ISSN: 2373-6367PPIJ

Pharmacy & Pharmacology International Journal
Conceptual Paper
Volume 2 Issue 4 - 2015
Addictive Potency of Substances
Alen J Salerian*
Neuroscience Institute, USA
Received: June 23, 2015 | Published: July 10, 2015
*Corresponding author: Alen J Salerian, Neuroscience Institute, 8409 Carlynn Dr., Bethesda, MD 20817, USA, Tel: 301-204-9004; Email: @
Citation: Salerian AJ (2015) Addictive Potency of Substances. Pharm Pharmacol Int J 2(4): 00030. DOI: 10.15406/ppij.2015.02.00030

Abstract

This article offers evidence supported by animal and clinical studies to propose that the addictive potency of a substance can be predicted based upon its properties: latency, euphoric potency, and half-life elimination and withdrawal effects. The correlations in which addictive potency vary with crucial influences were reviewed. Observations also suggests it is possible to predict the addictive potency of a substance by a mathematical formula of A = L x T where A represents L represents latency and T Is elimination half-life.
Perspective: This article presents the crucial properties which determine the addictive potency of various chemical substances. Our insights could potentially help clinicians with better informed decisions when prescribing controlled substances.

Keywords: Addiction; Addictive potency; Dependence; Latency; Withdrawal symptoms

Introduction

Psychoactive substances have been part of human existence since antiquity and known for their mood altering and addictive properties. Many psychoactive substances such as nicotine, cocaine, marijuana, caffeine etc. are natural plant products and accessible to people.
The Diagnostic and Statistical Manual of Mental Disorders specifies a group of substance related disorders which includes typical drugs of abuse as well as some psychoactive medications that have abuse potential [1]. Within the category of substance related disorders are two general disorders: substance dependence and substance abuse [1] The controlled substances act of 1970 established a system to classify substances with abuse potential (heroine mescaline and marijuana for instance are schedule one drugs with the highest that the potential whereas cocaine morphine and amphetamines are classified as a schedule two) [2] (Table 1).

Schedule Description

Representative Substances

Substances that have no accepted medical use in the US and have a high abuse potential

Heroine LSD mescaline marijuana

Substances that have a high abuse potential with severe sidekick or physical dependence liability

Opium morphine meperidine cocaine amphetamines methylphenidate PCP

Substances that have an abuse potential less than those in schedule 2 including compounds containing limited quantities of certain
narcotics  and non-narcotic drugs

Paregoric   barbiturates other than those listed in another schedule

Substances that have and the abuse potential than those in schedule 3

Phenobarbital  diazepam chloral hydrate  alprazolam

Substances that have an abuse potential less than those in the schedule 4

 

Table 1: Controlled substances act schedule.

In general many factors including latency before euphoric effect, elimination half-life, speed and amount of intake and route of administration seem to be important for addictive properties of various substances. The purpose of this review is to determine whether addictive potency of a substance can be estimated by its latency and half elimination life: the shorter the latency and the half-life elimination the greater its addictive potency.

Methods

We will review correlations in which addictive potency of substances vary with latency and half-life elimination. The correlations between addictive properties and diverse influences that contribute to addictive properties will be examined under the following headings:
I. Animal studies
II. Review of medical evidence

Results

Animal studies
Animal studies have elucidated various effects of addictive substances. Although animal and human responses cannot be viewed as identical animal studies are of importance to predict human responses. Below is a synopsis of major observations:
i. Opiates seem to both activate and inhibit dopaminergic activity [3].
ii. Opiates acutely dampened dopaminergic activity whereas chronic treatment reverses its inhibitory influence [3].
There are significant differences between the self administrations of opiates versus cocaine. Those self administering heroine maintained grooming behavior pretesting body weight in a good state of general health whereas rats self administering cocaine tend to cease grooming behavior, lose up to 47% of their pretesting body weight and experience profound deterioration in general health [4].

