**5. Ontogeny of pharmacodynamic processes**

Dosing considerations of the pediatric patient not only need to acknowledge the impact of agerelated changes in PK processes, but also the maturation of the endocannabinoid system and how this will influence PD and the relationship between exposure and response. Very little data, though, are available from human clinical studies on the developmental maturation of the endocannabinoid system and how these may influence cannabinoid pharmacology. What is known is that the endocannabinoid system is expressed early in fetal life and plays a critical role in normal neurological development. Cannabinoid receptor populations and levels of the enzyme systems and endocannabinoids are dynamic in pediatric development particularly during adolescence [70]. Some data suggest daily high dose exposure to THC may pose a risk to normal neurological development, although the data are not available for CBD [71].

The lack of data on PD ontogeny and age-specific exposure-response relationships risks development of inappropriate therapeutic ranges. In the absence of any data, the treating caregiver may apply therapeutic ranges in adults or older pediatric age groups to younger pediatric age classes on the assumption of a similar exposure-response relationship to help inform dose selection [72]. Yet drawing from examples with other drugs, changes in receptor density expression with maturation have altered the efficacy and safety of drugs in children, such as reduced PD sensitivity to propofol resulting in overdosing and subsequently myocardial failure, metabolic acidosis, multiorgan failure, and death [73]. Given that the endocannabinoid system undergoes continued development, therapeutic windows are likely to be different among the different pediatric age strata.

## **6. Other factors**

#### **6.1. Safety and adverse effects**

The toxicity of cannabinoids is generally considered quite low. In adults, cannabinoids have a number of central nervous system effects that include intoxication, appetite stimulation, disruption of psychomotor behavior, short-term memory impairment, antinociceptive actions, and anti-emesis. Lethal doses are unknown, but the size of a single lethal dose is likely to be very high. The apparent low toxicity in adults, though, cannot necessarily translate to a low adverse effect potential in pediatric patients. Very little information exists on the pediatric specific adverse effects of *Cannabis.* Further, its use as an adjunct therapy in conditions such as pediatric seizure creates uncertainty—are the reported adverse effects the result of the cannabinoid or due to a cannabinoid-drug interaction? Experience with other drugs suggests that the immature physiological system predisposes pediatric patients to an increased risk for adverse effects [74]. It is these examples that highlight the concern among the treating caregiver of the safety of *Cannabis* use in pediatric patients. Unfortunately, the typical short-term clinical trial is inadequate to determine safety of medical *Cannabis* on growth and maturation. Pharmacovigilance over the long-term will be necessary, and this will require reevaluation of the original cohort of patients in clinical trials years after termination of the trial.

#### **6.2. Pharmacokinetic and pharmacodynamic interactions**

**4.5. Transporters**

192 Recent Advances in Cannabinoid Research

Transporters are categorized into ATP-Binding Cassette (ABC) and Solute Carrier (SLC) families. ABC proteins are efflux transporters expressed apically at tissue-blood interfaces and function to limit penetration of compounds into these tissues. Maturation of ABC transporters can result in a developmental vulnerability to THC use. ABC transporter ontogeny as well as genetic variation (polymorphisms) is known to influence treatment response to drugs and increase risk for psychiatric disorders in pediatric populations as a result of altered disposition to the brain [69]. For example, the common P-glycoprotein (ABCB1) genetic variant C3435T, which results in altered p-glycoprotein expression, was associated with increased risk of *Cannabis* dependence [58]. As well, transporter ontogeny and genetic polymorphisms can contribute to the interindividual variability in response to *Cannabis*. In general, the ontogeny of ABC and SLC transporters is poorly known.

Dosing considerations of the pediatric patient not only need to acknowledge the impact of agerelated changes in PK processes, but also the maturation of the endocannabinoid system and how this will influence PD and the relationship between exposure and response. Very little data, though, are available from human clinical studies on the developmental maturation of the endocannabinoid system and how these may influence cannabinoid pharmacology. What is known is that the endocannabinoid system is expressed early in fetal life and plays a critical role in normal neurological development. Cannabinoid receptor populations and levels of the enzyme systems and endocannabinoids are dynamic in pediatric development particularly during adolescence [70]. Some data suggest daily high dose exposure to THC may pose a risk to normal neurological development, although the data are not available for CBD [71].

