Parepectolin.

5. Preclinical evaluation of drug dependence using experimental animals

When applying for a drug with a central nervous system effect or a new compound as a drug to the Ministry of Health, Labor and Welfare (reviewed by the Pharmaceuticals and Medical Devices Agency (PMDA)) in Japan, animal testing to evaluate dependence is required as one of the safety tests. The implementation of the test is in accordance with Good Laboratory Practice (GLP) standards. Dependence tests are not required for all pharmaceuticals, but rather for cases where the drug has a central nervous system effect and is similar in chemical structure, clinical application, and case history to compounds known to be addictive. Phenothiazine derivative antipsychotics such as chlorpromazine and tricyclic antidepressants such as imipramine are considered to be non-addictive even if they have central nervous system effects. Therefore, dependence tests have not been required for drugs similar to these. However, even for the above clinically applicable drugs, dependence tests are required for new types of chemical structures and drugs that have effects on the central nervous system.

The author has conducted drug dependence studies using rats and rhesus monkeys for many years at Preclinical Laboratories under the guidance of Dr. Tomoji Yanagida (1930-2016). In addition to basic research, the laboratories also conducted drug dependence evaluation tests for drug application approval. Reports on the implementation of such tests are usually subject to confidentiality. The following references are some of the studies that were published with the permission of the sponsors at the time.

Here, first, the characteristics of the central nervous system effects of the test drug (subject drug) were identified, and then, based on these, the presence or absence of psychic dependence of the drug and the presence or absence of physical dependence were examined. In each search, a typical dependence producing drug was used as a positive control drug, if necessary.

First, the central nervous system effects of the test drug or new compound were observed and identified by macroscopic observation of syndrome in rats and rhesus monkeys. Here, the presence or absence and the degree of occurrence of each syndrome item specified in advance on a record sheet were recorded for each drug dose.

Next, the presence or absence of psychic dependence potential of the test drug was observed by the drug self-administration behavior of rhesus monkeys. First, if the test drug was water-soluble, a catheter was surgically placed in the monkey's vein, and if the test drug was a suspension that was not water-soluble, a catheter was surgically placed in the monkey's stomach. The observation of the drug self-administration behavior of the monkeys by lever pressing was performed on a continuous reinforcement (Fixed Ratio 1) schedule, 24 hours a day, with a unit of observation period of 2 weeks. In the first control period, the monkeys were given a vehicle, saline or suspension, intravenously or intragastrically, instead of the test drug, for measuring the number of daily lever-pressings as the vehicle control. During this period, it was confirmed that the number of lever-pressings for the vehicle was low. Based on this, in the next 2-week observation period for the test drug, a fixed unit dose of the test drug was infused through an indwelling catheter for each lever-pressings of the monkeys. The unit dose of the drug infused for each lever-pressing was determined based on the previous observation of syndrome regarding the central nervous system effects in rhesus monkeys. In other words, the initial unit dose was determined to be 1/2 or 1/4 of the minimum dose at which ssyndrome was observed. Thereafter, the unit dose was increased or decreased every 2-week observation period, and the presence and degree of drug self-administration behavior by lever-pressing response was observed. The increase or decrease in the unit dose was determined based on the number of lever-pressing responses of the monkeys during the previous 2-week observation period. In addition, if the changes in syndrome due to the drug infused through the catheter were significant, the unit dose was changed to 1/2 or 1/4 of the previous dose. The increase or decrease in the number of self-administrations of the drug by the monkeys was compared with the number of vehicle self-administrations in the control period conducted before the test drug self-administration condition. If an increase in the number of self-administrations of the test drug was observed, the test drug was deemed to have a reinforcing effect. The presence of a reinforcing effect of a drug alone does not mean that the drug has psychic dependence. However, for a drug to have psychic dependence, it is first necessary to show that it has a reinforcing effect. Therefore, to further confirm the strength of the drug's psychic dependence, in the sense of observing compulsive self-administration behavior for the drug, observation of drug self-administration behavior in rhesus monkeys using a progressive ratio schedule is a step to confirm the strength of psychic dependence. Progressive ratio schedule is explained in this website as in the following.

