Cannabis as an Anticancer Therapeutic Agent

Preclinical Evidence, Current Clinical Uses and Limits of Our Knowledge

Note to the reader

This article is based on scientific data published mainly over the last two decades and reflects the state of knowledge at the time of writing, with minor updates (Velasco et al., 2016; Velasco & Guzmán, 2016; Ramer & Hinz, 2015; Abrams, 2016). Research in the field of cannabinoids is evolving rapidly, especially regarding their anticancer potential, safety profile, and interactions with other therapies.

This text provides general scientific information and does not constitute individualized medical advice, diagnosis, or treatment recommendation. Patients must consult their treating physician before making any change to their therapeutic regimen.

1. Introduction: cannabis as a controversial therapeutic tool

Cannabis remains a highly controversial subject. On the one hand, it still carries the stigma of long‑standing prohibition and ideologically charged, often misleading propaganda against it. On the other hand, many progressive and open‑minded individuals recognize its therapeutic potential (Oikonomopoulos, 2016).

As a potential anticancer agent, cannabis evokes even stronger and more polarized reactions, particularly among oncologists and patients who use it. These two groups often stand in opposition, which is partly understandable: physicians as a professional group tend to be conservative, yet hold strong opinions and institutional authority, while research on cannabis was actively hindered for almost a century (Velasco et al., 2016).

Cannabis was arbitrarily classified as a high‑risk “narcotic”, which meant that the investigation of its anticancer properties in humans through clinical trials was effectively blocked. As a result, we now face:

• widespread ignorance about its real capabilities,
• often unjustified expectations,
• and a pervasive unease both in the medical community and among the public.

2. Preclinical evidence: THC, CBD and anticancer effects

Serious clinical trials in humans have begun, but the available data are still insufficient to support definitive conclusions or changes to standard therapeutic guidelines (Velasco et al., 2016; Velasco & Guzmán, 2016; Moreno et al., 2016). In contrast, there is already a vast body of preclinical research in cell cultures and animal models showing that both Δ⁹‑tetrahydrocannabinol (THC) and cannabidiol (CBD) possess significant anticancer properties, at least in certain types of malignancies (Velasco et al., 2016; Ramer & Hinz, 2015).

In many areas of oncology, preclinical findings in animal models have later been confirmed in humans, which supports a cautious optimism regarding cannabinoids; however, this does not guarantee that the same will happen here, nor does it allow final clinical conclusions at this stage.

Both THC and CBD have been shown to:

• Induce apoptosis (programmed cell death) in cancer cells.
• Inhibit tumour growth.
• Prevent metastatic spread of cancer cells.
• Inhibit angiogenesis (the formation of new blood vessels that feed the tumour).
• Synergize with certain chemotherapeutic agents, enhancing their anticancer activity in preclinical models (Velasco et al., 2016; Ramer & Hinz, 2015; Donadelli et al., 2011).

3. Selected preclinical studies

Without attempting a systematic review (relevant publications now number in the thousands), it is worth briefly highlighting some key findings:

• In one of the most lethal malignancies, melanoma, THC was found to induce autophagy, loss of cell viability and apoptosis in cancer cells (Armstrong et al., 2015).
• The combination of the chemotherapeutic agent gemcitabine with cannabinoids strongly inhibited growth of human pancreatic cancer xenografts in mice through mechanisms involving reactive oxygen species and autophagy, with no apparent systemic toxicity (Donadelli et al., 2011).
• CBD has been shown to induce both apoptosis and autophagy in human breast cancer cells via mechanisms not dependent on classical cannabinoid receptors, but involving complex crosstalk between intracellular signalling pathways (Shrivastava et al., 2011).
• In animal models of breast cancer, CBD significantly reduced primary tumour size and the number of pulmonary metastatic foci, and inhibited proliferation and invasion of breast cancer cells (McAllister et al., 2011).
• Synthetic cannabinoids that activate CB1 and CB2 receptors have been administered to mice with non‑small cell lung cancer, resulting in reduced tumour cell proliferation, decreased angiogenesis and increased apoptosis (Preet et al., 2011).
• THC has been shown to inhibit proliferation and increase apoptosis in human glioblastoma multiforme cells, both in vitro and in animal models (McAllister et al., 2005).
• In colorectal cancer cells, THC inhibits survival pathways such as RAS–MAPK and PI3K–AKT, leading to apoptosis through activation of BAD (Greenhough et al., 2007).
• In leukemic cell lines, low‑to‑moderate concentrations of THC can induce apoptosis within hours, involving cannabinoid receptors and MAPK signalling pathways (Powles et al., 2005).
• CBD enhances uptake of certain chemotherapeutic drugs by malignant glioblastoma cells via activation of channels such as TRPV2, thereby sensitizing them to cytotoxic agents (Nabissi et al., 2013).
• Ligresti et al. (2006) systematically characterized the IC₅₀ values of multiple plant‑derived cannabinoids in various cancer cell lines, demonstrating potent growth‑inhibitory effects of CBD and other compounds.

