Research and Development Program for Domestic Production of Resiniferatoxin
Background
Our research on plants in the genus Euphorbia is focused on certain succulent African species that may contain resiniferatoxin (RTX), a compound of great contemporary interest primarily as an investigational drug for treating intractable pain from chronic conditions such as arthritis and advanced cancer. Their use may also eliminate or significantly reduce the frequency and amounts of opioid use in pain treatment. RTX, tinyatoxin and other compounds found in these plants may also have important future applications for a wide variety of other health conditions.
Demand for euphorbia sap, usually referred to as latex, or the dried sap resin (euphorbium) from which RTX is extracted has increased significantly to meet the near-term needs of research and clinical trials currently progress. We have received inquiries from domestic and international chemical and pharmaceutical companies intending to purchase very large amounts of latex or RTX. These amounts far exceed the known supplies. Approvals for the clinical use of RTX in two major applications are likely by 2027 and should greatly increase demand.
Sources for Euphorbia resinifera and other species that may contain RTX, have been primarily located in areas of Africa that are politically sensitive, unstable or in civil war. Unfortunately, these situations in Africa may not be resolved favorably for a long period of time. International trade in these succulent African Euphorbia plants and materials derived from them is also restricted under the Convention in International Trade in Endangered Species of Fauna and Flora (CITES). Multiple new, sustainable and reliable domestic sources of euphorbia latex need to be developed for production of RTX and related compounds. Development of these should be initiated as soon as possible because a long lead time may be needed to grow euphorbia crops to a harvestable size.
Production of latex from plants cultivated in Arizona deserts has now been reported but no details were provided (Szallasi 2023).
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 Structure of resiniferatoxin |
 Structure of Tinyatoxin |
Research and Development Objectives
The primary long-term objective of this project is to develop a reliable, sustainable domestic source of high-quality latex for production of RTX and related compounds for research and pharmaceutical applications. This will involve identifying and obtaining species and cultivars with economically extractible concentrations of RTX, development of methods of large-scale propagation and cultivation of these plants as a crop(s) in Hawai`i and elsewhere, and testing and deployment of new technologies for safe, efficient and sustainable collection and processing of the latex.
Some of these species may also have applications for bee forage, and as ornamental plants for xeriscaping.
Species of Research Interest
The Euphorbia species listed below were in our research collection in September 2025. Most of them have been tested by us to determine if economic concentrations of RTX are present. Some are being grown for production of surrogate sap for process development and other nonclinical uses.
- E. antisyphilitica (wax plant, candelilla)
- E. canariensis (Canary island spurge, Hercules club, Spanish cardón)
- E. ingens (candelabra tree, cactus spurge)
- E. makellenis (sausage plant, hamat kolkwal)
- E. officinarum (cardón moruno, resin spurge)
- E. officinarum subsp. echinus (tikiout, tikiwt, zaggoum, daghmus)
- E. poissonii (candle plant, cylindrical euphorbia)
- E. polyacantha (fish-bone cactus, fishbone-thistle)
- E. resinfera (Moroccan mound, resin spurge)
- E. subspina (candle plant)
- E. sudanica (sudanica milk bush, sudanica milk tree, sudanica spurge)
- E. tirucalli (Indian tree spurge, naked lady, pencil tree, pencil cactus, fire stick, aveloz or milk bush)
- E. trapaeifolia
- E. unispina (candle plant)
- E. venenifica = (candle plant, cylindrical euphorbia)
Specific information about these plants and images of them will be presented on the species pages under development in the Plant Information Section of this website. Links to these will be shown here when these pages are completed.
Project Milestones and Completion Status
This project consists of several steps summarized here with their completion status. The dates are approximate. The related clinical trials are being completed by others.
1. Acquisition of Research Specimens
Overview
In 2021 we began searching for plant specimens of the euphorbia species most likely to contain RTX. Accessions were sought from as many licit sources as possible to maximize genetic diversity of our collection. Most of the accessions were completed by 2023.
