I just skipped through ..[part of your posts] .. but noticed you saying to heat up the spoon and actives..

Well the ..[heating part]... makes ok sense for transdermal application....

example....Like using a heating pad on an area of skin .. causes blood to pool there and pain to reduce some ..and healing to begin because more blood acumilates in that area..

but doesnt dmt ..[readily desolve]... in grain alcohol without heating it up?

So.. since alcohol does help some in transdermal aplication.... making the alcohol hot... should increase absorbtion to a degree .. when placed upon the outer skin.... because the heat can cause skin pores to open up in that spot..and blood to pool in that area also..

[why not just use an electric heating pad?... on the area of transdermal application

[even wearing a compression sleeve around the area of transdermal aplication can increase blood flow to that area and increase heat there to a degree]

[example .. if you wrap enough plastic wrap around your wrist pores will open up.. and that area will feel hot and blood will pool there under the skin.. [this should increase transdermal absorbtion some what]


but you keep talking about THH ..and i doubt many people have good pure THH to use/???/

unless they extract it from caapi vine some way..

read this about heat and transdermal aplication...below...




Expert Opin Drug Deliv. Author manuscript; available in PMC 2017 May 1.
Published in final edited form as:
Expert Opin Drug Deliv. 2016 May; 13(5): 755–768.
Published online 2016 Jan 25. doi: 10.1517/17425247.2016.1136286
PMCID: PMC4841791
NIHMSID: NIHMS771879
PMID: 26808472
Heat effects on drug delivery across human skin
Jinsong Hao,a Priyanka Ghosh,b S. Kevin Li,c Bryan Newman,b Gerald B. Kasting,c and Sam G. Raneyb
Author information Copyright and License information Disclaimer
The publisher's final edited version of this article is available at Expert Opin Drug Deliv
See other articles in PMC that cite the published article.
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Abstract
Introduction
Exposure to heat can impact the clinical efficacy and/or safety of transdermal and topical drug products. Understanding these heat effects and designing meaningful in vitro and in vivo methods to study them are of significant value to the development and evaluation of drug products dosed to the skin.

Areas covered
This review provides an overview of the underlying mechanisms and the observed effects of heat on the skin and on transdermal/topical drug delivery, thermoregulation and heat tolerability. The designs of several in vitro and in vivo heat effect studies and their results are reviewed.

Expert opinion
There is substantial evidence that elevated temperature can increase transdermal/topical drug delivery. However, in vitro and in vivo methods reported in the literature to study heat effects of transdermal/topical drug products have utilized inconsistent study conditions, and in vitro models require better characterization. Appropriate study designs and controls remain to be identified, and further research is warranted to evaluate in vitro-in vivo correlations and the ability of in vitro models to predict in vivo effects. The physicochemical and pharmacological properties of the drug(s) and the drug product, as well as dermal clearance and heat gradients may require careful consideration.

Keywords: dermal clearance, heat effect, heat exposure, patch, skin blood flow, topical drug products, transdermal delivery systems (TDS)
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1. Introduction
Drug products administered via the skin are typically classified as being either topical or transdermal drug products. When the intended site of action for drugs dosed to the skin is the skin itself, the route of administration is considered to be topical (local). When the intended site of action is systemic, the route of administration is considered to be transdermal. This review focuses on topical and transdermal drug delivery systems that are designed to deliver drugs into and/or through the skin at a relatively controlled rate for a specified duration. The most common are the drug-in-adhesive-matrix-based products, which are classified as extended release film dosage forms, with which the drug is classified to be dosed by a transdermal route of administration. Compendial references often refer to these as transdermal delivery systems (TDS), although TDS can also include reservoir-based drug products or active iontophoretic delivery systems. Less common are topical patch delivery systems, which are indicated for local as opposed to systemic effect; for these products, the drugs are classified to be dosed by a topical route of administration, and the dosage form is classified as a patch. While we predominantly focus on TDS in this review, some of the issues may apply equally to topical patches.

An increasing body of evidence indicates that elevated temperature during the normal course of product wear can substantially disrupt the well-controlled, steady drug delivery rate that is characteristic of TDS. TDS deliver drugs across the stratum corneum (SC) barrier and viable epidermis into the dermis, from which the drug can be cleared by the dermal capillaries. Local or systemic exposure to heat can change the drug release from the TDS, as well as the barrier properties of the SC and/or the rate of dermal clearance, thereby collectively altering drug delivery. The effects of heat from hot showers or baths, saunas, electric blankets and other such heat sources on these dosage forms are of interest to characterize because in order to sustain a nominal drug delivery rate over a prolonged period, TDS routinely contain an excess drug load that is not intended to be delivered to the patient. In situations where the rate and extent of drug delivery are increased by heat exposure, the excess drug load can dose the patient substantially above approved levels. As such, heat effects with TDS dosage forms are critically important because these effects may result in an altered rate profile for dosing, along with a substantially increased total dose and an altered safety profile. Furthermore, since TDS deliver drugs into the systemic circulation, the increase in delivery rate and amount dosed could have significant, unintended systemic effects.