The lack of data on PD ontogeny and age-specific exposure-response relationships risks development of inappropriate therapeutic ranges. In the absence of any data, the treating caregiver may apply therapeutic ranges in adults or older pediatric age groups to younger pediatric age classes on the assumption of a similar exposure-response relationship to help inform dose selection [72]. Yet drawing from examples with other drugs, changes in receptor density expression with maturation have altered the efficacy and safety of drugs in children, such as reduced PD sensitivity to propofol resulting in overdosing and subsequently myocardial failure, metabolic acidosis, multiorgan failure, and death [73]. Given that the endocannabinoid system undergoes continued development, therapeutic windows are likely to be

The toxicity of cannabinoids is generally considered quite low. In adults, cannabinoids have a number of central nervous system effects that include intoxication, appetite stimulation,

**5. Ontogeny of pharmacodynamic processes**

different among the different pediatric age strata.

**6. Other factors**

**6.1. Safety and adverse effects**

In pediatric patients, medical *Cannabis* is typically administered as an add-on to standard of care therapies. This practice can result in clinically relevant competitive interactions involving metabolic enzymes, transporters, or plasma protein binding sites, and at times pharmacological receptors. Cannabinoids are known to inhibit the metabolism of drugs that share the same P450 enzymes, with inhibition constants in the low micromolar range [37]. Conversely, drug substrates of CYP2C and CYP3A4 can slow the metabolism of the cannabinoids. A wellknown interaction is the co-administration of CBD with clobazam in refractory pediatric epilepsy where CBD is reported to increase clobazam and norclobazam (active metabolite) circulating concentrations due to inhibition of CYP2C19 [75]. Interactions between CBD and THC are also possible. CBD is known to competitively decrease the metabolism of THC resulting in its persistence in the body [76]. Higher ratios of CBD:THC can attenuate THCinduced effects and can produce more THC active metabolites [77]. P450 enzyme induction is possible in all pediatric age classes and can result in clinically significant enhancements in the elimination of cannabinoids and shorter half-lives. Without dosage regimen adjustments, enzyme induction and inhibition can result in concentrations outside the therapeutic window.

Other PK and PD interactions of concern include interactions at efflux transporters and impact of disease. The exposure-response relationship can be affected by clinically relevant interactions at the efflux transporters expressed at the blood brain barrier. Such interactions can alter the brain distribution of the pharmacologically active cannabinoid fraction to enhance cannabinoid response at a given *Cannabis* dose. Although our understanding of the impact of disease on cannabinoid PK and PD is very limited, clear examples exist where dosing recommendations depend upon the specific comorbidity under treatment. As well, some childhood diseases result in unique pathophysiological changes not present in the adult precluding a simple extrapolation of dose from adult experience. In the absence of data, pediatric patients will need close monitoring to ensure effective, safe therapy in the presence of disease and other comorbidities.