Progress Notes: For most of the species only one or two suppliers were found and very few live specimens were available. These were purchased during visits to nurseries in Arizona and by mail order from domestic and international suppliers. Few of the specimens shipped from domestic suppliers complied with Hawaii’s import requirements and these had to be delivered to the Hawai`i Department of Agriculture for inspection. Most shipments from the international suppliers did not comply with permits, inspections and other requirements for entry. We delivered nonconforming shipments to the U.S. Department of Agriculture for review, and they were subsequently confiscated.
Upon receipt at our Discovery Harbour facility the plants were inspected, assigned unique identification numbers for entry into a tracking database, cuttings were prepared and then planted in artificial media in our certified nursery areas. For the purposes of this discussion plants of the same species received from different sources will be referred to as types or varieties, even though they may not be varieties as defined in botanical nomenclature.
As the plants grew some specimens of each species were maintained as certified nursery stock to facilitate future export shipments to other researchers and customers. The remainder were moved outside the facility for propagation and planting on our experimental farm.
Status: Completed.
2. Screening of Specimens to Determine RTX Content
Overview
Published literature has confirmed the presence of resiniferatoxin and related compounds of interest in a small number of succulent African euphorbia species, including Euphorbia resinifera, E. poissonii and E. unispina (Herganhahn, Adolph and Hecker 1975, Herganhahn, Kusomota and Hecker 1975). Few related species have been assayed and there is no published information on the range of concentrations that may be found in plants of the same species from different locations and growing conditions. This data was needed for multiple business purposes.
Progress Notes: Arrangements were made with a research partner to analyze sap samples that we collected from specimens of the various species and varieties of euphorbia in our collection. New euphorbia species containing economic concentrations of RTX were found. The results from these analyses are proprietary and were used to guide selection of species and cultivars for further research and the first field trials at our experimental farm.
Status: Initial screening and analyses were completed in 2023.
 Euphorbia resinifera |
 Euphorbia poissonii Type ES |
 Euphorbia unispina Type ALG |
3. Development of Rapid Screening Methods
Overview
Analyses for RTX in the complex matrix of the latex are difficult and costly to carryout and few, if any laboratories perform them for commercial clients. We will need to conduct numerous analyses of sap and extracts for cultivar selection and process development. This may require rapid screening test methods and local or onsite capability to conduct the testing.
Progress Notes: We will be contacting specialized laboratories to determine if these rapid screening methods can be developed.
Status: Not started.
4. Research on Propagation Methods
Overview
Only very limited numbers of plants of the species of interest were available for sale, far below the amounts required for our research and development activities. Large numbers were needed to serve as a source of sap for analyses, evaluating the efficiency of propagation methods and to produce plants for crops at our experimental farm. No information on large scale propagation methods for these species were published.
Progress Notes: Few seeds were produced by the species in our collection. They were difficult to collect and had low viability, so we decided to propagate our euphorbias only from cuttings. Numerous cuttings were made from the plants for propagation our research.
Observations from experiments using the cuttings indicated that the species containing or potentially containing economic levels of RTX may be divided into three propagation groups. Propagation Group A consists of species like Euphorbia poissonii, that usually have single, large diameter upright stems and leaves. Group B includes species like Euphorbia resinifera that have multiple shorter stems and no leaves. Group C are species have characteristics of Groups A and B with one to several stems and occasional leaves. Included in Group C is Euphorbia sudanica and perhaps others.
The plants in Group A tend to be slow growing and can only be propagated from stem cuttings. The leaves root readily but fail to grow and eventually die. The Group A plants are not deemed suitable for cultivation as crops under our growing conditions. Propagation by tissue culture methods may be an option to be investigated for these.
The plants in Groups B and C were easy to propagate from cuttings. They typically root in 1-2 months and grow well in both artificial media and our well-draining volcanic soils.
As of October 2025, approximately 2000 cutting grown plants, mostly species in Propagation Groups A and B have been produced at our Discovery Harbour nursery facility. Most of the Group B plants have been planted on our experimental farm. We are now planning additional large-scale production of rooted cuttings from the farm plants.
Status: Propagation research and production of plants for our initial farm plantings has been completed. Additional large-scale propagation from cuttings of the farm plants is planned for late 2025 or early 2026.