The effects of heat (i.e. elevated temperature) on TDS can vary in severity, depending on the formulation and/ or the design of the TDS; the effect of heat on certain drug products like fentanyl TDS could even be fatal.[1–4] A sufficient body of evidence now exists to support the need for a more comprehensive understanding of the effects of heat on the potential safety and effectiveness of TDS. This review will provide an overview of the effects of heat on factors that influence transdermal and topical drug delivery, including drug release from the TDS, drug partitioning into the SC, drug diffusion within the skin, and dermal clearance of the drug from the application site. The distinct effects of elevated temperature on the product formulation, on the release of drug from the delivery system, on the skin, and on the permeation of the drug through the skin have not been adequately characterized in the existing literature and may be difficult to deconvolute. In addition to the discussion of physiological factors related to thermal stress and their impact on dermal clearance, the emphasis in the present review will be given to reviewing the published studies demonstrating the impact of elevated temperature on drug release and skin permeation in vitro and in vivo from topical delivery systems and TDS. We have not attempted to review the impact of lowered skin or body temperature on drug delivery from these systems. There may be circumstances when a patient might wear a TDS on a region of skin transiently exposed to relatively cold (even freezing) temperatures. Based upon the relationship between temperature and TDS drug delivery in the normal to high temperature range, transdermal drug delivery would likely be reduced at colder temperatures. Although low temperatures are not expected to lead to a drug overdose, they could potentially lead to under-dosing of topical or transdermal drugs. This is somewhat speculative and currently inconclusive because of the very limited literature describing the effects of cooling on transdermal and topical drug delivery. A critical review of the effects of lowered temperature on transdermal and topical drug delivery is beyond the scope of this work.

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2. Thermoregulation and heat effects on the temperature of the body and the skin
2.1. Thermoregulation
Thermoregulation plays an important role in maintaining the physiological homeostasis during physical exercise as well as at rest. Human body temperature is controlled by the thermoregulatory center in the hypothalamus, which responds to signals from the receptors in the hypothalamus and in the skin. The receptors in the hypothalamus monitor the internal (core) body temperature while the receptors in the skin monitor the external temperature. Through the use of feedback control, the human body can make thermal adjustments so that body temperature is maintained in a normal range. For example, stress from high temperatures can stimulate cutaneous vasodilation caused by autonomic smooth muscle relaxation in the blood vessels, sweating, and/or the modulation of adrenaline and thyroxine secretion from adrenal and thyroid glands, respectively. These physiological responses to heat can work in concert to distribute heat from the body core to the extremities and the skin surface. At the skin surface, heat can be dissipated through conduction, convection, radiation, and water evaporation,[5–7] and these thermoregulatory cooling mechanisms can be complemented by a reduction in metabolic heat production.

2.1.1. Cutaneous vasodilation and skin blood flow
2.1.1.1. Systemic exposure to heat and internal heat sources
Thermoregulatory vasodilation is vital to maintain normal body temperatures during heat exposure. Resting skin blood flow in a thermoneutral environment is approximately 0.25 L/min, which dissipates the 80–90 kcal/h of metabolic heat produced during rest. However, to modulate thermoregulation under conditions of elevated temperature, the skin blood flow can increase to 6–8 L/min during severe hyperthermia.[8] Cutaneous vasodilation, controlled by both nerve reflexes and local factors,[9] is effective at facilitating heat loss and thereby cooling the body. The reflex control of skin blood flow is mediated by two types of sympathetic nerves (i.e. sympathetic adrenergic vasoconstrictor nerves and sympathetic vasodilator nerves). The sympathetic vasodilator system is activated when the internal temperature or skin temperature increases beyond its threshold for cutaneous vasodilation. Factors that influence the threshold (and the sensitivity) of cutaneous vasodilation include heat acclimation, exercise training, circadian rhythm, and the production of nitric oxide from whole body heat stress.[8]

2.1.1.2. Local exposure to heat and external heat sources
Locally applied heat can increase the skin blood flow at the site of heat application. Short heat application (43°C for 60 s) was reported to cause significant cutaneous hyperemia with up to a twofold increase in skin perfusion and a 5°C increase in skin temperature, lasting up to 15 min from a single heat application.[10] As much as a ninefold increase in local blood flow was also reported in response to a rise of 9–13°C in skin temperature.[11,12] During local heating of the skin, factors such as local skin temperature contribute directly to the control of local skin blood flow, complementing the reflex neural control of skin blood flow that occurs via the sympathetic vasodilator nerves and any other contributing factors such as nitric oxide production.[13] The local sensory nerves are temperature sensitive and it has been reported that the activation of local nerves at temperatures ranging from 29°C to 40°C contributed to local vasodilation.[8,14] Charkoudian [8] characterized a typical cutaneous vasodilation pattern during 30 min of local skin heating at a skin temperature of 42°C, in which the skin blood flow rapidly increased in the first 3–5 min, decreased moderately, and then slowly increased to a maximum after 25–30 min of heating.[8,9,15,16] The activation of local sensory nerves and nitric oxide were the predominant contributors to the initial (rapid) and the subsequent (slow) increases in the skin blood flow, respectively.