See the page in the present WEB site (Drug Dependence and Behavioral Analysis).

Physical dependence property of the test drug (compound) was examined using rhesus monkeys and rats. In rhesus monkeys, repeated drug administration by manual injection was used, and in rats, a drug-admixed food method was used, in which a certain concentration of drug was mixed into powdered feed and the rats ingested the drug through their daily food intake.

In rhesus monkeys, either a morphine-type or barbital-type physical dependence model was created in advance as necessary. Here, morphine was administered subcutaneously and barbital was administered intragastrically, each four times a day, to prepare physically dependent monkeys. After four weeks of continuous administration, a drug-free period was set up and the appearance of withdrawal syndrome was observed. A test drug or a new compound was then acutely administered to the monkeys showing either morphine or barbital withdrawal sydrome, Then, it was observed whether the previous withdrawal syndrome was suppressed by the test drug or the compound. If the administration of the test drug suppressed withdrawal syndrome in either monkeys administered morphine or barbital continuously, it was determined that the test drug had morphine-type or barbital-type cross-physical dependence, respectively. In each case, control physically dependent monkeys were also prepared with acute administration of the vehicle.  This was confirmed that clear withdrawal syndrome was present after four weeks of continuous administration of morphine or barbital. In terms of determining whether monkeys should be prepared and used to develop physical dependence on morphine or barbiturate, the chemical structure and pharmacological action of the test drug were considered.

Different from using above morphin- or barbital- phsyical dependent monkeys, the test drug at the optimal dose may be administered four times a day for 4 weeks to drug-naive rhesus monkeys from the beginning, and physical dependence may be developed from scratch with this test drug. However, in this case, the test period and costs will vary significantly.

In addition to physical dependence test using rhesus monkeys, another physical dependence test is performed using rats by drug-admixed feed method. This is performed by using four groups of 10 rats each, and a four-week feeding observation period was set up. That is, the control group was given regular powdered feed. For the test drug (test compound), a medium concentration group and a high concentration group were set up. Previously, two concentrations of the test drug to be mixed into each powdered feed were determined based on the results of the central nervous system effects of the test drug in rats observed by gross observation method with the naked eye. For the last positive control rat group and therefore had physical dependence, was mixed into the powdered feed. For these four groups, the daily food intake and drug dose of each rat were measured every day for four weeks. In addition, syndrome and body weight were regularly observed every week. Therefore, in the fourth week, the drug-mixed feed for the three groups was changed back to normal powdered feed, just like the control group. During the withdrawal test period from the drug admixed feed to the normal powdered feed, weight loss and withdrawal syndrome was observed. In particular, the results of the diazepam group, which showed clear weight loss and withdrawal syndrome, and the test drug admixed feed groups were compared. This confirmed the presence or absence of physical dependence on the test drug in rats, an animal species other than rhesus monkeys.

Even if dependence is detected in a preclinical study using laboratory animals, this does not in itself mean that the value of the drug is lost. The appropriate clinical application of the drug is determined in balance with the usefulness of the clinical effect of the drug, and within legal regulations even if dependence is present. Therefore, it is important that preclinical evaluation tests using animals accurately and to the greatest extent possible detect the dependence potential of the test drug. Furthermore, drug dependence tests should be conducted using the most appropriate and sensitive methods known to modern science.

5. Preclinical evaluation of drug dependence using experimental animals

When applying for a drug with a central nervous system effect or a new compound as a drug to the Ministry of Health, Labor and Welfare (reviewed by the Pharmaceuticals and Medical Devices Agency (PMDA)), dependence evaluation tests using animals are required as one of the safety tests. The implementation of such tests is based on Good Laboratory Practice (GLP) standards. Dependence tests are not required for all drugs, but are applicable when the drug (compound) has a central nervous system effect and is similar in chemical structure, clinical application, and case history to compounds known to be addictive. Phenothiazine derivative antipsychotics such as chlorpromazine and tricyclic antidepressants such as imipramine are considered to be non-dependable even if they have a central nervous system effect. Therefore, dependence tests have not been required for drugs similar to these. However, dependence tests are required for the above-mentioned clinically applicable drugs, such as new types of drugs with a chemical structure or drugs that have a stimulant effect on the central nervous system.