5. Permitting of Specimens and Facilities for CITES Compliance
Overview
All the succulent African euphorbia species in our collection, and products derived from them such as euphorbia latex are regulated under the Convention on International Trade in Endangered Species of Wild Fauna and Flora (CITES). They are listed in CITES Appendix II, which includes species not currently threatened with extinction, but that may become so without trade controls. An export permit (or re-export certificate) from the country of export/re-export is required for trade, but no import permit is needed unless required by a country’s national law.
In the United States the CITES rule making, compliance and issuance of permits and exort certificates is carried out by the Division of Management Authority in the International Affairs Program of the U.S. Fish and Wildlife Service (USFWS).
Progress Notes: We have attempted to ensure that all euphorbia plants in our collection have been obtained from CITES compliant suppliers and that all these plants at our Discovery Harbour nursery were reviewed and listed in a 2023 amendment to our original USFWS Master File (permit) that previously covered unrelated species of Hoodia. In 2024 we applied for and received an additional amendment to add our new experimental farm in Hawaiian Oceanview to the facilities listed under the permit. All African euphorbia plants for RTX production and our facilities are now included in the USFWS CITES permit.
Status: Permitting completed.
6. Invasiveness Assessments
Overview
Most of the African euphorbia species that we work with had not been previously introduced into Hawai`i. As a Plant Pono Endorsed Business it is our policy to not introduce new species unless their invasiveness has been evaluated and they have been determined to present low risk. These evaluations are requested from and carried out by the Hawai`i-Pacific Weed Assessment (HPWRA) Project.
Progress Notes: All newly introduced euphorbia species evaluations completed so far have received a Low Risk HPWRA rating indicating that they are not currently recognized as invasive in Hawaiʻi, and not likely to have major ecological or economic impacts on other Pacific islands. Two species already in Hawai`i have high risk ratings. Euphorbia tirucalli has been widely planted in our area and trees covered much of our Discovery Harbour facility when we acquired it. It has been removed from all our facilities and is no longer used in our research. Euphorbia ingens has also been distributed in Hawai`i and widely grown as a house plant. It is a current research subject. We take measures such as removal of seeds that form on the plants to prevent it from spreading from our facilities.
Status: Assessments of most of our new species introductions have been completed and all indicated low risk of invasiveness.
 Euphorbia ingens |
7. Land Purchase for Experimental Farm
Overview
Our small research nursery facility at Discovery Harbour lacked space to grow euphorbia crops and conduct field trials. Much of the arable land in our area of Hawai`i is not suitable for growing euphorbia crops because of high rainfall and heavy growth of guinea grass (Megathyrsus maximus), Christmas berry (Schinus terebinthifolia), glycine (Neonotonia wightii) and other fast growing invasive weeds.
Progress Notes: We purchased a sloped, graded one-acre parcel of land in Hawaiian Ocean View in the District of Ka’ū, Hawai`i County for the future location of an experimental farm primarily for growing our African euphorbia crops. The site is at an elevation of about 600 m (2,000 ft) on a recent lava flow of the Mauna Loa volcano. There is little soil on the site, which consists of highly porous crushed `a’ā, a basaltic lava characterized by rough, jagged surfaces. One of the reasons this site was selected is that the conditions there do not support significant growth of invasive grasses. The site was named “Moana Experimental Farm” because of its location on Moana Drive.
Status: The purchase completed in mid-2023.
 Moana Experimental Farm Site Before Development in Hawaiian Oceanview, Kau District, Hawai’i Island |
8. Farm Site Construction and Operation
Overview
The Moana farm site is in an area with numerous abandoned cars and some recent homeless people’s encampments. There is also a high rate of agricultural theft and other property related crimes in the area. The site also had no water supply or electrical service.
Progress Notes: Priorities for site development included installation of chain link fencing and a security measures, portable water tanks, a storage shed, signage and delivery of topsoil for the areas to be planted. These improvements have been completed. Installation of a large water tank and an irrigation system was deferred because of construction and funding issues.
Status: All site improvements have been completed; the farm is fully operational.
9. Commencement of Farm Operations
Overview
How the African euphorbia plants would adapt to and grow at the new farm site was unknown. To minimize potential shock or other adverse effects of moving the euphorbia cuttings from our nursery to the farm site the cuttings were started in a soil mixture of predominantly volcanic cinders with minimal fertilization and grown in full sun. Most of the euphorbia species planted were from the Sahara and other areas of Africa with prolonged dry seasons so it was likely that they could tolerate the very dry conditions and porous soils of the farm site.