#### **6.3. Perspectives on the use of medical cannabis in pediatric populations**

We face a clinical and ethical dilemma in the use of medical *Cannabis* in pediatric populations. Product quality, limited age-appropriate formulations, the lack of PK and efficacy data spanning the specific pediatric age categories, the possible adverse effects of *Cannabis* on normal growth and development, and limited pediatric-specific safety data cause considerable uncertainty regarding the use of medical *Cannabis* and identification of an appropriate dosage regimen. It is not surprising that treating caregivers hesitate to give medical authority for use. Just as the regulatory agencies have identified a critical need for pediatric data in new drug development, so must the medical *Cannabis* field recognize the danger of inadequate safety and efficacy data and inadequate regulation of *Cannabis* product quality. To realize the full advantages of medical *Cannabis*, well-powered and rigorous clinical trials will be needed. Ethical justification for such studies should weigh toward benefit of the need to understand its safety and effectiveness in different pediatric age strata. Such studies must acknowledge the impact of physiological maturation and clinical variables on dose requirements and have sufficient power to enable evaluation of these factors on cannabinoid PK and PD. In fact, our current knowledge of the impact of maturation on PK and exposure-response relationships invalidates the practice of empirical methods for dose selection despite their simplicity for treating caregivers. Pediatric clinical trials for medical *Cannabis* should be considered mandatory and such trials should focus on both PK and the target PD outcome. Finally, a framework for assessing and reporting adverse effects and benefits should accompany the use of medical *Cannabis* in the pediatric population. Eventually, these studies will make possible the development of pediatric dosage regimens that are safe and precisely address the therapeutic need. Until then, the treating caregiver can rationally approach dose selection in different pediatric age groups with an understanding of the impact of growth and maturation on cannabinoid PK and PD.

[2] Kuddus M, Ginawi IAM, AL-Hazimi A. Cannabis sativa: An ancient wild plant of India.

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## **Author details**

Jane Alcorn1 \*, Stephanie Vuong1 , Fang Wu<sup>2</sup> , Blair Seifert<sup>3</sup> and Andrew Lyon<sup>2</sup>

\*Address all correspondence to: jane.alcorn@usask.ca

1 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon, Saskatchewan, Canada

2 Department of Pathology and Laboratory Medicine, University of Saskatchewan and Saskatchewan Health Authority, Saskatoon, Saskatchewan, Canada

3 Department of Pharmacy Services, Royal University Hospital, Saskatchewan Health Authority, Saskatoon, Saskatchewan, Canada

## **References**

[1] Brand JE, Zhao Z. Cannabis in chinese medicine: Are some tradition indications referenced in ancient literature related to cannabinoids? Frontiers in Pharmacology. 2017; **8**(108):1-11

[2] Kuddus M, Ginawi IAM, AL-Hazimi A. Cannabis sativa: An ancient wild plant of India. Emirates Journal of Food and Agriculture. 2013;**25**:735-745

**6.3. Perspectives on the use of medical cannabis in pediatric populations**

**Author details**

194 Recent Advances in Cannabinoid Research

Saskatchewan, Canada

\*, Stephanie Vuong1

Authority, Saskatoon, Saskatchewan, Canada

\*Address all correspondence to: jane.alcorn@usask.ca

, Fang Wu<sup>2</sup>

1 College of Pharmacy and Nutrition, University of Saskatchewan, Saskatoon,

Saskatchewan Health Authority, Saskatoon, Saskatchewan, Canada

2 Department of Pathology and Laboratory Medicine, University of Saskatchewan and

3 Department of Pharmacy Services, Royal University Hospital, Saskatchewan Health

[1] Brand JE, Zhao Z. Cannabis in chinese medicine: Are some tradition indications referenced in ancient literature related to cannabinoids? Frontiers in Pharmacology. 2017;

, Blair Seifert<sup>3</sup>

and Andrew Lyon<sup>2</sup>

Jane Alcorn1

**References**

**8**(108):1-11

We face a clinical and ethical dilemma in the use of medical *Cannabis* in pediatric populations. Product quality, limited age-appropriate formulations, the lack of PK and efficacy data spanning the specific pediatric age categories, the possible adverse effects of *Cannabis* on normal growth and development, and limited pediatric-specific safety data cause considerable uncertainty regarding the use of medical *Cannabis* and identification of an appropriate dosage regimen. It is not surprising that treating caregivers hesitate to give medical authority for use. Just as the regulatory agencies have identified a critical need for pediatric data in new drug development, so must the medical *Cannabis* field recognize the danger of inadequate safety and efficacy data and inadequate regulation of *Cannabis* product quality. To realize the full advantages of medical *Cannabis*, well-powered and rigorous clinical trials will be needed. Ethical justification for such studies should weigh toward benefit of the need to understand its safety and effectiveness in different pediatric age strata. Such studies must acknowledge the impact of physiological maturation and clinical variables on dose requirements and have sufficient power to enable evaluation of these factors on cannabinoid PK and PD. In fact, our current knowledge of the impact of maturation on PK and exposure-response relationships invalidates the practice of empirical methods for dose selection despite their simplicity for treating caregivers. Pediatric clinical trials for medical *Cannabis* should be considered mandatory and such trials should focus on both PK and the target PD outcome. Finally, a framework for assessing and reporting adverse effects and benefits should accompany the use of medical *Cannabis* in the pediatric population. Eventually, these studies will make possible the development of pediatric dosage regimens that are safe and precisely address the therapeutic need. Until then, the treating caregiver can rationally approach dose selection in different pediatric age groups with an understanding of the impact of growth and maturation on cannabinoid PK and PD.


