UNSW Embryology

Abnormal Development - Illegal Drugs

© Dr Mark Hill (2009)

Acknowledgements

Introduction

This page introduces the possible effects of maternal use of illegal drugs on development. In all cases, a discussion with a medical practioner should had prior to any reproductive decision. This page has information from Australian and USA drug use surveys.There are a large number of typically used illegal drugs that may impact on development either indirectly (through maternal health) or directly (through embryonic/fetal development). In addition, there are some examples of "legal drugs" used illegally, for example in performance enhancement. Of the 4 million women who gave birth in the United States (1992) 5% used illegal drugs while they were pregnant. This same study also showed strong link between cigarette smoking and alcohol use (legal drugs) and the use of illicit drugs in this population. (More? National Pregnancy and Health Survey) Illegal drug use abnormal effects are 100% preventable.

Page Links: Introduction | Some Recent Findings | Illegal Drugs | Australian Data | USA Data | Cannabis | Cocaine | Australian NHMRC Recommendations | Maternal Derived Abnormalities | WWW Links | References | Glossary

Some Recent Findings

Neurobiological consequences of maternal cannabis on human fetal development and its neuropsychiatric outcome. Jutras-Aswad D, Dinieri JA, Harkany T, Hurd YL. Eur Arch Psychiatry Clin Neurosci. 2009 Jul 2. PMID: 19568685

"Despite the high prevalence of marijuana use among pregnant women and adolescents, the impact of cannabis on the developing brain is still not well understood. However, growing evidence supports that the endocannabinoid system plays a major role in CNS patterning in structures relevant for mood, cognition, and reward, such as the mesocorticolimbic system."

Lee CT, Chen J, Hayashi T, Tsai SY, Sanchez JF, Errico SL, Amable R, Su TP, Lowe RH, Huestis MA, Shen J, Becker KG, Geller HM, Freed WJ. A mechanism for the inhibition of neural progenitor cell proliferation by cocaine. PLoS Med. 2008 Jun 10;5(6):e117.

"Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. ...In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A."

Hu S, Cheeran MC, Sheng WS, Ni HT, Lokensgard JR, Peterson PK. Cocaine alters proliferation, migration, and differentiation of human fetal brain-derived neural precursor cells. J Pharmacol Exp Ther. 2006 Sep;318(3):1280-6.

"Our data show that cocaine treatment markedly inhibited the proliferation of NPCs, a phenomenon that was associated with cell cycle arrest, possibly because of increased expression of the cyclin-dependent kinase inhibitor p21. In addition, treatment of NPCs with cocaine inhibited their migratory response to CXCL12 (stromal cell-derived factor-1alpha), a finding that correlated with cocaine-induced down-regulation of CXCR4 on NPCs. Finally, these data demonstrated that NPCs exposed to cocaine underwent differentiation into cells expressing neuronal markers that was associated with an inhibition of SOX2 (SRY-related HMG-box gene 2), a transcription factor that inhibits NPC differentiation."

Ludlow JP, Evans SF, Hulse G. Obstetric and perinatal outcomes in pregnancies associated with illicit substance abuse. Aust N Z J Obstet Gynaecol. 2004 Aug;44(4):302-6.

Illegal Drugs

Below is a list of typically used illegal drugs that may impact on development either indirectly (through maternal health) or directly (through embryonic/fetal development). In some cases these are "legal drugs" used illegally, for example in performance enhancement.

• Cannabis/Marijuana
• Methamphetamine/Amphetamine
• Cocaine
• Heroin
• Lysergic Acid Diethylamide (LSD)
• Ecstasy, methylenedioxymethamphetamine (MDMA) -like substances
• Magic Mushrooms, psilocin and psilocybin
• Nitrous Oxide
• Organic Solvents
• Performance and Image Enhancing Drugs (PIEDs)
• Anabolic-Androgenic Steroids
• Insulin
• Insulin-Like Growth Factor (IGF-1)
• Human Growth Hormone (hGH)
• Clenbuterol
• Creatine Monohydrate
• Human Chorionic Gonadotrophin (hCG)
• Erythropoietin (EPO)

Australian Data

The following statistics are based on the 1995 Australian National Drug Strategy Household survey.