The extent of increased skin blood flow is influenced by the skin temperature during local heating. A study of the relationship between forearm blood flow and local skin temperature showed that the increases in the skin blood flow were small between 20°C and 35°C, significant at 37°C and above, and maximal at approximately 42°C.[17] Similar observations were reported in other studies.[18,19] A later study confirmed that maximal vasodilation in the skin was reached when the skin temperature was maintained at 42°C.[9]

2.1.2. Sweating and water evaporation
The endothermic evaporation of sweat decreases the skin temperature, resulting in the cooling of the blood in the dilated skin vessels and the body. Sweating is regulated by internal body temperature as well as skin temperature. Sweat secretion and evaporation are also influenced by the environmental temperature and humidity. In a dry environment, the sweat evaporates almost immediately following secretion. This process is suppressed in a hot humid environment, with the consequence that the evaporative heat loss is less efficient and does not effectively cool the skin. One study [20] determined the skin temperature during a 45 min rest followed by 45 min exercises in a hot environment with normal humidity (49.5°C and 32% relative humidity (RH)). This study showed that the skin temperature increased rapidly during the first 20 min and then gradually to 37°C during the last 25 min of rest. During exercise, the skin temperature increased linearly from 5 min after the start of exercises and reached 39.1–39.8°C at the end of the exercises. An additional study was conducted on one subject during 45 min exercises in dry (15% RH) and normal (32% RH) environment at 49.5°C and reported that the skin temperatures were 37.5°C and 38.4°C in dry and normal environments, respectively.[20]

2.2. Skin temperature during heat exposure
Table 1 summarizes the skin temperatures during heat exposure under different conditions studied previously. Despite heat exposure and physical exercise, in most of the studies, the skin temperature does not exceed 43°C. For example, the mean skin temperature increased to 40–41°C during sauna bathing in a hot environment with an air temperature of 80–100°C.[21] A controlled heat-aided drug delivery (CHADD) system was reported to increase the skin temperature to approximately 41°C. [22,23] Independently, skin temperatures were reported to vary between 33°C and 40°C during exercises in a hot environment, depending on the RH of the environment. [20,24,25] Collectively, these findings suggest that a maximal skin temperature of approximately 42–43°C is most relevant for studying heat effects with topical and transdermal dosage forms.

Table 1
Skin temperatures during in vivo heat exposure studies.

Reference Study objective Heat application Skin temperature
[24] Uptake of glyceryl trinitrate Exercise 20 min; sauna air temperature 90°C 20 min Exercise: 33.3°C; sauna: 37.6– 38.1°C
[22] Transdermal delivery of fentanyl CHADD 4 h 41 ± 1°C
[26] Serum fentanyl concentrations during treatment of transdermal patches Electric heating pad 0–10 h and 26–36 h post-dosing 36–37°C
[23] Transdermal delivery of testosterone CHADD 4 h 41 ± 1°C
[12] Transdermal delivery of nicotine Local controlled heat 43°C 1 min every 5 min intervals for 30 min 43 ± 0.2°C
[27] Pharmacokinetic studies of granisetron transdermal system A heating pad over the transdermal system Around 42°C
[20] Thermoregulation Rest or exercise in a hot chamber of 49.5°C, 15% or 32% relative humidity 37°C at rest and 39.1–39.8°C during exercise
[25] Thermoregulation Three 20 min exercises followed by 7 min rest periods in hot and dry conditions (41 ± 1°C and 21% relative humidity) 31–32°C before exercise and
37–38°C at the end of exercise
[21] Thermoregulation Sauna air temperature 80–100°C, 5–20 min sessions 40–41°C
[9] Cutaneous vasodilation A water-perfused suit to control local temperatures from 18°C to 42°C 18–42°C
[16] Cutaneous vasodilation Peritemp local heating unit temperature at 42°C 50–80 min or increased from 33°C to 42°C at a rate of 0.5°C every 5 s 39–40°C
[13] Cutaneous vasodilation Local heating to 41°C by a special laser-Doppler flowmetry holder 41°C
[15] Cutaneous vasodilation Local heating to 42.5°C 30 min by a special laser-Doppler flowmetry holder 42.5°C
[14] Local thermal control of skin blood flow A Peltier cooling/heating device to change skin temperature between 20°C and 42°C 20–42°C
[28] Plaster splint application Plaster splint application in conjunction with the use of pillows or blankets 41–45°C
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CHADD: controlled heat-aided drug delivery.

