## Cannabis and the developing brain : Insights from behavior

Viviana Trezza, Vincenzo Cuomo, Louk J.M.J. Vanderschuren

European Journal of Pharmacology, 2008, 585, 441-452.

Doi : 10.1016/j.ejphar.2008.01.058

A B S T R A C T

The isolation and identification, in 1964, of delta-9-tetrahydrocannabinol (THC), the primary psycho-active compound in cannabis, opened the door to a whole new field of medical research. The exploration of the therapeutic potential of THC and other natural and synthetic cannabinoid compounds was paralleled by the discovery of the endocannabinoid system, comprising cannabinoid receptors and their endogenous ligands, which offered exciting new insights into brain function. 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. For this reason, changes in its activity during stages of high neuronal plasticity, such as the perinatal and the adolescent period, can have long-lasting neuro-behavioral consequences. Here, we summarize human and animal studies examining the behavioral and neuro-biological effects of in utero and adolescent exposure to cannabis. Since cannabis preparations are widely used and abused by young people, including pregnant women, understanding how cannabinoid compounds affect the developing brain, leading to neurobehavioral alterations or neuropsychiatric disorders later in life, is a serious health issue. In addition, since the endocannabinoid system is emerging as a novel therapeutic target for the treatment of several neuropsychiatric diseases, a detailed investigation of possible adverse effects of cannabinoid compounds on the central nervous system (CNS) of immature individuals is warranted.

Keywords : Cannabis, Behavior, Development, Pregnancy, Adolescence

Contents
1. Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 441
2. The endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . . . . . . . . . . 442
2.1. Endocannabinoid-mediated synaptic plasticity. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443
2.2. Interaction between endocannabinoid and opioid neurotransmission . . . . . . . . . . . . 443
2.3. The endocannabinoid system and brain development . . . . . . . . . . . . . . . . . . . . .  . . . . 444
2.3.1. Ontogeny of the endocannabinoid system . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . . . . . 444
2.3.2. Effects of cannabinoids on neurotransmitter maturation. . . . . . . . . . . . . . . . . . . . . . 444
3. Behavioral consequences of cannabinoid exposure during pregnancy and/or lactation ..  445
3.1. Neurobehavioral teratology. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 445
3.2. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. . 445
3.3. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 446
4. Behavioral consequences of cannabinoid exposure during adolescence . . . . . . . . . . . 447
4.1. Human studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 447
4.2. Animal studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 448
5. Conclusions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 449

### 1. Introduction

Ten years ago, the British newspaper The Independent launched a campaign to decriminalise cannabis (Boycott, 1997), considering it a relatively harmless “soft” drug. This campaign culminated in a pro-cannabis march of 16,000 people to London’s Hyde Park, that led the British Government to downgrade the legal status of the drug. A few months ago, the same newspaper, with “Cannabis: an apology” as front-page headline (Owen, 2007), reversed its landmark campaign for cannabis use to be decrimina lised because, as it stressed, there is increasing evidence that cannabis is far from harmless. The newspaper reported record numbers of British teenagers requiring drug treatment as a result of smoking highly potent cannabis strains that are 25 times stronger than the cannabis strains sold a decade ago. With its “apology”, The Independent reflects the strong, current debate on the health consequences of cannabis use, and highlights two important recent trends in cannabis consumption: first, the availability of more potent varieties of cannabis, termed sinsemilla or skunk; second, the increasing popularity of cannabis among young people, which makes cannabis the world’s third most popular recreational drug, after alcohol and tobacco (NIDA, 2005).

In recent years, the exceptional blooming of research around cannabis has aided the understanding of its effects on the brain, and a number of reports have claimed cannabis derivates as novel, promising therapeutic tools for a variety of pathological conditions (Di Marzo et al., 2004; Lambert and Fowler, 2005; Mackie, 2006a; Pacher et al., 2006). At the same time, more and more studies have quantified the extent of the risks of short- and long-term cannabis use (Di Forti et al., 2007; Grotenhermen, 2007; Moore et al., 2007), and cannabis consumption by young people has become a serious health issue.

In humans, cannabis use peaks between 15 and 30 years of age, although there is an emerging trend for continued cannabis consumption by people aged 30–40 years (NIDA, 2005). This pattern of use potentially exposes the developing brain to cannabis during two critical developmental periods. First, in offspring of cannabis-using mothers during the perinatal period. Cannabis preparations are indeed among the illicit drugs most widely abused by pregnant women in Western societies (Fried and Smith, 2001; NIDA, 2005).

Since the psychoactive ingredients of cannabis can cross the placenta and be secreted in maternal milk (Hutchings et al., 1989; Jakubovic et al., 1977), understanding whether developmental exposure to cannabis derivates might interfere with the rigidly ordered temporal sequence of events that occur during the ontogeny of the central nervous system (CNS) represents an urgent and exciting challenge.

Second, the adolescent brain, undergoing its final development and maturation, may also be exposed to exogenous cannabinoids through use at that particularly sensitive age. The CNS develops over a long period of time extending from the embryonic stage through adolescence until adulthood, with both synaptogenesis and myelination continuing from the perinatal period through puberty in both animals and humans (Spear, 2000). Thus, given the increasing abuse of cannabis among young people, research into the long-lasting neurobehavioral effects of adolescent cannabis use is warranted.

In this review, we outline recent research into the endocannabinoid system, discussing how cannabinoid compounds may interfere with neuronal signalling and interact with other neurotransmitter systems, such as the endogenous opioid system.We then focus on the role of the endocannabinoid system in brain development and discuss the behavioral and neurobiological effects of cannabinoid exposure during the perinatal and adolescent periods, as highlighted by both human and animal studies. Particular emphasis will be given to the long-term psychiatric implications of cannabinoid exposure during these critical stages of brain development.

### 2. The endocannabinoid system

The powerful effects of cannabis on the brain have been known for thousands of years (Mechoulam, 1986; Russo, 2007). A variable, subjective combination of euphoria and relaxation, mood changes and altered perception, loss of motor coordination and impaired attention, distorted perception of time and hallucinations, has lead different societies to regard cannabis as an ideal remedy for everyday pains, or as a harmful poison that induces madness. While the psychoactive properties of cannabis have long been recognized, research into its active chemical constituents turned out to be more time consuming than expected (Mechoulam and Hanus, 2000).

Although chemical studies of the constituents of cannabis started in the early 1800s, the most important page in the field of cannabinoid research was not written until 1964 by Gaoni and Mechoulam, who were the first to identify delta-9-tetrahydrocannabinol (THC), the primary psychoactive compound in cannabis (Gaoni and Mechoulam, 1964).

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