Overall, these data indicate that cannabinoids can target multiple hallmarks of cancer—cell survival, proliferation, angiogenesis and metastasis. The crucial question is to what extent these effects translate to human disease.

4. The first pilot clinical study in humans

The most emblematic clinical trial to date involved patients with recurrent glioblastoma multiforme, in whom THC was administered directly into the tumour (intratumoral/intracavitary administration) in a phase I pilot study (Guzmán et al., 2006).

Key findings were:

• Intratumoral THC administration proved technically feasible and generally safe, without severe psychotropic adverse effects.
• There was evidence of inhibition of tumour cell proliferation, with decreased expression of the proliferation marker Ki‑67 in post‑treatment tumour samples.
• Overall survival was comparable to what would be expected with standard treatment in similar patient series, but the sample size and study design did not allow firm conclusions regarding survival benefit.

The primary aim of this study was to assess safety and feasibility, rather than efficacy, yet it represented an important step towards exploring the anticancer effects of cannabinoids in humans.

5. Regulatory paradoxes and current patterns of use

In several countries—most notably the United States—the regulatory framework is highly contradictory: cannabis may be legal for medical use at the state level, while remaining illegal at the federal level. As a result, human research is often hindered or delayed, since federal approval and funding are required for many clinical trials (Moreno et al., 2016; Abrams, 2016).

Paradoxes exist elsewhere as well. For many years, the United Kingdom was one of the leading producers and exporters of medical cannabis preparations, while domestic medical use remained severely restricted (Cannabisnews.gr, 2016).

At the same time, in jurisdictions that have legalized medical cannabis, many patients with cancer use it not only to manage chemotherapy‑induced side effects (nausea, vomiting, anorexia) and cancer‑related pain, but also, in some cases, as a primary anticancer therapy (Abrams, 2016).

There are thousands of anecdotal reports of patients using concentrated cannabis oils (classically known as Simpson oil – RSO) rich in THC, CBD or both, and describing complete or major remissions of their cancers. However, such reports almost never come with full clinical documentation, adequate follow‑up or publication in peer‑reviewed medical journals; therefore, they cannot substitute for well‑designed clinical trials.

6. Palliative use: pain, nausea, appetite and mood

The palliative use of cannabis in oncology is currently the most established clinical field:

• Its use to alleviate nausea, vomiting and anorexia associated with chemotherapy is well‑documented and widely accepted (Vinciguerra et al., 1988; Abrams, 2016).
• As a treatment for cancer‑related pain, cannabis is gaining ground and, in some cases, can reduce the need for opioids, which are responsible for a substantial burden of adverse effects and overdose deaths (Cleeland et al., 1994; Johnson et al., 2010).
• As an antidepressant and anxiolytic in cancer patients, cannabis can significantly improve quality of life; however, it often meets moralistic objections concerning the risk of dependence, even in terminally ill patients whose overriding priority is the quality of their remaining time (Abrams, 2016).
• The use of cannabis as an orexigenic agent in cancer cachexia is subject to similar reservations, although available data suggest that it can be particularly useful in appropriately selected patients (Fairmond et al., 2010).

In all these indications, cannabis is not administered with curative or antineoplastic intent, but as an adjunctive tool within comprehensive palliative care, ideally in a controlled, physician‑guided manner.

7. Safety, toxicity and immunosuppression

Compared with classical cytotoxic chemotherapy, cannabis and cannabinoids are considered relatively non‑toxic in terms of acute, life‑threatening adverse events (Velasco et al., 2016; Ramer & Hinz, 2015). This does not mean that they are entirely harmless.

In particular, CBD, despite its multiple beneficial properties, has a significant immunosuppressive effect. Mechanisms include:

• induction of apoptosis in immune cells,
• inhibition of their proliferation,
• suppression of cytokine and chemokine production,
• induction of regulatory T cells, mainly via the CB2 receptor that is predominantly expressed on immune cells (Kaplan et al., 2008; Rieder et al., 2010).

This immunosuppressive property of CBD may be very useful in autoimmune diseases and chronic inflammatory conditions; however, it is not desirable in patients receiving immunostimulatory anticancer therapies, such as immune checkpoint inhibitors, where an effective anti‑tumour immune response is crucial (Rieder et al., 2010; Moreno et al., 2016).