The author has been conducting drug dependence studies using rats and rhesus monkeys for many years at the Preclinical Laboratories under the guidance of Dr. Tomoji Yanagida (1930 - 2016). These studies were conducted separately from our basic scientific research as part of studies aimed at obtaining approval for pharmaceutical applications. Reports on the implementation of such studies are normally subject to confidentiality obligations. The references below list some of the studies that were published with the permission and agreement of the sponsors at the time.

First, the characteristics of the central nervous system action of the test drug (subject drug) were identified, and then, based on this, the presence or absence of psychological dependence of this drug and the presence or absence of physical dependence were examined. In each search, a typical addictive drug similar to the test drug was used as a positive control drug as necessary.

First, the central nervous system action of the test drug or new compound was observed and understood by macroscopic symptom observation in rats and rhesus monkeys. Here, the presence or absence and the degree of each symptom item specified in advance on the record sheet were recorded for each drug dose.

Next, the presence or absence of psychological dependence of the test drug was observed by the drug self-administration behavior of the rhesus monkeys. First, a catheter was surgically placed in the monkey's vein when the test drug was water-soluble, or in the stomach when the test drug was a suspension that was not water-soluble. The observation of the monkey's self-administration behavior by lever pressing was performed on a continuous reinforcement (Fixed Ratio 1) schedule, 24 hours a day, with a unit of 2 weeks as one observation period. In the first control period, the monkey's lever pressing response was conditioned by administering the vehicle, saline or suspension, intravenously or intragastricly, rather than the test drug. During this period, it was confirmed that the number of times the monkey self-administered the vehicle by lever pressing was low. Based on this, in the next 2-week observation period for the test drug, a fixed dose of the test drug was injected through the indwelling catheter for each lever pressing response of the monkey. The unit dose of the drug injected for each lever pressing response was determined based on the symptom observation of central nervous system effects in rhesus monkeys mentioned above. That is, the initial unit dose was set to 1/2 or 1/4 of the minimum dose at which symptoms appeared. Thereafter, the unit dose was increased or decreased every 2-week observation period, and the presence and degree of drug self-administration behavior by lever pressing was observed. The increase or decrease in the unit dose was determined based on the number of lever pressing responses of the monkeys during the previous 2-week observation period. If the symptom change due to the drug injected through the catheter was significant, the unit dose was changed to 1/2 or 1/4 of the previous dose. The increase or decrease in the number of times the monkeys self-administered the drug was determined by comparing it with the data on the number of self-administrations of the vehicle in the control condition conducted before the test drug self-administration condition. If an increase was observed in the number of times the test drug was self-administered, the drug (test drug) was deemed to have a reinforcing effect. The mere existence of a reinforcing effect of a drug does not mean that the drug has psychological dependence. However, for a drug to have psychological dependence, it is first necessary to demonstrate that it has a reinforcing effect. Therefore, to further confirm the strength of psychological dependence on drugs, in the sense of observing compulsive self-administration behavior for drugs, observation of drug self-administration behavior in rhesus monkeys using a progressive ratio schedule is a step to confirm the strength of psychological dependence. Progressive ratio schedules are explained in this website, Behavioral Analysis and Drug Dependence.

Physical dependence on test drugs (compounds) was performed using rhesus monkeys and rats. In rhesus monkeys, repeated drug administration by injection was used, and in rats, a drug-mixed feeding method was used, in which a certain concentration of drug was mixed into powdered feed and the drug was ingested through the rats' daily feeding.

