INTRODUCTION:

Substance abuse is defined as a maladjusted pattern of a use of a substance leading to addiction and clinically significant disability or distress after which a person may also suffer from tolerance and withdrawal symptoms. The American Psychiatric Association (APA) defines substance dependence as a cluster of symptoms indicating that the individual’s continuous use of the substance despite significant substance related problems. The epidemiology of drug addiction in given society seems to be dependent on culture, values, beliefs, morals and attitudes to drug use which differs from one culture to another. Evidence of tolerance and withdrawal symptoms is incorporated in the list of symptoms but neither tolerance or withdrawal is necessary or sufficient for diagnosis of substance dependence. All sorts of contrasting drugs can be exploited including illegal drugs (cocaine, morphine) or prescription drugs (barbiturates) and the other medicine that is easily available in the market.

A person looks on drug as a heal or end to unwanted feelings and they become resolution to their distress and discomfort. Moreover, the drugs differ in their potentiality to produce good feelings in the user straight away. They induce the state of euphoria and are more likely to be taken over and over again. Reinforcement all attention to the ability of the drug to produce effects that makes the exploiter uses them again^1,5. The more the reinforcement, the greater are the chances of the drugs to be abused or exploited over time.

Table 1: Multiple variable affecting inception and continuation of Drug Abuse and Addiction

Agent (Drug)

Host (User)

Environment

1. Availability

2. Potency

3. Capital/Cost

4. Mode of administrations-

(a) Oral

(b) Sublingual

(d) Intravenous

(e) Subcutaneous

Heredity

Tolerance

Metabolism of the drug

Psychiatric symptoms

Prior experiences

Peer influence

Social settings

Community attitudes

Accessibility of other reinforces

Employment/Educational opportunities

Reinforceive attribute of drug are associated with their ability to increase the level of neurotransmitter such as dopamine in the critical brain areas. Cocaine, opoids, nicotine, etc, all reliably rise the extracellular dopamine level in the nucleus accumben region in the basal forebrain.

Tolerance:

Tolerance is a decrease in response to a drug that is used repeatedly. During this it require of increase dose of a drug to show a given therapeutic effect. It is the most common response for the monotonous use of the same drug; therefore, increase dose is required to produce same effect that was obtained in decrease dose earlier. Example: Sulfonylureas in type-2-diabetes or Beta- agonist in Bronchial asthma. Tolerance is of different types-

Figure 1: Types of tolerance

Innate tolerance is pre-existing or genetic sensitivity towards a drug that is determined from the first time the drug is administered.

Acquired tolerance is defined as a body ability to resist the effect of drug it occurs due to continuous consumption of drug.

Acute tolerance is rapid tolerance development within a single of exposure of drug. Reverse tolerance is also known as sensitization referred to the increase in response to the repetitions of the same dose of
drug^2,3,7-10. Cross tolerance is the development of tolerance to pharmacologically related drugs, for instance alcoholic are relatively tolerant to barbiturates and general anaesthetic.

Figure 2: Development of tolerance

Withdrawal syndrome:

It is the amalgamation of physical and mental effects of a person when the administration of the drug is terminated. It is biological phenomenon and has two origins

1. Removal of the drug of dependence

2. Central Nervous System hyper arousal due to re-adjustment to the deprivation of drug of dependence.

Nicotine:

Nicotine is a plant alkaloid obtained from Nicotianatobacum and Nicotianarustica belonging to the family Solanaceae. It is a sympathomimetic drug that releases catecholamine. The nicotinic receptor is a pentamer comprising of four distinct subunits (α, β, γ, δ) in schoitiometric ratios (2:1:1:1) respectively. It is a primary psychoactive and addictive agent in tobacco and cigarette. Nicotinic receptors are prototypical cation- selective, ligand- gated ion channels that mediate fast neurotransmission in central and peripheral nervous system. Cigarette (nicotine) addiction is influenced by multiple variables. Nicotine itself produce reinforcement and has both stimulant and depressant actions. The smoker feels alert yet there is some muscle
relaxation^4,7-9. The dependence produced by nicotine can be extremely durable as exemplified by high failure rate among smokers who try to quit.