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**Chapter 11**

**Provisional chapter**


**Cannabis for Pediatric and Adult Epilepsy**

**Cannabis for Pediatric and Adult Epilepsy**

DOI: 10.5772/intechopen.85719

Epilepsy is a chronic disease of the central nervous system characterized by recurrent unprovoked seizures. Up to 30% of patients continue to have seizures despite treatment with appropriate anticonvulsant medications. The presence of abnormal oscillatory events within neural networks is a major feature of epileptogenesis. The endocannabinoid system can modulate these oscillatory events and alter neuronal activity making the phytocannabinoids found in *Cannabis* a potential therapeutic option for patients with treatment resistant epilepsy. Many in vitro and in vivo studies have demonstrated the


Recently, there has been renewed interest in the use of cannabis in patients with treatment resistant epilepsy. This has, in large part, been driven by a public perception that cannabis offers a safe and natural alternative to conventional anticonvulsant therapies. However, the

anticonvulsant effects of several phytocannabinoids including Δ<sup>9</sup>

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

© 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use,

distribution, and reproduction in any medium, provided the original work is properly cited.

Richard James Huntsman, Richard Tang-Wai and

Additional information is available at the end of the chapter

Additional information is available at the end of the chapter

Richard James Huntsman, Richard Tang-Wai

http://dx.doi.org/10.5772/intechopen.85719

Jose Tellez-Zenteno

**Abstract**

(Δ<sup>9</sup>

cannabidiol

**1. Introduction**

and Jose Tellez-Zenteno


#### **Cannabis for Pediatric and Adult Epilepsy Cannabis for Pediatric and Adult Epilepsy**

DOI: 10.5772/intechopen.85719

Richard James Huntsman, Richard Tang-Wai and Jose Tellez-Zenteno Richard James Huntsman, Richard Tang-Wai and Jose Tellez-Zenteno

Additional information is available at the end of the chapter Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/intechopen.85719

#### **Abstract**

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children under 2 years of age. Pediatrics. 2002;**110**(5):e53

2002;**54**(4):415-422

200 Recent Advances in Cannabinoid Research

Psychiatry. 2001;**178**:107-115

Epilepsy is a chronic disease of the central nervous system characterized by recurrent unprovoked seizures. Up to 30% of patients continue to have seizures despite treatment with appropriate anticonvulsant medications. The presence of abnormal oscillatory events within neural networks is a major feature of epileptogenesis. The endocannabinoid system can modulate these oscillatory events and alter neuronal activity making the phytocannabinoids found in *Cannabis* a potential therapeutic option for patients with treatment resistant epilepsy. Many in vitro and in vivo studies have demonstrated the anticonvulsant effects of several phytocannabinoids including Δ<sup>9</sup> -tetrahydrocannabinol (Δ<sup>9</sup> -THC) and Cannabidiol (CBD). Several small observational studies demonstrated a favorable response to cannabis herbal extracts (CHE) containing high concentrations of CBD in children with treatment resistant epilepsy. Two large double blinded clinical trials assessing the efficacy of pharmaceutical grade CBD have also been performed in children with treatment resistant seizures in Dravet syndrome and Lennox-Gastaut syndrome. Both studies demonstrated an improvement in seizure reduction in children taking CBD as compared to the placebo groups. To date there is very limited data regarding the use of cannabis based products to treat adult patients with treatment resistant epilepsy with only one randomized double blinded placebo controlled clinical trial underway.