• Marijuana is the most commonly used drug after tobacco and alcohol.
  • 31% of persons aged 14 or more have tried it, and 13% have recently used marijuana.
  • Marijuana use is no higher in South Australia or the Australian Capital Territory, where its consumption has been decriminalised.
• Analgesics is the next most frequently tried and used drug, with 12% having tried them, and 3% recently using them.
• Hallucinogens, particularly LSD, come in next at 7% ever tried, and almost 2% have used in the past 12 months. Nearly all recent users are aged under 35.
• Amphetamines have been tried by 6% of the population, and used in the past 12 months by 2%. Nearly all recent users are aged under 35.
• Cocaine has been tried by 3% of the population, and 1% have used it in the past 12 months.
• Designer drugs, particularly Ecstasy (MDMA) have been tried by nearly 3 % of the population, and used in the past 12 months by 0.8% of the population.
• Inhalants have been tried by 4% of the population, and are currently used by 0.4%
• Heroin has been tried by nearly 1% of the population, and is currently used by 0.4%.
• Illegal drugs have been injected by nearly 1.5% of the population, and currently illegal drugs are injected by .5%.
• Of the 26,355 deaths caused by drugs, 72% were due to tobacco, 25% to alcohol and 3% to illicit drugs. Alcohol is responsible for the majority of drug related deaths in persons aged 15 to 34.
• In the 1994 Urban Aboriginal and Torres Strait Islander Peoples Household survey supplement, 62% of the Aboriginal and Torres Strait Islander community drink alcohol compared to 72% of the general urban population. Those who do drink alcohol, however, consume much higher quantities of alcohol than the general population.
• 54% of urban Aboriginal and Torres Strait Islander people are current smokers, compared to 29% of the general population.
• Illicit drug use is more widespread among the Aboriginal and Torres Strait Islander urban community than in the general population. 50% have tried an illicit drug compared with 38% in the general community. 24% are current users compared with 15% in the general population with marijuana being the most popular illicit drug.

(More? email CEIDA Information Centre)

USA Data

The data below is from National Institute Drug Abuse (USA) (More? NIDA Homepage)

NIDA Survey Provides First National USA Data on Drug Use During Pregnancy(September 1994)