  1. The increase in self administration of opiates is not infinite and corresponds to a specific pattern. The animal self administers morphine just a sufficient amount to prevent discomfort associated with withdrawal symptoms [5].
  2. Morphine micro injections into the ventral tegmental area of the midbrain produces dopaminergic activation of the meso limbic pathway consistent with conditions place preference and reduction of threshold for intracranial electrical self-mutilation [6].
  3. Bioengineered mice that had become dependent on morphine like substances may still benefit from the analgesic effect yet not experience any withdrawal symptoms upon the discontinuation of the substance. A study by Basile and colleagues compared genetically normal mice with mutant mice in which the M5 receptor gene had been inactivated. Loss and five receptor function reduced withdrawal symptoms in mice that were dependent on morphine but it had no effect on morphine induced analgesia. These findings are consistent with the observation that M5 muscarinic receptors selectively influence the addictive properties of opiates. This further supports the critical influence of withdrawal symptoms in the genesis of addiction [7].
  4. Review of medical evidence suggests several psychobiological mechanisms influence substance addiction. Evidence suggests that positive reinforcement mechanism is mediated by pleasure and reward pathways of dopaminergic activation. There is also solid research to serve the validity of a positive correlation between the euphoric and addictive potency over substance. It is also true that there is a linear relationship between C -Max (maximum concentration of a substance) and Tmax (time to reach maximum concentration) and the euphoric effect.

Various studies reveal withdrawal responses also mediate addictive behavior. Physiological responses to withdrawal from opiates -morphine like substances can be described the following way. Soon after the discontinuation of morphine like substances a constellation of symptoms defined and is morphine abstinence syndrome develops. Most of the symptoms slowly emerge in the first 24 hour gradually resolving within 7 to 10 days from the onset of withdrawal. The symptoms include increased anxiety, restlessness, irritability, dilated pupils, gooseflesh, hot flashes, vomiting, diarrhea, fever, elevated blood pressure, increased heart rate, abdominal and generalized muscle cramps. Morphine abstinence syndrome seems to represent increase noradrenergic parasympathetic input the liturgical activity. The emergence of withdrawal symptoms coincides with plasma concentration half-life and total clearance of a morphine like substance.
In general medical findings can be summarized by stating that four factors seem to influence the addictive properties of various substances
A. Euphoric potency
B. Latency before effect
C. Withdrawal symptoms
D. Elimination half-life
In general it can be observed that there is a negative correlation between latency and euphoric potency of a substance. The shorter latency the greater the euphoric effect. There seems to be a similar negative correlation between elimination half-life and withdrawal symptoms. The shorter the half-life the more intense withdrawal. In summary it can be hypothesized that a substance with the shortest latency and the shortest half-life elimination would be most addictive. Interestingly this hypothetical model match two previously proposed subjective rating scales (Henningfield-Benowitz and Salerian) [8].
The above observations can be mathematically expressed by the following equation: A = L xT with A representing addictive potency L representing latency in hours and E representing elimination half-life in hours.
Example
Tobacco 0.1×0.1 = 0.01
Methadone 0. 5×72 = 36
Cocaine 0.1×0.1 = 0.01
Oxycodone 0.2 5×3 = 0 .75
Alcohol 0.1×0.3 = 0.03
Amphetamine salts 0.1×10 = 1 in essence in the above small sample the smallest numbers (tobacco and cocaine) would represent the most addictive substances. (Please see Table 2 which includes all major drugs with addictive potential). Interestingly and of significance the results of this mathematical model match very well two previously proposed subjective rating scales ( Henningfield-Benowitz and Salerian) [8].

Substance

A=LxT

Addictive Potency

1. Cocaine (inh)

0.01 x 0.2

0.002

2.Tobacco

0.01x0.3

0.003

3. Alcohol

0.01x 0.3

0.003

4. Heroine (IV)

0.01 x 1.5

0.015

5. Morphine (IV)

0.01x2.5

0.025

6. Morphine (PO)

0.1 x 2.5

0.25

7. Oxycodone (po)

0.1x 3

0.3

8. Alprazolam

0.1x3

0.3

9. Methylphenidate

0.1x3

0.3

10.Oxycodone (long-acting)

0.1x 8

0.8

11. Amphetamines

0.2 x 10

2

12. Methylphenidate (long-acting)

0.2x10

2

13. Diazepam

0.2 x 24

4.8

13. Methadone

0.2x 48

9.6

14. Heroine (im long-acting)

0.2 x 360

72

Table 2: Addictive Potency*.

Discussion

The present study was conducted to evaluate the platelet augmentation activity of A. paniculata aqueous extract and its active constituent Andrographolide by using CPx, an alkylating agent as per previous studies. CPx at 25mg/kg was induced stable thrombocytopenia in rats without causing mortality. It can induce the thrombocytopenia by suppressing the production of megakaryocytes from bone marrow, which is the site of blood cell production.