Progress Notes: In late 2023 we moved several hundred potted euphorbia plants from our research nursery at Discovery Harbour and planted them at the Moana Experimental Farm site. Virtually all of the plants appear to be doing well and by February 2024 many were producing new stem buds. As of October 2025, they were continuing to grow well. The estimated loss rate was very low – less than 0.1% of the rooted cuttings planted. All the species have bloomed except for Euphorbia resinifera.
Status: The farm is fully operational.
 Early Plantings of African Euphorbia |
10. Pest and Disease Surveillance and Control
Overview
Scant information on the pests and diseases affecting the euphorbia species planted was available. Hawai`i has one of the highest rates of new invasive pest and disease occurrences in the world. We have observed numerous pests and diseases affecting hoodia, caralluma and other succulent African species of plants in our nursery but none affecting the African euphorbias.
Progress Notes: We check all our euphorbia plants frequently, usually weekly, for pests and diseases. After the initial plantings at the farm several rooted cuttings, mostly small, poorly rooted specimens died out of several hundred planted. They appeared to have soft rot for which the pathogens have not been identified.
In April of 2024 several species of one cultivar of Euphorbia resinifera were observed with abnormal coloration, spotting and scaring. On closer inspection numerous small jumping and flying insects were observed on the plants and on the rocks near them. Some micro droplets of white sap, apparently emitted from bite wounds were seen on the plants and small black ants were also present, perhaps associated with the insect infestations.
Specimens of the insects on the plants were obtained by fogging them with alcohol over a white towel. They appeared to be hemipterans, about two mm in length, and were submitted to the Hawai`i Department of Agriculture in Hilo for identification. They were determined to be plant bugs, probably members of the Miridae family but the HDoA was not able to provide more definitive identification. It’s our understanding that the taxonomy of the Hawaiian species is not well established.
Following the first infestation, which was short lived, stunted growth, severe scarring and deformed stem buds were observed on the affected plants. Those plants were removed and destroyed. No additional active infestations have been observed since then, but more plants are showing similar scarring and deformities, and these symptoms have now been observed on an additional species, Euphorbia officinarum ssp. echinus.
While only a very small percentage of the euphorbia plants at the farm have been affected, we are continuing to monitor all of them for new infestations. We are also attempting to obtain more definitive identification of the pests causing this but entomologists with expertise on this group of insects could not be located.
Status: Surveillance for pests and diseases is ongoing. Plants with scaring and deformities in several areas of the farm are being observed indicating that additional infestations with the unidentified plant bugs may be occurring but these affect only a small percentage of the plants in cultivation. The scarring and deformities are only found on the two species previously mentioned.
 Deformed Euphorbia offinarum subspecies echinus |
11. Development of Sap Collection Methods and Apparatus
Overview
While complete synthesis of RTX has now been resolved [Hashimoto et al. (2017), Hikone et al. (2022) and Vasiliev et al. (2022)] it is still produced from euphorbia latex collected from plants much in the same way as in ancient times (Szallasi (2023).
We collect the latex from the African euphorbias by making vertical scratches on the stems or severing stems from the plant for cuttings, and removing the exuded sap with pipettes, spoons or other manual tools. This method is advantageous because the latex is at the highest levels near the surface of the stems and the plants recover quickly from the wounds. It is also a very slow, labor intensive, tedious and potentially hazardous process. The liquid sap flows quickly from the wounds but congeals rapidly into a sticky semi-solid latex material that clogs collection equipment. Removal and crushing of whole plants could be a more efficient alternative process but it may not be sustainable because it destroys plants that can take years to grow to a harvestable size.
The toxic, adherent latex is poisonous, highly irritating to the skin, and even tiny droplets in the eyes can cause severe irritation and blindness. Use of appropriate personal protective equipment (PPE) including goggles, face shields, gloves and disposable overalls is recommended when working with the sap. Portable eye wash stations must be maintained and available close to the work areas. This PPE ensemble is uncomfortable to wear for prolonged periods, particularly in hot sunny conditions where heat stress is of great concern. Our farm plants are growing in basalt lava rock rubble that has sharp edges, is unstable and difficult to walk on.