• More than 5 percent of the 4 million women who gave birth in the United States in 1992 used illegal drugs while they were pregnant, according to the first nationally representative survey of drug use among pregnant women. The NIDA sponsored survey, which was released last fall, provides the best estimates to date of the number of women who use drugs during pregnancy, their demographic characteristics, and their patterns of drug use.
• The survey gathered self report data from a national sample of 2,613 women who delivered babies in 52 urban and rural hospitals during 1992. Based on these data, an estimated 22 1,000 women who gave birth in 1992 used illicit drugs while they were pregnant. Marijuana and cocaine were the most frequently used illicit drugs - 2.9 percent, or 119,000 women, used marijuana and another 1.1 percent, or 45,000 women, used cocaine at some time during their pregnancy.
• The survey found a high incidence of cigarette and alcohol use among pregnant women. At some point during their pregnancy, 20.4 percent, or 820,000, pregnant women smoked cigarettes and 18.8 percent, or 757,000, drank alcohol.
• The survey also uncovered a strong link between cigarette smoking and alcohol use and the use of illicit drugs in this population. Among those women who used both cigarettes and alcohol, 20.4 percent also used marijuana and 9.5 percent took cocaine. Conversely, of those women who said they had not used cigarettes or alcohol, only 0.2 percent smoked marijuana and 0. I percent used cocaine.
• Besides providing the fist national estimates of drug use during pregnancy, the survey also examined differences in the amount and types of drugs used by several racial and ethnic groups of women. Overall, 11.3 percent of African-American women, 4.4 percent of white women, and 4.5 percent of Hispanic women used illicit drugs while pregnant. While African Americans had higher rates of drug use, in ten-ns of actual numbers of users, most women who took drugs while they were pregnant were white. The survey found that an estimated 11 3,000 white women, 75,000 African-American women, and 28,000 Hispanic women used illicit drugs during pregnancy.
• The survey also described different patterns of licit and illicit drug use among white women and ethnic minorities. African-American women had the highest rates of cocaine use, mainly "crack," during pregnancy. About 4.5 percent of African-American women used cocaine compared with 0.4 percent of white women and 0.7 percent of Hispanic women who did so.
• White women had the highest rates of alcohol and cigarette use. Nearly 23 percent of white women drank alcohol and 24.4 percent smoked cigarettes. By comparison, 15.8 percent of African-American women and 8.7 percent of Hispanic women drank alcohol and 19.8 percent of African-American women and 5.8 percent of Hispanic women smoked cigarettes. "These findings point to the importance of attending to cultural issues in drug abuse prevention and treatment efforts," said Dr. Finnegan.
• Although women who used drugs during pregnancy generally decreased their rates of drug use throughout their pregnancy, they did not discontinue drug use.
• NIDA's National Pregnancy and Health Survey reveals different patterns of substance use among black, white, and Hispanic women. The survey found that an estimated 113,000 white women, 75,000 African-American women, and 28,000 Hispanic women used illicit drugs during pregnancy.

Drug use During Pregnancy Among Racial and Ethnic Groups in the USA
Percent of American women who gave birth in 1992 and used drugs during pregnancy.
Blacks Any Illicit Drug 11.3% Marijuana 4.6% Cocaine 4.5% Alcohol 15.8% Cigarettes 19.8%	Whites Any Illicit Drug 4.4% Marijuana 3.0% Cocaine 0.4% Alcohol 22.7% Cigarettes 24.4%	Hispanics Any Illicit Drug 4.5% Marijuana 1.5% n Cocaine 0.7% Alcohol 8.7% Cigarettes 5.8%

Source: NIDA- Pregnancy and Drug Use Trends

Cannabis

Cannabis leaf

Cannabis psychoactive ingredient is delta-9-tetrahydrocannabinol (THC). Trezza V, Cuomo V, Vanderschuren LJ. Cannabis and the developing brain: insights from behavior. Eur J Pharmacol. 2008 May 13;585(2-3):441-52. Review. "Besides its well-known involvement in specific brain functions, such as control of movement, memory and emotions, the endocannabinoid system plays an important role in fundamental developmental processes such as cell proliferation, migration and differentiation."

Links: BBC - cannabis

Cocaine

Erythroxylon coca

Cocaine is an alkaloid derived from leaves of the South American shrub Erythroxylon coca. Hyman SE. How might cocaine interfere with brain development? PLoS Med. 2008 Jun 10;5(6):e130. "...not surprisingly, as the outcomes of different cohorts of pregnant women who use drugs are examined, diverse findings have been reported. Overall, however, children exposed to cocaine prenatally appear to have neurological and cognitive deficits. "

Lee CT, Chen J, Hayashi T, Tsai SY, Sanchez JF, Errico SL, Amable R, Su TP, Lowe RH, Huestis MA, Shen J, Becker KG, Geller HM, Freed WJ. A mechanism for the inhibition of neural progenitor cell proliferation by cocaine. PLoS Med. 2008 Jun 10;5(6):e117.

"Prenatal exposure of the developing brain to cocaine causes morphological and behavioral abnormalities. Recent studies indicate that cocaine-induced proliferation inhibition and/or apoptosis in neural progenitor cells may play a pivotal role in causing these abnormalities. ...In the developing rat brain, the P450 inhibitor cimetidine counteracted cocaine-induced inhibition of neural progenitor cell proliferation as well as down-regulation of cyclin A."