THC, on the other hand, may cause:

• euphoria (welcome by some, unpleasant for others),
• anxiety, dysphoria or panic attacks in susceptible individuals,
• tachycardia and other cardiovascular effects that may not be well tolerated in patients with heart disease or in the elderly.

Thus, while the overall safety profile of cannabinoids is far better than that of many chemotherapeutic agents, their use still requires careful individualization and medical supervision.

8. Individualization: therapeutic goal, dosing and formulations

Patients who decide—often driven by desperation—to “take matters into their own hands” and use cannabis as part of their anticancer strategy are typically confronted with four key questions:

1. What is the therapeutic goal;
2. What dosing regimen is appropriate;
3. What CBD/THC ratio and overall phytochemical profile should be used;
4. Which route of administration, dosing interval and duration are appropriate;

The most important and most challenging of these is the definition of the therapeutic goal (e.g., pure palliation, slowing disease progression, or active anticancer intent). This can realistically be determined only through close collaboration between physician and patient and is the first and fundamental element of individualization.

Dosing is the most «burning» issue: many patients and even practitioners look for a «magic protocol», which in reality does not exist. Nevertheless, there is a clear conceptual dichotomy that physicians need to respect: in benign and neurodegenerative diseases, doses are generally low to moderate; the same applies to palliative care in cancer. If the patient has set an anticancer goal, then doses need to be high to very high. Practically, this means that palliative cannabinoid therapy can be administered to cancer patients only when they are in a truly terminal stage, with no realistic prospect of chronic control or cure.

This dosing distinction stems from the molecular biological behaviour of cells exposed to cannabinoids, as demonstrated in a large number of preclinical studies. Ligresti et al. (2006) determined the half‑maximal inhibitory concentration (IC₅₀) of THC and other plant cannabinoids for various neoplasms in vitro. In addition, several studies have shown the biphasic behaviour of cannabinoids in malignancies: at increasing low concentrations, a pro‑neoplastic or pro‑migratory effect may be observed up to a turning point, beyond which higher concentrations exert anticancer effects (McHugh et al., 2012; Lueder et al., 2017).

The pharmacodynamic profile of cannabis does not resemble that of most conventional drugs. When the aim of cannabinoid administration is to modulate a dysfunctional endocannabinoid system in the patient, small to moderate doses are usually sufficient, and a stepwise “dose‑finding” process is followed to identify the dose to which the patient responds. In malignant disease, by contrast, the endocannabinoid system needs to be bypassed by high doses, at which cannabinoid receptors tend to undergo internalization, and are therefore no longer responsive in a regulatory sense.

In oncologic practice:

• If the dose is low, the effect will be primarily palliative, without meaningful anticancer impact.
• If the dose is sufficiently high, depending on the tumour type, the endocannabinoid system will be «overridden», and other mechanisms will predominate, driving apoptosis of neoplastic cells.

For benign and degenerative diseases, it is the physician’s duty to help determine the patient’s individual optimal dose for the therapeutic goal in question. In practice, this usually means low starting doses with slow upward titration, under careful monitoring.

Cannabis does not have a single “fixed dose” in the way many classical drugs do. Dosing is inherently individualized. A general rule—with many exceptions—is that younger patients often require higher doses than older ones, partly due to age‑related weakening of the endocannabinoid system.

The appropriate formulation also plays a crucial role. CBD, with all its beneficial properties, has—as discussed—immunosuppressive actions, which limit its use in some cancer settings, particularly in patients receiving immunotherapies. THC, in turn, carries the burden of psychotropic and cardiovascular adverse effects.

9. Beyond the THC/CBD ratio: chemovariation and the “entourage effect”

Discussion about cannabis formulations often focuses narrowly on the THC/CBD ratio. However, more advanced research—among others from Israeli teams—shows that other phytocannabinoids, in synergy or antagonism with terpenes and flavonoids, may be equally or even more important for the overall therapeutic effect (Meiri, CANATECH presentation; Velasco et al., 2016).

This overall phenomenon is often referred to as the “entourage effect”: the idea that cannabis constituents act synergistically, and that the total therapeutic effect of a full‑spectrum extract is not equivalent to the sum of the actions of isolated THC and CBD.

The “palette” of constituents:

• differs from cultivar to cultivar,
• varies from year to year,
• and can even differ from greenhouse to greenhouse growing the same nominally identical strain,

and these differences may have clinically relevant implications.

It is therefore reasonable to ask: Do we know that we do not know? Humility in the face of this complexity is essential, especially when we are called upon to provide therapeutic guidance.