There are also ongoing and worsening shortages of agricultural labor nationally, and this problem is most severe in Hawai`i. This issue, the difficulties of collecting euphorbia by traditional methods and emerging requirements for compliance with good quality assurance practices dictate development of safer, and more efficient automated collection processes.
Progress Notes: We are developing a proprietary portable latex collection system for use on our euphorbia crops.
Status: A prototype of the system will be available for testing in late 2025.
12. Quality Assurance Program and Certifications
Overview
We intend to become a prime domestic producer of euphorbia latex for production of RTX and related pharmaceuticals and to meet or exceed all standards and quality certifications for this product. Good Agricultural Practices (GAPs) have been developed for food crops, and the Food and Drug Administration’s Current Good Manufacturing Practice (CGMPs) apply to manufacturing of pharmaceuticals. It is unclear if either of these standards are applicable to euphorbia latex, a natural agricultural product, to be provided to others for extractions and manufacturing a pharmaceutical.
Progress Notes: We will be contacting state and federal agencies to determine what requirements and recommended quality assurance standards should be followed.
Status: Incomplete. Preliminary contacts have been made.
13. First Sap Harvest
Overview
Our previous collections of sap made from limited numbers of plants in our nursery have only generated small milliliter volumes of sufficient for analyses and reference samples.
Progress Notes: The first collection from our farm plants is expected to take place when we generate additional cuttings for planting and test our sap collection system prototype. It is not expected to generate a quantity sufficient for initial sale, which is estimated to require be a volume of at least one liter.
Status: This first collection of sap from the farm plants is expected to be in late 2025.
 Freshly collected sap from Euphorbia resinifera |
14. Mass Propagation of Cuttings for Large Scale Farming
Overview
Thousands of rooted cuttings may need to be produced for planting on larger farms of sufficient size to produce the amounts of sap anticipated to be required by pharmaceutical companies.
Progress Notes: Most our farm plants began as small cuttings 1-2 years ago and are not of sufficient size to facilitate collection of large amounts of latex. Their growth rates are uncertain and vary among the species, but it appears that most of them could take several years to mature. However, most of the farm plants already have numerous stems that can be used to produce cuttings for rooting. These could be used to plant larger farms operated by our company or be supplied to other growers.
Status: Supplies for larger scale production and rooting of cuttings are being procured. Production of cuttings from the most promising species and cultivars is expected to commence in late 2025.
Market Outlook
Large-scale Applications
Recent progress in clinical trials testing the safety and efficacy of RTX in applications for single-administration, opioid sparing treatment of intractable pain caused by diseases affecting large populations has been reported:
Severe Pain Associated with Advanced Cancer. Pain continues to be a major problem in patients with advanced cancer. It varies by the primary site of the cancer and according to its degree of progression (Daut and Cleeland 1982), is often of at least moderate severity and interferes with the patient’s quality of life. Despite published guidelines for pain management, many patients with cancer have considerable pain and receive inadequate analgesia (Cleeland et al. 1994). Refractory cancer pain remains one of the most difficult challenges in palliative care (Shah and Dar 2025).
Intrathecal injection of RTX in several animal species has demonstrated a high level of safety, specificity, and efficacy in treating severe pain. In 2009 the National Institute of Dental and Carniofacial Research (NIDCR), National Institutes of Health (NIH) began clinical trials to examine the safety of using RTX to treat patients with severe pain associated with advanced cancer. Patient recruiting and the trials are still in progress (NIDCR 2025).
In 2014 Sorrento Therapeutics, Inc., working under a Collaborative Research and Development Agreement with the NIDCR, announced the first results from dosing six patients in the PhaseI/II clinical trial using RTX for the treatment of intractable cancer pain. A single injection of RTX resulted in pain reductions and significant improvements in the quality of life. Most of the patients were able to increase their activity level and one-third of patients who were bed or wheelchair bound due to pain were able to resume ambulation soon after the injection. The drug was well tolerated with no unexpected side effects (Sorrento Therapeutics 2014).