In India, the most common cause of thrombocytopenia is dengue fever, in which thrombocytopenia is a result of platelet sequestration, destruction, and bone marrow suppression [21,22]. Thrombocytopenic disorder having limited supportive treatments, hence studies on herbal medicinal products for its treatment are increasing significantly. In the present study, after treatment with A. paniculata extract and Andrographolide in thrombocytopenic rats a significant (p ≤ 0.001) increase in platelet count was observed. These finding are correlating with the results of other studies and justifies its traditional use in the treatment of dengue fever in Indian sub continent. The mechanism behind CPx induced thrombocytopenia and dengue virus induced thrombocytopenia are similar i.e. bone marrow suppression [23]. Hence A. paniculata extract and Andrographolide may also effective to treat dengue virus induced thrombocytopenia.

The findings revealed that A. paniculata contains active constituents (Andrographolide) with haemostatic property and significant decrease (p ≤ 0.001) in bleeding time and clotting time were observed which may be due to increased production of platelets. These results are correlating with reported literature [24].

Under normal healthy body conditions, platelets are produced from megakaryocytes within 4 to 6 days [25]. In this study an increase of platelets was observed within two weeks. Under normal healthy body conditions spleen tends to hold one third of the platelets produced by megakaryocytes [26]. The smooth muscle contraction of the spleen, release stored platelets in to the circulation. Hence it is hypothesising that the platelet augmentation effect of the A. paniculata extracts and Andrographolide is either due to megakarypoietic stimulatory activity and or to induce splenic contractions. The effect of these two mechanisms may also responsible. Treatment A. paniculata and Andrographolide may also cause the recovery of platelet production by enhancing the release of thrombopoietin from liver which plays a role in thrombopoiesis.

The results obtained reveal that, A. paniculata and its chemical constituent Andrographolide treatment may have beneficial effect in dengue hemorrhagic fever. In this study we observed that, A. paniculata extract alone exhibited protective effect in dose dependant manner and preventive effect at high dose (400mg/kg). The high dose of A. paniculata extract does not affect the RBC count. Andrographolide alone also showed platelet augmentation activity. At the end of study with Andrographolide, it was observed that, there is no much difference between low (3mg/kg) and high dose (6mg/kg) of Andrographolide on platelet count. It is acknowledged that the platelet increasing activity of the A. paniculata is mainly due to its active constituent Andrographolide.

Conclusion

The whole study is observed in view of the recent epidemics in some states of India, where in the dengue virus infection induces, dengue shock syndrome, which is an acute condition and lethal. This study scientifically claimed for the first time that the A. paniculata and Andrographolide is safe and effectively increased platelet count in thrombocytopenic rats and justifies the claim of its traditional use. Hence Andrographolide is a potential candidate for further research leading to the development of an herbal therapeutic agent for thrombocytopenia due to dengue fever.

Acknowledgement

Authors are thankful to Ministry of Chemicals and Fertilizers, Govt. of India for providing financial support.

References

  1. Tahe Diagnostic Statistical Manual Of Psychiatric Disorders (2014) American Psychiatric Association Washington DC, USA.
  2. Physicians’ Desk Reference (2015) New Jersey PDR
  3. Meyer JC, Quenzer LF 2005 Psychopharmacology Sinauer Associates.
  4. Shippenberg TS, HERZ Spansgel (1991) Neural substrates motivational effects of opiates. Biological psychiatry.
  5. Woods JH, France CP, Bertalmio AJ, Schwartz Stevens K (1993) Book your abuse liability assessment in rhesus monkeys. In: HerZz A et al. (Eds.), Opioids 2 handbook of experimental pharmacology. Springer publisher, New York, USA, pp.609-632.
  6. Bozarth MA, Wise RA (1995) Toxicity associated with long-term intravenous heroine and cocaine self administration in the rat. JAMA 254(1): 81-83.
  7. Basile AS, Fedorova I, Zapata A, Liu X, Shippenberg T, et al. (2002) Deletion of the M5 muscarinic acetylcholine receptor attenuates morphine reinforcement and withdrawal but not morphine analgesia. Proc Natl Acad Sci USA 99(17): 11452-11457.
  8. Salerian AJ (2010) Addictive potential. Med Hypotheses 74(6): 1081-1083.
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