Hu S, Cheeran MC, Sheng WS, Ni HT, Lokensgard JR, Peterson PK. Cocaine alters proliferation, migration, and differentiation of human fetal brain-derived neural precursor cells. J Pharmacol Exp Ther. 2006 Sep;318(3):1280-6.

"Our data show that cocaine treatment markedly inhibited the proliferation of NPCs, a phenomenon that was associated with cell cycle arrest, possibly because of increased expression of the cyclin-dependent kinase inhibitor p21. In addition, treatment of NPCs with cocaine inhibited their migratory response to CXCL12 (stromal cell-derived factor-1alpha), a finding that correlated with cocaine-induced down-regulation of CXCR4 on NPCs. Finally, these data demonstrated that NPCs exposed to cocaine underwent differentiation into cells expressing neuronal markers that was associated with an inhibition of SOX2 (SRY-related HMG-box gene 2), a transcription factor that inhibits NPC differentiation."

Search Pubmed: cocaine and human development | cocaine and brain development

Heroin

Heroin molecular structure

The opium poppy is the original source of the synthesized opioid known as heroin (diacetylmorphine, diamorphine) and morphine. Morphine (morphine sulphate) is a drug used clinically and therapeutically as a strong analgesic (painkiller). Ornoy A. The impact of intrauterine exposure versus postnatal environment in neurodevelopmental toxicity: long-term neurobehavioral studies in children at risk for developmental disorders. Toxicol Lett. 2003 Apr 11;140-141:171-81. Review. "Children born to heroin dependent mothers adopted at a young age and hence being raised in a good environment had normal intellectual function but a high rate of inattention and behavioral problems." Yanai J, Steingart RA, Snapir N, Gvaryahu G, Rozenboim I, Katz A. The relationship between neural alterations and behavioral deficits after prenatal exposure to heroin. Ann N Y Acad Sci. 2000 Sep;914:402-11. Steingart RA, Abu-Roumi M, Newman ME, Silverman WF, Slotkin TA, Yanai J. Neurobehavioral damage to cholinergic systems caused by prenatal exposure to heroin or phenobarbital: cellular mechanisms and the reversal of deficits by neural grafts. Brain Res Dev Brain Res. 2000 Aug 30;122(2):125-33.

Links: AHFS Consumer Medication Information - Morphine Sulfate Injection

Search Pubmed: heroin and human development | heroin and brain development

Organic Solvents

Chemical Identification Label

Inhalation of volatile organic solvents such as toluene. Solvents are substances that are capable of dissolving or dispersing one or more other substances and organic solvents are those with carbon within their molecular structure. Funada M, Sato M, Aoo N, Wada K. [Role of the monoamine system in the brain on the development of psychological dependence on toluene] Nihon Arukoru Yakubutsu Igakkai Zasshi. 2006 Feb;41(1):31-8. Review. Japanese. "We found toluene produced the rewarding effect in this new conditioned place preference (CPP) system. The mesolimbic dopamine pathway, which includes dopaminergic neurons in the ventral tegmental area (VTA) of the midbrain and their targets in the limbic forebrain, especially the nucleus accumbens (NAC), is one of the most important substrates for the development of psychological dependence on drugs such as stimulants, cocaine, and heroin."

Links: NIOSH - Organic Solvents

Search Pubmed: volatile organic solvent inhalation | organic solvents and development

Australian NHMRC Recommendations

The Australian NHMRC (1988) recommends neonates be assessed for follow-up care under the following conditions.

