schizophrenia

Cannabidiol may treat psychosis while tetrahydrocannabinol can induce schizophrenia in those susceptible  

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 6, 2018

Introduction

There is a well-known correlation of use of cannabis whether it is medical or recreational to the onset of schizophrenia. It unclear if this could be to a direct correlation and disinhibition of the genetic component or the behavior of using it is a prodrome leading up to schizophrenia. This review seeks to elucidate the mechanisms in the correlation of the use of cannabis and onset of schizophrenia.

Mechanisms related to the underlying genetic composition

Schizophrenia may be linked when some of the normal pathways become disrupted with an introduction of THC.  There are 4 genes that were described after a lifetime use of cannabis including KCNT2 which were THC responsive, NCAM1 and CADM2 are significant in functioning in post-synapse. With THC in the system, there are more post-synaptic density genes (1).

Mechanisms related to other neurotransmitter pathways influenced by cannabinoids

In one study, because of the alarming rate of potent synthetic cannabis used recreationally which was found to leave long-lasting schizophrenia disorder in recreational users, this has accelerated research into the pathophysiology. Because cannabinoids work on the CB1 receptor, it is likely that it plays a modulatory role on the other neurotransmitters that can give rise to schizophrenia including dopaminergic, glutamatergic and serotonergic pathways. These pathways are well-established as playing a role in a pro-psychotic state. High efficacy synthetic cannabinoids which are manufactured for recreational purposes are highly more potent compared to natural organic cannabinoids and there is an alarming increase in the correlation of schizophrenia in these users (2).

In one study it is thought to be due to the hypofunctioning of the glutamate system which is directly affected by THC. Exposure to tetrahydrocannabinol appears to reduce the activity at the level of the glutamate receptor as well as deregulate genes for synaptic function(1).

IMG_5934_preview.jpeg

Susceptibility is related to the development of schizophrenia

In one animal model, the set-up tried to mimic a more real state seen where not all adolescents exposed to synthetic cannabinoids react by developing schizophrenia, there are some studies where all animals develop schizophrenia with exposure. In this animal model, they provided a model that resembles the human model more closely and found that exposure to synthetic cannabinoids in schizophrenia-prone animals caused hyperfunctioning of dopaminergic pathways compared to the control group who were not susceptible at the same dosages. There may be underlying genetic or environmental factors that cause certain individuals to become more prone (2).

THC can cause anxiety and behavioral disorders but can be prevented with CBD

In one animal study, it was found in a rat study that THC can induce anxiety and behavioral disorders. With THC  administration object recognition was impaired in adolescent rates. The studies support effect on the developing brain in relation to cognitive impairment in the animal model. In addition, when rats were exposed to THC there was increased marble burying behavior which in scientific research is thought to signify anxiety or obsessive-compulsive type behavior usually ameliorated with serotonin reuptake inhibitors or benzodiazepines(4).

It was found, however, that a combination of CBD and THC or cannabidiol alone was administered, these behaviors were not produced or produced only minimally. The thought is that CBD is an allosteric competitive inhibitor at the CB1 receptor so that one sees less of the toxic undesirable effects of THC if administered alone (4).

Cannabinoids have a similar profile to atypical anti-psychotics and may be a possible adjunctive treatment in the treatment of psychotic events (5).

IMG_5620_preview.jpeg

In summary

There is historical evidence that exposure to THC can give rise to schizophrenia in those individuals that are susceptible accounting for the fact that it does not happen to everybody exposed to it. This is related to its influence on serotonergic, dopaminergic and glutamate pathways. THC can induce anxiety, repetitive behaviors which are ameliorated by CBD. CBD may be a useful adjunctive treatment for psychotic disorders. However, the elucidated mechanisms are based on scientific research based on animal models which may not translate into humans.

About

Introduction/Disclaimer

https://neurologybuzz.com/

 

References

  1. Guennewig, et al, “THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorder,” Transl. Psychiatry, 2018, Apr., 8(1):89.
  2. Fantegrossi, et al, “Pro-psychotic effects of synthetic cannabinoids: interactions with central dopamine, serotonin and glutamate systems, Drug Metab. Review, 2018, Jan, 50(1)
  3. Aguilar, et al, “Adolescent synthetic cannabinoid exposure produces enduring changes in dopamine neuron activity in the rodent model of schizophrenia,” Int. J. Neurpsychopharmacol., 2018, Apr., 31 (4):393-403.
  4. Murphy, et al, “Chronic adolescent delta9-tetrahydrocannabinol treatment of male mice leads to long-term cognitive behavioral dysfunction which is prevented by concurrent cannabidiol treatment,” Cannabis Cannabinoid Res., 2017, 2(1):235-246.
  5. Deiana, et al, “Medical use of cannabis: a new light for schizophrenia?” Drug Test Analysis, 2013, Jan., (5)1:46-51
Standard
autism

Medical marijuana: effects on pediatric patients with autism and the developing brain

Virginia Thornley, M.D., Neurologist, Epileptologist

@VThornleyMD

May 6, 2018

Introduction

Medical cannabis is being more and more commonly used in medical conditions specifically neurological. The CB1 receptor is found predominantly within the nervous system and in a few other organs on a lesser basis. The CB2 receptor is mainly in the immune system and found in other organs to a lesser extent.

Recent arguments have arisen promoting medical cannabis in children particularly in those with autism and attention deficit hyperactivity disorder.  It has already been well-established in patients with epilepsy. However, the effects on the developing brains of children have not yet been well-documented as it is not yet widely used or studied in the pediatric population. There are many animal models but this does not always correspond to translate into similar human findings.