**Keywords:** epilepsy, endocannabinoid system, cannabis, tetrhydrocannabinol, cannabidiol

#### **1. Introduction**

Recently, there has been renewed interest in the use of cannabis in patients with treatment resistant epilepsy. This has, in large part, been driven by a public perception that cannabis offers a safe and natural alternative to conventional anticonvulsant therapies. However, the

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2019 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

phytocannabinoids found in the cannabis plant do offer some very unique anticonvulsant pharmacological properties that warrant further exploration.

result in excessive synchronous firing of neurons causing an epileptic seizure with alteration in the patient's behavior, motor activity or sensorium. Epilepsy can result from injury (either ischemic or traumatic) to cortical brain structures or genetic, inflammatory, structural and metabolic disturbances within the brain. The main components of the development of the abnormal oscillations within neuronal networks and epileptogenesis (seizure development) are (a) neuronal hyperexcitability—the ability of neurons to generate abnormal intrinsic burst discharges (b) a loss of GABA mediated interneuron neuronal inhibition that would normally prevent these discharges from spreading to adjacent neurons and (c) neuronal hypersynchrony in which excessive synaptic enhancement of neighboring neurons through the development of excitatory pathways allows these bursts to spread in a synchronous manner within a group of neurons [15]. Neuronal hyperexcitability can arise from abnormalities in excitatory or inhibitory neurotransmitter receptors resulting in a loss of the normal balance between neuronal excitation and inhibition. Of particular interest in epileptogenesis are the excitatory glutamatergic N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA) receptors [16]. Alterations in ion channel function as is seen in the channelopathy associated epilepsies such as Dravet syndrome also lead to neuronal

Cannabis for Pediatric and Adult Epilepsy http://dx.doi.org/10.5772/intechopen.85719 203

The endocannabinoid system comprises the two endogenous endocannabinoid receptors (CB1R and CB2R) their two endogenously produced endocannabinoids; anandamide (*N*-arachidonyl-ethanolamide) and 2-AG (2-arachadonoylglycerol) which act as endogenous CBR ligands as well as the enzymes involved in endocannabinoid production and breakdown. Of the endocannabinoids produced in the human brain, 2-AG is produced in much higher concentrations and plays the most significant role in regulation of oscillatory networks [18]. For a full review of the endocannabinoid system please refer to this book's introduction and the review article by Ligresti et al. [19] CB1R is one of the most abundant G proteincoupled receptors (GPCR) within the mammalian brain and is expressed on the presynaptic axon terminal. In response to activation of the postsynaptic neuron, anandamide (a partial CB1R agonist) and 2-AG (a full CB1R agonist) are both produced within and released by the postsynaptic neuron. Activation of the presynaptic CB1R receptors by the endocannabinoids then results in a temporary suppression in voltage gated Ca2+ channels and activation of K+ channels resulting in suppression of further neurotransmitter release from the presynaptic

Although CB1R is one of the most abundantly expressed GPCRs in the brain, its expression is concentrated within certain groups of neurons. For example, in the hippocampus, CB1R expression is concentrated on the axon terminals of inhibitory GABAergic CA1 region interneurons and Schaffer collaterals arising from CA3 pyramidal cells [22]. These interneurons play a key role in the formation and maintenance of normal oscillatory behavior in the hippocampus essential for memory formation [18]. The effect of stimulation of CB1R is very localized within neuronal networks both from a spatial and temporal point of view. This

hyperexcitability [17].

neuron [20].

**3. The endocannabinoid system and epilepsy**

In this chapter the authors will provide a brief review of epilepsy and epileptogenesis followed by a review of how the endocannabinoid system can alter the processes involved in the propagation and suppression of epileptic seizures. This is then followed by a review of the phytocannabinoids and their anticonvulsant mechanisms of action. Finally, the authors provide a historical background on the use of cannabis to treat patients with epilepsy and a review of the most recent clinical trials.