(see the NHMRC WWW Page)

• Birthweight less than 1500g or gestational age less than 32 weeks
• Small-for-gestational-age neonates
• Perinatal asphyxia
• Apgar score less than 3 at 5 minutes
• clinical evidence of neurological dysfunction
• delay in onset of spontaneous respiration for more than 5 minutes and requiring mechanical ventilation
• Clinical evidence of central nervous system abnormalities ie., seizures, hypotonia
• Hyperbilirubinaemia of greater than 350umol/l in full term neonates
• Genetic, dysmorphic or metabolic disorders or a family history of serious genetic disorder
• Perinatal or serious neonatal infection including children of mothers who are HIV positive
• Psychosocial problems eg., infants of drug-addicted or alcoholic mothers.

References

Links: Reviews | Articles | Online Textbooks | Search Textbooks | Search PubMed | Glossary

Reviews

Trezza V, Cuomo V, Vanderschuren LJ. Cannabis and the developing brain: insights from behavior. Eur J Pharmacol. 2008 May 13;585(2-3):441-52. Review.

Ornoy A. The impact of intrauterine exposure versus postnatal environment in neurodevelopmental toxicity: long-term neurobehavioral studies in children at risk for developmental disorders. Toxicol Lett. 2003 Apr 11;140-141:171-81. Review.

Ludlow JP, Evans SF, Hulse G. Obstetric and perinatal outcomes in pregnancies associated with illicit substance abuse. Aust N Z J Obstet Gynaecol. 2004 Aug;44(4):302-6.

Frank DA, Augustyn M, Knight WG, Pell T, Zuckerman B. Growth, development, and behavior in early childhood following prenatal cocaine exposure: a systematic review. JAMA. 2001 Mar 28;285(12):1613-25.

Articles

Lee CT, Chen J, Hayashi T, Tsai SY, Sanchez JF, Errico SL, Amable R, Su TP, Lowe RH, Huestis MA, Shen J, Becker KG, Geller HM, Freed WJ. A mechanism for the inhibition of neural progenitor cell proliferation by cocaine. PLoS Med. 2008 Jun 10;5(6):e117.

Cambell S. Prenatal cocaine exposure and neonatal/infant outcomes. Neonatal Netw. 2003 Jan-Feb;22(1):19-21.

Online Textbooks

Health Services/Technology Assessment Text (HSTAT) Bethesda (MD): National Library of Medicine (US), (2003)

Improving Treatment for Drug-Exposed Infants

Pregnant, Substance-Using Women

Search PubMed

Search Sep 2008 "illegal drugs and human development" 14 reference articles of which 4 were reviews.

Search PubMed: term = illegal drugs and human development | cocaine and human development | cocaine and brain development | heroin and human development | cannabis and human development | volatile organic solvent inhalation | organic solvents and development

WWW Links

United Nations International Drug Control Programme

Australia

• National Drug and Alcohol Research Centre - Factsheets

• Addiction Research Institute
• Australian Drug Foundation (ADF)
• Centre for Education and Information on Drugs and Alcohol (CEIDA)
• Child Health and Safety
• Australian Medicines Handbook (no electronic version yet)

USA

• NIDA Consequences of Prenatal Drug Exposure
• CDC A-Z Index

Glossary of Terms

A | B | C | D | E | F | G | H | I | J | K | L | M | N | O | P | Q | R | S | T | U | V | W | X | Y | Z

Other Maternal Factors Prenatal

Maternal derived abnormalities

Relate to lifestyle, environment and nutrition. Some examples of this form of abnormality are the impact of excess alcohol on neural development (Fetal alcohol syndrome), viral infection (rubella) at a critical stage of development, inadequate dietry folate intake (neural tube defects), effects of prescription drugs (Thalidomide- limb development) and even maternal endocrine function (thyroid development).

In addition to these obvious maternally-derived abnormalities, there is growing evidence that the interuterine environment has a strong influence on later postnatal health. This theory is based on the early statistical analysis of disease/longevity in babies with low birth weights in England by Barker, and has been called the "Barker Hypothesis". (More? Barker Hypothesis)