Additional initial results reported by Mannes et al. continued to show encouraging impacts on pain. On May 29, 2025, a news release announced that NIH scientists had reported “that a first-in-human clinical trial of a new therapy based on the plant-derived molecule resiniferatoxin (RTX) shows that it is a safe and effective agent for pain control in patients with intractable cancer pain. Researchers tested a single injection of small quantities of RTX into the lumbar cerebral spinal fluid (by lumbar puncture) of advanced-stage cancer patients and found that it reduced their reported worst pain intensity by 38% and their use of pain-relieving opioids by 57%.”
The next steps include additional, larger clinical trials to move RTX toward eventual approval by the U.S. Food and Drug Administration and clinical availability (National Institutes of Health 2025).
Osteoarthritis (OA) of the Knee is a major health problem affecting over 360 million people worldwide and its prevalence is increasing. The condition can make walking extremely painful, adversely impacts the quality of life and leads to high economic costs (GDHx 2019, Long et al. 2019).
Grünenthal, a leading pharmaceutical company focused on pain management and working in partnerships with NovaQuest and Shionogi, is conducting clinical trials to explore the safety and efficiency of RTX as a treatment for the pain associated with knee OA of the knee. They are currently conducting a global Phase III clinical program comprised of three trials for this purpose. It will be conducted across Europe, the US, Latin America, South Africa and Japan at about 200 sites involving more than 1,800 patients (Grüenthal 2025). The program aims to obtain market authorization in Europe, the US and Japan in 2026.
The global osteoarthritis therapeutics market is expected to reach $11.0 billion by 2025 with knee osteoarthritis expected to hold the largest share of that market (Anonymous 2020).
If these large-scale applications receive approval for use there will be a multi-billion dollar market for these treatments and an exponentially increasing demand for RTX.
Other Applications
Acute respiratory distress syndrome (ARDS) is one of the major causes of mortality associated with COVID-19 disease. It is hypothesized that the events leading to mortality are closely linked to the TRPV1 expressing neuronal system in the lungs. It is proposed that RTX as a potent TRPV1 agonist, could be used to ablate this system in patients with advanced COVID-19 disease (Nahama et al. 2020).
Burn pain analgesia. Opioids are undesirable for treatment of trauma patients due to side effects. Studies using a rat model indicate that local applications of RTX, a non-opioid compound have been found to induce long-lasting analgesia of pain associated with burns (Salas et al. 2017). These applications reversed pain behaviors within 24 hours and lasted through recovery at three weeks. Targeted approaches with RTX may be useful in management of severe burn injuries (Salazzi 2023).
Diabetic polyneuropathy and postherpetic neuralgia. Clinical trials to evaluate the topical use of RTX to relieve pain from these conditions were in progress (Appendino and Szallasi 1997).
Premature ejaculation. Topical applications of RTX may be suitable for treating patients with lifelong premature ejaculation and particularly those with redundant prepuce (Shi et al. 2014).
Interstitial cystitis. Resiniferatoxin has potential applications in treatment of this disease (Mourtzoukou, Iavazzo and Falagas 2008). Numerous studies have been published about the use of RTX in treating various urinary conditions.
Trichinellosis. Host defenses against infection by Trichinella spiralis can be increased by RTX resulting in decreased intestinal pathology and muscle parasite burden. This places it as a potential new drug modulator for immune response (Muñoz-Carillo et al. 2017).
Veterinary uses. Resinferatoxin is being explored for relief of chronic and surgical pain in animals. Its ability to provide long-term relief with minimal side effects makes it a valuable tool for veterinarians.
Research Partners and Investors Needed
Our research and development of African euphorbia has been constrained by the lack of outside funding, and it is unlikely that revenue will be received from sales until production of significant quantities of sap commences. Meanwhile, large investments in land, infrastructure and personnel need to be made to be ready to produce sufficient latex to meet the anticipated growth in demand for RTX. We are seeking a research partner that can provide funds for acquiring more land, planting, growing and harvesting the euphorbia latex.
Please CONTACT US if you are interested in learning more about this unique opportunity.
Reviews
The review by Idarola and Gonnella (2013) lists several other pain conditions that may be susceptible to treatment with local injection or topical RTX.
Readers are referred to the recent review by Szallasi (2023) for the history and status of RTX drug development from preclinical studies through veterinary medicine to clinical trials.
References
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