Figure 3: Structure of nicotine

Inhalation of nicotine via smoking distils nicotine and carries it into lungs where it is absorbed into pulmonary venous circulation. From the venous circulation nicotine then enters into the arterial circulation and travel from lungs to brain. It then binds to the nicotinic cholinergic receptor present in the brain. The binding of nicotine opens the sodium and voltage dependent calcium channel which leads to the release of neurotransmitter like Dopamine which signals a pleasurable experience to the user. The various nicotine withdrawal syndromes are irritability, impatience, anxiety, restlessness, decrease heart rate etc. Depressed mood is associated with nicotine dependence. Depression significantly decreases during smoking withdrawal. Tobacco is one of the primary causes of death from cancer, pulmonary disease^5,6. Cigarette smoking is also a leading factor for respiratory tract infection, reproductive disorder, delayed wound healing, diabetes, osteoporosis, duodenal and gastric ulcer and many more.

Alcohol:

Alcohol is the 2^nd most common form of substance abuse after tobacco addiction. The consumption of ethyl alcohol obtained from the fermentation of sugar, starches and other carbohydrates dated back in early history. Ethanol is classed as depressant because it produces sedation and sleep. Ethanol goes and binds with GABA type A (Gama amino butyric acid type A). The activation of GABA –A receptor by GABA tends to decrease neuronal excitability. However ethanol also binds with ligand gated ion channels (LGIC) and voltage dependent calcium channel. LGICs are the family of neurotransmitter present in CNS and regulate neuronal excitability. Voltage gated calcium channel play a key role in the release of neurotransmitter, gene regulation and hormone secretion^7,8,9.

The abuse of alcohol has a societal impact in general health as well as in economic output of the country. Alcohol abuse has much long term effect that result in premature death. Moreover fetal alcohol syndrome is major heath issue worldwide. One of the most critical alcohol related health issue is ethanol drug interaction which may result to death. Alcohol impairs recent memory and in high doses, produces black outs after which the abuser has no memory of his or her behaviour while intoxicated. Alcohol causes physical dependence and refrainment in consumption causes various withdrawal symptoms such as tremor, irritability, tachycardia, hypertension, seizures, sleep disturbance and alcohol craving. In a complicated withdrawal of alcohol delirium tremens is seemed to occur and the various symptoms are severe agitation, confusion, visual hallucination, fever, tachycardia, dilated pupils. Alcohol produces cross tolerance to sedation such as benzodiazepine. It is toxic to many organ systems and can cause liver disease, cardiovascular disease, gastrointestinal and endocrine effects, malnutrition and various CNS dysfunctions. Detoxification is only the first step of treatment of alcohol abuse.

Opioids:

Opioids are the class of drug naturally found in opium poppy; Papaversomniferum belonging to the family of Papaveraceae primarily used for the treatment of pain. They are sometimes referred as narcotic even when they relieve pain but do not fall in the category of other pain killer such as aspirin and Tylenol. Opioid receptor are G- protein coupled receptor and mediate the human body response to most hormone, neurotransmitter and drugs. Five types of opioid receptor are being discovered till date^10,11. Centrally this receptor are present in high concentration at periaqueductal grey, locus ceruleus and rostral ventral medulla while they are also present in substiantiagelatinosa of dorsal horn at low concentration.

They are-

1. mu- receptor (mu1, mu2, mu3): mu1,2,3 receptor bind to endogenous ligand such as Beta- endorphin, endomorphine 1 and 2. The mu1 receptor is liable for analgesia dependence. The mu2 receptor account for euphoria, dependence, decreased digestive tract motility or constipation and respiratory depression. Mu3 receptor is at the helm of vasodilation.

2. Kappa receptor (kappa1, kappa2, kappa3): Kappa receptor coheres to dynorphin A and B which provide analgesia, diuresis and dysphoria.