Effect in autism in animal models and clinical studies

A current topic of debate is not only using THC in pediatric patients but those with autism. Autism is part of the pervasive developmental disorder consisting of social inhibition and isolation including poor eye contact, delayed language skills, aggressive behavior and may be characterized as having stereotypies such as flapping of the arms. Self-injury, eating and sleep disorders may occur. The etiology may be related to genetic, neurobiochemical or environmental and the exact cause is unclear.

In one animal model study, mice with induced Dravet syndrome-like symptoms was noted to improve in autistic-like social interactions with the addition of low dose cannabidiol (2) of 10mg/kg. At low doses, the DS mice interacted more with stranger mice. At higher doses, this was not noted. Dravet syndrome is a type of epileptic syndrome affecting the SCN1A gene causing medically refractory seizures combined with autism.  However, this was an animal model. Scientific studies do not necessarily translate into positive human clinical results.

There was one case report of a six-year-old boy with early autism. Dronabinol  (delta-9-THC) was administered at 3.62mg a day and followed for 6 months. Using the ABC scale (aberrant behavior checklist), the patient improved in terms of stereotypies which were less, lethargy was reduced, hyperactivity improved, and inappropriate speech improved (4).

10454352_10152824048348841_3211150018156156082_o.jpg

Endocannabinoid system and mechanisms in relation to autism

There are several lines of thinking regarding the role of the endocannabinoid and autism. It is thought that the endocannabinoid system plays a role in neurological development, but can also be modulated by outside cannabinoids. Another line of thinking is that autism spectrum disorders may be related to disrupted pathways that have been affected by the endocannabinoid pathway (5). In one animal study, it was found that the oxytocin peptide may be responsible for disrupting normal signaling pathways giving rise to autism spectrum disorders. Oxytocin appears to be crucial in mediating social reward which is impaired in autistic patients. Anandamide seems to play a role in the signaling pathways for oxytocin which is responsible for the social reward.   Social reward is aberrant in those with autism and this pathway thought to play a key role in causing its pathogenesis. By increasing anandamide at the CB1 receptor, ASD and social impairment is improved (5).

Effect on a fetus

Tetrahydrocannabinol is lipophilic and crosses the blood-brain barrier. It can get stored in the fatty stores which are likely the reason it may have a long-lasting effect.  Cannabinoids have been found to cross the placenta and affect the fetus. It may result in hyperactivity and impulsivity in babies with cannabinoid exposure in utero.

 

Effect on early cerebral development

It was found that in adolescents who used cannabis, there is a reduction in the IQ by the age of 38. It was found that cannabinoid receptors influence axonal migrations as well as subcortical projections within the cerebrum. This affects synaptic connections during childhood and adolescence(3).

The adolescent brain is still not fully matured and likely still subject to neuronal plasticity and changes. It may be affected by substances. One study showed that the frontal lobe is vulnerable to cannabis in adolescents who used it heavily and that cannabis use may impact working memory. (1)

 

 

10636938_10152824044463841_8538878751618950986_o.jpg

 

During adolescence, when cannabis is initiated it may affect the neuronal circuitry developing in the immature brain. The richest regions in the brain with cannabinoid receptors are the prefrontal cortex, medial temporal lobes, striatum, white matter connections, and cerebellum. When cannabis is introduced during this neurocritically important time of development, these regions can become dysfunctional although some functional studies have shown altered, weakened, strengthened or combination of changes (6).

Some of the most common adverse effects

At high doses in chronic users, it was found to induce anxiety, panic attacks. It can increase blood pressure. However, clinically, it may control seizures

 

In summary

There is a small body of evidence from a scientific standpoint that cannabis may work to help alleviate autism-like symptoms based on the animal models. There is a not enough evidence from a clinical evidence standpoint in human studies to support its use in pediatric patients, with one case report that it helped with impulsivity, reduced lethargy, and inattention. Randomized placebo-controlled clinical trials are needed.

Research has found that cannabinoids may help oxytocin and disrupted signaling pathways that play a role in social reward which is impaired in autism. At present, there is evidence that cannabis may affect neurocognitive development but these are studies in pregnant mothers who used it heavily recreationally and adolescents who used it heavily. It is unclear if there may be a similar impact when used in the pediatric population at a medical dosage and administration as there are not enough studies to expound on this.

About

Introduction/Disclaimer

https://neurologybuzz.com/

Reference

  1. Jager, et al, “Cannabis use and memory brain function in adolescent boys: a cross-sectional multicenter fMRI study,” J. Am. Acad. Child Adolesc. Psychiatry, 2010, Jun., 49(6):561-572.
  2. Kaplan, et al, “Cannabidiol attenuates seizures and social deficits in a mouse model in Dravet syndrome,” Proceedings of the National Academy of Science, 2017, Oct.. 114 (42):11229-11234.
  3. Scott, et al, “Medical marijuana: a review of the science and implications for developmental-behavioral pediatric practice,” J. Dev. Behav. Ped., 2016, Feb., 36 (2):115-123.
  4. Kurz, et al, “Use of dronabinol  (delta-9-THC) in autism: a prospective single-case study with early infantile autistic child,” Cannabinoids, 2010, 5 (4):4-6.
  5. Wei, et al, “Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment,” Cannabis Cannabinoid Research, 2016, 1(1):81-89
  6. Kelly, et al, “Distinct effects of childhood ADHD and cannabis use on brain functional architecture in young adults, Neuroimage Clin., 2017, 13:188-200.

 

Standard