The burgeoning prevalence of mental health disorders poses an enormous global challenge. Almost one in two US citizens will receive a DSM-IV diagnosis during their lifetime, and a mood disorder is second only to hypertension in frequency as the presenting condition to British GPs.
Schizophrenia is a chronic disease that manifests through disturbances of perception, thought, cognition, emotion, motivation and motor activity. Over a lifetime, about 1% of the population will develop schizophrenia.
All antipsychotic treatments for schizophrenia rely primarily upon their antagonistic action at the dopamine D2 receptor for their antipsychotic effect. They produce a wide range of adverse events, and are often poorly tolerated by patients resulting in poor compliance with treatment.
Current antipsychotics also have little or no effect upon the ‘negative’ symptoms (blunted mood and lack of pleasure, motivation and movement) of schizophrenia or the associated cognitive deficit. Furthermore, the ‘positive’ symptoms (such as hallucinations, delusions and thought disorder) of at least one third of patients fail to respond adequately to current treatments. As cannabinoids do not operate through the D2 receptor, they have the potential to combine with current standard of care. There is also evidence to suggest that they can target both the positive and negative symptoms of this disease.
Cannabinoids in Schizophrenia
GWP42003 has shown notable anti psychotic effects in accepted pre clinical models of schizophrenia and importantly has also demonstrated the ability to reduce the characteristic movement disorders induced by currently available anti psychotic agents. The mechanism of GWP42003 does not appear to rely on the D2 receptor augmentation of standard antipsychotics and therefore has the potential to offer a novel treatment option in this therapeutic area. We are currently preparing to commence a Phase 2a trial of GWP42003 in the treatment for schizophrenia in the first half of 2014.
Additionally, our pre clinical research findings suggest that a range of other psychiatric conditions may be promising targets for cannabinoid therapeutics.
Cannabinoids in Psychiatric Disease
According to W.H.O., five of the ten leading causes of chronic disability world-wide are psychiatric disorders (major depression, schizophrenia, bipolar disorder, alcohol abuse, obsessive/compulsive neurosis). In the UK, 80 million working days are lost each year as a result of mental illness. There is considerable unmet clinical need as a result of the limited efficacy and potential toxicity of standard medicines.
The therapeutic (and risk) potential of cannabis-based medicines for psychiatric patients remains uncertain for the following reasons: questionable validity of animal models for psychiatric disorders; conflicting results from laboratory studies; questionable reliability and validity of clinical diagnoses; limited availability of controlled human data. Observations deriving from smoked cannabis or recreational users are unreliable for many reasons, including selection bias, inappropriate pharmacokinetics, reliance on self-report, and uncontrollable confounding factors.
On the basis of laboratory evidence, anxiety and depression are promising targets for cannabinoid medicines and there are some preliminary human data in support of thisi,ii. Emerging evidence suggests that the cannabinoid, cannabidiol (CBD), possibly in combination with other cannabinoids, may have potential utility in schizophrenia not only as an anti-psychotic, but also in the alleviation of the metabolic and inflammatory abnormalities associated with the disease. CB1 antagonists may have a role in relapse-prevention in the treatment of addictioniii. Other possible targets for the future based on human anecdote or limited laboratory research include bipolar affective disorder, post-traumatic stress syndrome, eating disorders, and insomnia. For the future, manipulation of the endocannabinoid system through inhibition of FAAHiv or the anandamide transporterv offers exciting therapeutic possibilities for many of these conditions.
ii. Fride E, Russo EB. Neuropsychiatry: Schizophrenia, depression, and anxiety. In: Onaivi E, Sugiura T, Di Marzo V, editors. Endocannabinoids: The brain and body's marijuana and beyond. Boca Raton, FL: Taylor & Francis; 2006. p. 371-82.
Publications for Cannabinoids Schizophrenia
Robson PJ, Guy GW, Di Marzo V. Curr Pharm Des. 2013 Jun 14. [Epub ahead of print]
Leweke FM, Piomelli D, Pahlisch F, Muhl D, Gerth CW, Hoyer C, Klosterkötter J, Hellmich M, Koethe D. Transl Psychiatry. 2012 Mar 20;2:e94
Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.
Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS. Philos Trans R Soc Lond B Biol Sci. 2012 Dec 5;367(1607):3364-78.
Neural mechanisms for the cannabinoid modulation of cognition and affect in man: a critical review of neuroimaging studies.
Bhattacharyya S, Atakan Z, Martin-Santos R, Crippa JA, McGuire PK. Curr Pharm Des. 2012;18(32):5045-54.
Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Δ⁹-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour.
Deiana S, Watanabe A, Yamasaki Y, Amada N, Arthur M, Fleming S, Woodcock H, Dorward P, Pigliacampo B, Close S, Platt B, Riedel G. Psychopharmacology (Berl). 2012 Feb;219(3):859-73.
Cannabidiol and clozapine reverse MK-801-induced deficits in social interaction and hyperactivity in Sprague-Dawley rats.
Gururajan A, Taylor DA, Malone DT. J Psychopharmacol. 2012 Oct;26(10):1317-32.
Opposite effects of delta-9-tetrahydrocannabinol and cannabidiol on human brain function and psychopathology.
Bhattacharyya S, Morrison PD, Fusar-Poli P, Martin-Santos R, Borgwardt S, Winton-Brown T, Nosarti C, O' Carroll CM, Seal M, Allen P, Mehta MA, Stone JM, Tunstall N, Giampietro V, Kapur S, Murray RM, Zuardi AW, Crippa JA, Atakan Z, McGuire PK. Neuropsychopharmacology. 2010 Feb;35(3):764-74.
Zuardi AW, Crippa JA, Hallak JE, Moreira FA, Guimarães FS. Braz J Med Biol Res. 2006 Apr;39(4):421-9.
Long LE, Malone DT, Taylor DA. Neuropsychopharmacology. 2006 Apr;31(4):795-803.