3. Delta receptor: Delta receptor bind to enkephalins and result in analgesia and decrease in gastric motility.

4. Noceptin receptor: They are viable to nocieptin or orphanin FQ resulting in analgesia and hyperalgesia.

5. Zeta receptor: These receptors regulate events related to development of normal and tumorigenic cell.

Despite having analgesic activity, opioid drug are taken outside the medical channels for the purpose of obtaining effect on mood. Medication that do not act on opiate, such as NSAIDs have important role in certain type of pain. Opioids should never be retained from cancer patients out of fear of producing addiction. The major risk of abuse occurs in patients complaining of pain with no proper evidence of chronic disorder that is not life- threatening. As tolerance and physical dependence develop, the patients may however experience the early symptoms of withdrawal between the doses and during withdrawal, the threshold of pain decreases.

Heroin is the most important opioid that has been talked of abuse. It is widely available in illicit market all across the world. Injection of a heroin solution produces a variety of sensation such as warmth, taste or high and intense pleasure often referred to sexual orgasm. Being highly lipophilic it crosses blood brain barrier given rise to intense euphoria lasting from 45 second to several minute. The various opioidwithdrawal symptom are restlessness, irritability, increase sensitivity to pain, muscle ache, dysphoric mood, anxiety and insomnia.

Benzodiazepines:

Benzodiazepines are the class of antipsychotic drug which are used in the treatment of anxiety disorder and insomnia and are the most commonly prescribed drug worldwide. Benzodiazepine bind to GABA receptor (Gama amino butyric acid) and are found on the neuronal membrane present in the supramolecular protein complex. GABA is one of the major inhibitory neurotransmitter of Central Nervous System. These benzodiazepine acts by increasing the affinity of GABA receptor and augmenting the inhibitory effect of a given concentration of GABA. When benzodiazepines are consumed continuously upto several weeks, there is very little tolerance and the user finds no difficulty in stopping the medication. However after several month of intake the tolerance increases. Thus, reducing the dose or stopping the medication causes withdrawal symptoms. Following moderate dose usage the withdrawal symptoms of benzodiazepine seemed to be anxiety, increased sensitivity to light sound, paresthesias (strange sensation), muscle cramps, sleep disturbance and dizziness. Nevertheless, following high dose usage severe withdrawal symptoms came to light such as seizures and delirium. Even if very few patients who are prescribed benzodiazepine as medication abuse it, there are individuals who specifically seek benzodiazepine for their ability to produce a ‘high’(feeling of pleasure). Diazepam and alprazolam are the most popular and desirable drug among the abuser^1,3,12-16. A specific benzodiazepine receptor antagonist flumazenil has been found useful in the treatment of over dose and reversing the effect of long acting benzodiazepine. Hence it is also used in the treatment of persistent withdrawal symptoms.

Figure 4: Structural formula of benzodiazepines

Cocaine:

Cocaine is a tropane alkaloid obtained from leaves of coca plant Erythroxylumcoca belonging to the family Erythroxylaceae. It is a stimulant that reacts with body’s CNS producing energy and euphoria. Also gaining the title of ‘rich man’s drug’, cocaine is expensive and addictive as compared to other drugs. It produces its psychoactive effects by acting on the brain’s limbic system: a set of interconnected regions that regulate pleasure and motivation. Cocaine acts by binding to the dopamine transporter hence blocking the removal of dopamine from the synapse. The build-up of neurochemical dopamine gives rise to euphoria. Dopamine acts as a pacesetter for many nerve cells and is responsible for keeping those cells operating at appropriate levels of activity to accomplish our needs.

Figure 5: Structural formula of cocaine

For instance, if we need to mobilize our muscles to run faster in a marathon dopamine regulates some of the involved brain cells to setup the challenge. Administered through IV route or nasal route, cocaine rapidly enters the blood stream crossing the blood brain barrier and penetrates the brain causing the build-up of dopamine. The more dopamine molecules come in contact with receptor. It produces more electrical signals as such. Cocaine produces dopamine build up in the dopamine receptor of brain and hence produces pleasure, loss of control and euphoria. It also blocks norepinephrine(NE) and serotonin (5-HT) reuptake. Cocaine has been reported to produce a prolonged and intense orgasm if taken prior toan intercourse. However long term use of cocaine result in reduced sex drive. Pregnant cocaine user may experience premature labour causing abnormalities in the new born. Refraining from the use of cocaine the abusers experience various withdrawal symptoms such as dysphoria, depression, insomnia, fatigue, bradycardia and cocaine craving^1,4. The major challenge in the treatment of cocaine addiction is not detoxification but helping the patients to resist the urge to restart the use of cocaine.

