Future cancer treatment: using cannabis along with standard methods

It is getting easier to prove the beneficial effects of cannabinoids, but using these chemical compounds in practice will need to be backed by clinical trials.

Cannabinoids are organic bioactive compounds found in the cannabis plant and produced during biochemical transformations in nature. Some can be synthesised.

The most famous ones are cannabidiol or CBD and tetrahydrocannabinol or THC, the only cannabinoid having psychoactive effects.

Those natural chemicals, which are also anti-carcinogens, have lately been in the spotlight of studies at the National Institute of Biology's (NIB) Genetic Toxicology and Cancer Biology unit.

Professor Tamara Lah Turnšek, the former long-time head of the institute, who has conducted these trials, believes that the future of cancer treatment lies in combining chemotherapeutics and cannabinoids.

This combination improves cancer treatment efficiency, providing an opportunity to reduce the dose of chemotherapeutic agents, a goal pursued by oncologists.

The Slovenian scientist has been researching cancer for 20 years, focussing in the past few years on the brain tumour or glioblastoma, including the effects of cannabinoid on cancer cells.

Delicate but promising research field

According to Lah Turnšek, hemp holds a special position among biological and natural substances tested for cancer treatment due to the controversial psychoactive effects found only in THC. Nevertheless, doctors and other experts are getting increasingly aware of its upsides.

It has been proven that cannabinoids have a positive impact on a number of health conditions. For example, they alleviate the pain and nausea caused by chemotherapy, and improve appetite.

They also help treating epilepsy in children, Alzheimer's disease, high blood pressure and hepatitis, and show great potential in the primary treatment of early-stage cancer.

It is getting increasingly evident that cannabinoids inhibit tumour growth and invasiveness, while in animal testing they even radically slow the systemic progress of cancer cells.

However, clinical trials have yet to include a greater number of participants and thus provide reliable data on certain effects.

Lah Turnšek believes that in the initial stage of clinical trials, which is already under way, cannabinoids will be mainly tested as a symptom alleviation treatment, while the institute's study is mostly targeted at primary-cancer treatment - if cannabinoids are proven to be an anti-carcinogen, they would be used in early stages.

NIB cannabinoid research

Lah Turnšek is leading Slovenian researchers in exploring the effects of cannabinoid on the treatment of the most common and aggressive type of brain cancer - glioblastoma.

Most cannabinoid studies focus on this type partly because a significant number of cannabinoid receptors are situated in the brain.

Such receptors, in particular CBI receptors, balance out neuron links in the brain - a situation which made researchers hypothesise that chemicals such as cannabinoids could be used in fighting brain tumours.

Brain tumour cells and cancer stem cells used in research are extracted from samples provided by the Ljubljana University Medical Centre's neurosurgery department.

Those cells are then studied, with researchers testing cannabinoid effect on them. What follows is animal testing, with the most effective test species being the zebrafish (Danio rerio).

The studies include a wide spectrum of various cannabinoid relations and assess their compatibility with chemotherapeutics to determine which chemical combination would be most suitable for a specific cancer type.

Along with the Ljubljana Oncology Institute's research group led by Simona Bošnjak and Nataša Debeljak of the Ljubljana Faculty of Medicine, they have found that cannabinoids do not affect the efficiency of tamoxifen chemotherapeutic or other such anti-cancer drugs in treating breast cancer - an argument used to oppose their use in such treatment.

"On the contrary, we could even improve treatment," said Lah Turnšek.

Stem cells as target of research

Lately, researchers have been focussed on cancer stem cells, mutated normal cells with a gene-encoded cancer progression, which makes them a good treatment target as well as a challenge.

Cancer stem cells are extremely resistant. Chemotherapy does not kill them, it merely puts them to sleep, with cells being able to wake up again. "If we discover why stem cells are more sensitive than other cancer cells, that would be a major achievement in cancer treatment," said Lah Turnšek, adding that finding an anti-cancer stem cell cure is the priority of all researchers today.

NIB researchers have already determined that CBD cannabinoid has a major effect on stem calls. It has undergone trials in combination with standard treatment methods as well.

Cooperation with Italian partners

Slovenian researchers have been working with their Italian colleagues on cannabis research for almost a decade. Following the successful Glioma project of the Interreg Italia-Slovenija programme, which wrapped up in 2013 and was run by Lah Turnšek, both countries got a go-ahead for the follow-up Trans-Glioma project four years later, managed by Radovan Komel of the Ljubljana Faculty of Medicine.

Trans-Glioma aims to improve cooperation between key researchers and doctors - neurosurgeons and neurooncologists.

Their main target is setting up a joint regional glioblastoma bank including tissue samples as well as analytical and clinical tumour data for research and treatment of this aggressive disease. Biosistemika, a NIB spin-off, is in charge of this initiative.

Respecting strict safety regulations

The institute had to obtain special illicit-drug research permits of the Commission for Medical Ethics and the Health Ministry for its cannabis research.

Safety regulations are very strict, even excessive, but the institute has met them, said Lah Turnšek. Test tubes with cannabis extracts are thus safely stored in a safe in a fridge located in a locked room with bars on the windows.

The extracts are provided by the Israeli-Australian company MGC Pharmaceuticals, which has a branch office in Ljubljana.

Synthetic cannabinoids are the future

One of the problems encountered while registering clinical trials is that cannabinoid extracts or isolates from plants contain various elements, which is why they cannot always be identical or at least standardised enough to meet the synthetic drugs requirements despite the plants being grown in greenhouses under constant conditions.

In pre-clinical trials, researchers thus study if those deviations from the norm are acceptable.

Another promising solution is synthetic cannabinoid treatment, similar to endocannabinoids produced by the human body. Raphael Mechoulam, the 89-year-old trailblazer in cannabis research, who was first to describe THC in the 1960s, conducts synthetic cannabinoid research today.

He presented his innovative research for the first time at this year's international CannMed conference in the US, coming up with a new family of stable synthetic molecules of cannabinoid acids in which he sees a great potential for medical use.

Legalising hemp for research and black market regulation

Lah Turnšek believes that cannabis research worldwide lacks funding as well as cooperation between researchers and oncologists.

The state should invest money in such research and legalise marijuana for medical use, "in particular because patients themselves want or even demand this", she said.

Due to a lack of clinical trials, a consequence of cannabis being criminalised for almost a century, "an almost unbearable situation has developed in which patients are treating themselves, with or without their doctor's consent, while oncologists feel uncomfortable with prescribing something that has not been thoroughly researched yet".

Lah Turnšek pointed to recent debates on cannabinoid toxicity, such as CBD toxic properties, explaining that cannabinoids, including CBD, were not toxic, except for when the cannabis plant contains heavy metals and bacteria or fungal toxins.

That depends on the soil though. Hemp has the ability to accumulate toxins from soil - as a result, if the plant grows in polluted soil, it will contain harmful substances.

Lah Turnšek thus advocates hemp regulation, "with which we would provide access to tested, clean and non-toxic extracts with a number of scientifically proven positive effects".

By delaying the adoption of proper legislation in this field, the authorities are acting socially irresponsibly, she said.