10. The risks of self‑medication and the “authority of the internet”

In real‑world practice, many patients who do not respond to conventional anticancer therapies—and they are numerous—turn to cannabis as an alternative or complementary treatment. They seek advice from other, more experienced patients and from dispensary staff, and often rely on the so‑called “authority of the internet” for dosing and regimen instructions.

Peer‑to‑peer exchange of experience is both legitimate and necessary, particularly in the context of insufficient official information. However, when such information is not integrated into a medical framework, it can become harmful. Cannabis may be relatively safe, but cancer is an extremely complex disease, deeply rooted in the patient’s biology and life, both agonizing and potentially fatal. It is not adequately addressed by chemotherapy alone, nor by diets, nor by “little oils”.

It is neither realistic nor ethically acceptable simply to tell patients «do not do this» as long as no better, evidence‑based alternatives are being offered. What we can—and must—do is to advise them to:

• be highly cautious and critical of advice received,
• evaluate the seriousness and reliability of sources,
• educate themselves as much as possible,
• and, crucially, seek collaboration with physicians willing to become informed and to accompany them in this journey.

Medical problems should be handled by appropriately trained physicians. Only someone who underestimates the complexity of the matter can offer detailed therapeutic instructions «light‑heartedly».

The distinction between information and medical advice is fundamental: the former should be disseminated generously; the latter, when provided by non‑physicians, may be dangerous and, in some jurisdictions, even legally actionable.

11. Cancer as a “Lernaean Hydra” and the future place of cannabis

Cancer has been aptly described as “The Emperor of All Maladies” (Mukherjee, 2010). Each malignancy—and even more, each patient—is a unique case. Cancer is a “Lernaean Hydra”: when one head is cut off, others may appear (Papassotiriou, online lecture).

Its management:

• demands extreme prudence,
• requires strategic deployment of multiple therapeutic modalities (surgery, radiotherapy, chemotherapy, immunotherapy, targeted agents, supportive and complementary treatments),
• and calls for a deep appreciation of its individualized nature.

Cannabis, as a quintessentially individualized therapeutic tool, is very likely, in the coming years, to occupy a prominent position within an integrative, personalized therapeutic framework for cancer—either as an adjuvant, or, in specific settings and protocols, possibly as a primary agent (Velasco et al., 2016; Abrams, 2016). For this to happen, we need a critical mass of physicians who are knowledgeable about both the potentials and limitations of cannabinoid‑based therapies.

12. Key messages

To summarize, the key messages of this article are:

1. The discovery of the endocannabinoid system and the expanding medical applications of cannabis will almost certainly trigger an explosion of research and lead to new clinical applications in oncology (Velasco et al., 2016; Ramer & Hinz, 2015).
2. The palliative use of cannabis to alleviate chemotherapy‑related side effects (nausea, vomiting, anorexia) is well established when applied appropriately (Vinciguerra et al., 1988; Abrams, 2016).
3. Its use as an analgesic in cancer‑related pain is gaining ground and may, in some cases, reduce reliance on opioids (Cleeland et al., 1994; Johnson et al., 2010).
4. Use as an antidepressant and anxiolytic in cancer has a solid theoretical and clinical rationale but still faces moralistic resistance that is not always aligned with patient needs, especially in advanced disease (Abrams, 2016).
5. Cannabis as an orexigenic agent in cancer cachexia is a promising application, but requires careful individualization and close monitoring (Fairmond et al., 2010).
6. Based on preclinical evidence and multiple anecdotal reports, it is plausible that cannabis will play a significant future role as an anticancer drug, either as a primary or adjunctive agent, with fewer severe side‑effects than many conventional drugs (Velasco et al., 2016; Ramer & Hinz, 2015). However, the required clinical evidence is still under development.
7. The composition and stability of cannabis preparations—and thus the reproducibility of clinical outcomes—remain unsatisfactorily resolved issues, related both to the plant’s chemovariation and to pharmaceutical manufacturing techniques (Velasco et al., 2016; Meiri, CANATECH presentation).
8. Cancer is not a simple disease, and no two cases are alike. Patients should not rely on simplistic protocols or casual advice. It is far better to discuss cannabis use with their physicians, to raise their questions, and, if necessary, to seek healthcare professionals with greater expertise or interest in cannabinoid medicine.
9. Providers of “medical advice” via social media and informal channels should take seriously the difference between providing information and practicing medicine. Our patients deserve something better.
10. The training of a sufficient number of physicians in cannabinoid therapeutics is both necessary and urgent. If official bodies fail to take the initiative soon, the medical community—together with patients—may need to do so.

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