In rhesus monkeys, either a morphine-type or barbital-type physical dependence model was created in advance as necessary. Here, morphine was administered subcutaneously and barbital was administered intragastrically, each four times a day, to prepare physically dependent monkeys. After four weeks of continuous administration, a rest period was set and the appearance of withdrawal symptoms was observed. A test drug (test drug or new compound) was then acutely administered to either morphine or barbital withdrawal symptoms, and observations were made to see if the previous withdrawal symptoms were suppressed. If the test drug administration suppressed withdrawal symptoms in either monkeys administered morphine or barbital, it was determined that the test drug had morphine-type or barbital-type cross-physical dependence, respectively. In each case, control monkeys were also acutely administered the vehicle, and it was confirmed that clear withdrawal symptoms were present after four weeks of continuous administration. The chemical structure and pharmacological action of the test drug were used as a reference to determine whether the monkeys to develop physical dependence on morphine or barbital should be prepared in advance. In addition, the optimal dose of the test drug was administered four times a day to drug-naive rhesus monkeys from the beginning, and physical dependence could be developed from scratch with the test drug. However, in this case, the test period and cost will change significantly.

In addition, to check whether the test drug has physical dependence using the rat drug-mixed feeding method, four groups of 10 rats each were set up and a four-week feeding observation period was set up. That is, the control group was given regular powdered feed. For the test drug (test compound), a medium concentration group and a high concentration group were set up. Based on the results of the central nervous system effects of the test drug by macroscopic symptom observation of rats that had been conducted in advance, two concentrations of the test drug to be mixed into each powdered feed were determined. For the last positive control group, a certain concentration of diazepam, which was confirmed to show clear withdrawal symptoms and therefore has a clear presence of physical dependence, was mixed into the powdered feed. For these four groups, the daily food intake of each rat and the ingested drug dose were measured every day for four weeks. In addition, symptom observation and body weight were regularly performed every week. Therefore, in the fourth week, the drug-mixed feed for group 3 was returned to regular powdered feed like the control group. During the withdrawal test period from the feeding of the drug to the feeding of the normal powdered feed, weight loss, withdrawal symptoms, etc. were observed. In particular, the results of the diazepam group, which showed clear weight loss and withdrawal symptoms, and the test drug feeding group were compared. This confirmed the presence or absence of physical dependence of the test drug in rats, an animal species other than rhesus monkeys.

Even if dependence is detected in a preclinical study using laboratory animals, this does not in itself mean that the value of the drug is lost. The appropriate clinical application of the drug is determined in balance with the usefulness of the clinical effect of the drug, and within legal regulations even if dependence is present. Therefore, in preclinical evaluation tests using animals, it is important to accurately detect the dependence of the drug to the maximum extent possible. In addition, in drug dependence tests, the presence or absence of dependence should be detected using the most appropriate and sensitive test method known in modern science. The final report on the results of the dependence test must clearly and concisely state in its conclusion what kind of central nervous system effects were observed with the test drug within the range of animal testing conditions used, whether results were predictive of psychic dependence, whether physical dependence was observed, or whether there were any unclear aspects under the experimental conditions used.

6. Dr. Tomoji Yanagita, who contributed to clarifying

the concept of drug dependence and promoting research

Dr. Tomoji Yanagida (1930 - 2016) studied at the Department of Pharmacology, University of Michigan Medical School, which was one of the world's central centers of drug dependence research at the time, and there perfected the intravenous drug self-administration method using rhesus monkeys. This method paved the way for research on psychic dependence, the core of drug dependence, in experimental primete with high brain function. After returning to Japan, he opened the Preclinical Medicine Research Institute at the Central Institute for Experimental Animals, where drug dependence research and preclinical medicine research were vigorously promoted. Part of his achievements are described in many of his papers. Here, we have described the explanation of drug dependence terms published in "Clinical Pharmacology" and a review of drug dependence research published in "Japanese Pharmacology Journal." You can read the full text in PDF by clicking the URL below (but in Japanese). Drug dependence research is premised on a clear understanding of the concept of drug dependence, and we believe that only then can drug dependence research be carried out appropriately. Dr. Tomoji Yanagida strongly promoted research in this direction.

Yanagita, T: Problems with Drug Dependence Terminology (in Japanese)

https://www.jstage.jst.go.jp/article/jscpt1970/6/4/6_4_347/_pdf

Yanagita, T: Perspectives on Drug Dependence Research - Focusing on Mental Dependence (in Japanese)

https://www.jstage.jst.go.jp/article/fpj1944/100/2/100_2_97/_pdf

7. The harsh reality of drug dependence and drug abuse society

The problem of drug abuse in Japan is extremely serious, but there are many more serious and tragic situations overseas. The YouTube URL attached below contains a video of a homeless drug abuser on Kensington Avenue in Philadelphia, Pennsylvania, USA. This was produced with the strong intention of making the American public aware of this reality and of changing this situation.