Cannabinoids:

Cannabinoids are naturally occurring compound obtained from Cannabissativa belonging to the family of Cannabaceae. Also known as Indian hemp and Marijuana, it is the most commonly used non legal drugs. The smoke from burning cannabis contains many chemicals, including 61 different cannabinoids out of which Δ-9-tetrahydrocannabinoid (Δ9-THC) is the principal psychoactive ingredient. Δ9-THC binds to various cannabinoids receptor.

They are

1. CB1 receptor:

This receptor is widely distributed in the mammalian tissues with highest concentration found in brain neurons. They are coupled to modulation of adenylate cyclase and ion channels.

2. CB2 receptor:

This receptor is found in the cells of immune system and this coupled to the inhibition of adenylate cyclase.

Both receptor types selectively bind to Δ9-THC and anandamine (arachidonylethanolamide), an endogenous cannabimimeticeicosanoid. The high lipophilicity of cannabinoid helps them to be distributed all over the brain. Marijuana produces complex behavioural changes such as giddiness and increase hunger. One of the most controversial effects of marijuana is the production an “a motivational syndrome” although it is not officially diagnosed. Tolerance to most of the effects of cannabis can developed rapidly after a few doses but also disappear rapidly. The various withdrawal symptoms are restlessness, irritability, mild agitation, insomnia etc. Marijuana abuse has no specific treatments. Heavy users however may suffer from depression and thus may respond to antidepressant medication.

Lysergic acid (LSD):

LSD is one of the most potent hallucinogenic drug obtained from Ergot alkaloid. Ergot is obtained from dried sclerotium of fungus Claviceps purpurea belonging to the family of Clavicipitaceae arising in the ovary of the rye plant Secale cereal belonging to the family Graminaceae. It comes under the category of Psychedelic agents and produce hallucinations at microgram doses that last up to 15 hours. First synthesized on 1938 LSD interacts with proteins on the surface of brain cells called serotonin receptors. It appears to act through particular receptors namely5-HT2A and 5-HT2B. Serotonin receptors activate two major pathways within cells: Through G-proteins and through β-arrestin. LSD binds its receptors in a way that causes it to act mostly through β- arrestin pathway than G- protein pathway.

LSD has gained a lot of attention recently for its ability in the treatment of alcohol abuse and depression and in alleviating the anxiety of patients suffering from various diseases. Although the drug targets a lot of receptors in-vivo, the psychedelic effects are mainly due to the binding primarily with 5HT2A and with 5HT2B (in smaller proportions). The drug is sold illegally in various illicit markets all over the world in variety of forms. LSD is rapidly absorbed after oral administration producing perpetual distortions, paranoia, depressions, hallucinations, intense arousal and sometimes feeling of panic^36,9. Signs of LSD ingestion include pupillary dilation, flushing, lacrimation, increased pulse and blood pressure. Visual effects are distinguished. Colours seemed to be more intense and shapes may be altered. Schizophrenic episodes may also occur in some individuals. Frequent repeated use of psychedelic drugs is very rare and thus tolerance is not commonly seen. Tolerance does develop to the behavioural effects of LSD but only lasts to 3-4 days. A particularly troubling after effect of the use of LSD and similar drugs is the occurrence of the visual episodic disturbances in small fractions and seems to be stable.

Figure 6: Structural formula of lysergic acid

CONCLUSION:

Drug addiction has become a major cause of concern all over the globe. It is a complex problem that results from the psychological as well as environmental factors. Recovery from substance abuse is possible even if in chronic condition although recovery requires long term care. Substance addiction by its nature is difficult to treat as it changes the way the brain works hence effecting self-control and decision making. Teen drug abuse can have a long term behavioural changes. Therefore inorder to save oneself, the main course of action is to prevent from getting into danger of drug addiction and abuse.

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Received on 17.05.2022 Modified on 12.09.2022

Asian J. Pharm. Res. 2023; 13(3):186-190.

DOI: 10.52711/2231-5691.2023.00035