Please click on the URL below to watch the video only if you understand the above intention and acknowledge in advance that the content is extremely tragic.

https://www.youtube.com/watch?v=l6dXUsjtOLU&list=RDCMUCOuf_kStlWnhuauw4ce8l-w&index=2

8. References

Ando K, Hironaka N (1991) Behavioral pharmacological studies on LY127809 in rats. Preclinical Research Reports of the Central Institute for Experimental Animals, 17 (1):1-14 (Text in Japanese with tables, figures and abstract in English).

安東潔，廣中直行： ラットにおける LY127809 の行動薬理試験。実中研・前臨床研究報，1991, 17 (1) :1-14.

https://researchmap.jp/read0179769/published_papers/51530391

LY127809: Dopamine agonist; Anti Parkinson's disease drug

Ando K, Kawaguchi T, Yanagita T (1991) Dependence study on LY127809 in thesus monkeys and rats. Preclinical Research Reports of the Central Institute for Experimental Animals, 17 (1):55-81 (Text in Japanese with tables, figures and abstract in English).

安東潔，川口武，柳田知司： アカゲザルおよびラットにおける LY127809 の依存性試験。実中研・前臨床研究報，1993, 17 (1) :55-81.

https://researchmap.jp/read0179769/published_papers/51530488

LY127809: as above

Ando K, yanagita T (1993) Additional dependence study on LY127809 in rhesus monkeys. Preclinical Research Reports of the Central Institute for Experimental Animals, 19 (1):1-10 (Text in Japanese with tables, figures and abstract in English).

安東潔，柳田知司： アカゲザルにおける LY127809 の依存性追加試験。実中研・前臨床研究報，1993, 19 (1) :1-10.

https://researchmap.jp/read0179769/published_papers/51530513

LY127809: as above

Ando K, Kawaguchi T, Kawakami Y, Yanagida T (1993) Dependence study on LY170053 in rhesus monkeys and rats. Preclinical Research Reports of the Central Institute for Experimental Animals, 19 (2):73-92 (Text in Japanese with tables, figures and abstract in English).

安東潔，川口武，河上喜之，柳田知司 (1993)    LY170053 のアカゲザルおよびラットにおける薬物依存性試験。実中研・前臨床研究報, 19 (2) :73-92.

https://researchmap.jp/read0179769/published_papers/51524747

LY170053: Olanzapine or Zyplexa; atypical antipsychotic, bipolar disorder treatment, antiemetic.

Ando, ​​K., Kawaguchi, T.: Drug dependence study on SM-9018 in rhesus monkeys and rats. Basics and Clinical Practice, 1997: Vol; 31, No. 2, 321-341 (Text in Japanese with abstract, tables and figures in English).

安東潔，川口武：SM-9018 のアカゲザルおよびラットにおける薬物依存性試験。基礎と臨床，1997: Vo; 31, No. 2, 321-341.

https://researchmap.jp/read0179769/published_papers/51397707?lang=en

SM-9018: Perospirone, antipsychotic drug

Yanagita, T.: Problems with drug dependence terminology. Clinical Pharmacology, 1975: Vol; 4, 347-350 (in Japanese) .

柳田知司：薬物依存関係用語の問題点。臨床薬理，1975：Vol;4,347-350.

https://www.jstage.jst.go.jp/article/jscpt1970/6/4/6_4_347/_pdf

Yanagita, T.: Perspectives on drug dependence research - with a focus on psychological dependence. Japanese Pharmacology Journal (Folia Pharmacol japon), 1992: Vol; 100, 97-107 (in Japanese).

柳田知司：薬物依存研究の展望 - 精神依存を中心に。日本薬理学雑誌 (Folia pharmacol japon)，1992: Vol;100, 97-107.

https://www.jstage.jst.go.jp/article/fpj1944/100/2/100_2_97/_pdf