2.3. Body and skin temperature tolerance
The deviation of human body core temperatures by 3.5°C higher than the normal body temperature of 37°C can result in physiological impairments and even death.[7] High skin temperature can cause pain and may result in vasoconstriction.[8,12] The first phase transition of the skin SC lipids begins to occur around 40°C [29] and skin barrier function is compromised at high temperatures.[11] Brief heating to high temperature (i.e. <1 s exposure and >100°C) has been found to increase skin permeability by causing thermal damage to the SC without damaging deeper tissues.[30] Thermal exposure over 40°C for an extended period of time may cause thermal injury to skin and can cause burns.[28,31] Thermal conditions that cause skin burns are a function of the time and potentially the method of heat exposure as well as the skin temperature, and a skin temperature above 42°C should typically be avoided when studying heat effects.[32] Prolonged exposure of skin to 43°C or higher could lead to blister formation.[33] A physiologically tolerable temperature of 40°C has been proposed previously,[34] and as discussed in the preceding section, it may not be clinically relevant to study heat effects at skin temperatures higher than 42–43°C.

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3. Heat effects on dermal clearance
Local skin perfusion can be significantly increased during heat application and, in turn, can affect dermal clearance of drugs delivered by topical or transdermal administration. Reducing the rate of blood flow in the skin (i.e. reducing dermal clearance) was found to affect topical delivery of drugs by altering the residence time of drugs in the skin and underlying tissues.[35,36] Coadministration of vasoconstrictors has been shown to alter the absorption and distribution of topically applied drugs.[37] Therefore, blood flow changes in skin due to elevated skin temperatures can have an effect on relative processes of local and systemic drug distribution and absorption. It was suggested that the observed increase in plasma nitroglycerin concentrations in healthy subjects wearing nitroglycerin TDS during a 20 min sauna (air temperature 90°C and peak skin temperature 39°C) were partly due to cutaneous vasodilation.[24] In another study, the relationship between the skin blood flow and transdermal absorption of nitroglycerin was explored. The transdermal nitroglycerin systems were applied to the subjects’ upper arm and exposed to 15 min of local heat by an infrared heating bulb. The plasma drug concentrations increased when the skin blood flow increased due to heat exposure.[38] A recent clinical study on nicotine TDS proposed that the increased drug absorption after application of controlled heat (43°C) was largely due to enhanced microcirculation and local blood flow; the heat application was found to increase blood flow by approximately tenfold as compared with the blood flow at 32°C.[12] The results from these clinical studies suggest that local blood flow and dermal clearance of a drug are important considerations impacting transdermal and topical modes of dose administration, particularly under conditions of elevated temperature.

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4. Heat effects on TDS drug release and delivery through skin
4.1. Concerns related to heat effects on drug release from TDS
Application of heat can change the rate of drug release from a TDS. These systems are widely varied in design and their individual susceptibility to heat effects can also vary. Typical components of a matrix TDS include a backing film/membrane, drug dissolved and/or suspended in an adhesive matrix, and a release liner to protect the TDS until the drug product is dosed. The TDS formulation modulates the rate of drug release, drug partitioning into the SC, and drug diffusion/delivery into and through the skin. The goal of modern TDS product development is to optimize the rate of drug delivery per unit area (e.g. μg/h/cm2) and to minimize drug load. To achieve this goal, TDS formulation development typically involves the evaluation of a variety of different adhesives and excipients. The adhesives traditionally used in TDS are acrylates, silicones, and polyisobutylenes.[39] Some of the most commonly used excipients include mineral oil, colloidal silicon dioxide, dipropylene glycol, alcohol, and fatty acid esters. Under conditions of elevated temperature, the behaviors of these chemically distinct components, either individually or in a complex formulation mixture, are difficult to anticipate. Therefore, without experimental evaluation, it has been difficult to predict how drug release characteristics would change for a TDS under conditions of elevated temperature. As a further complexity, reservoir-type TDS contain an additional rate-limiting membrane which can also modulate the rate of release under conditions of elevated temperature exposure.

During the process of product development and approval, drug delivery from TDS is usually evaluated under conditions of relevant use, i.e. anticipated patient use without the application of heat or additional stress on the system. Drug manufacturers may also evaluate drug release from TDS under conditions of elevated temperature and incorporate corresponding cautionary statements in TDS product labels whenever it is anticipated or observed that exposure to elevated temperature could lead to higher drug plasma levels. Examples of TDS products that include warnings in product labels are those containing buprenorphine, fentanyl, granisetron, and methylphenidate, among others. This issue has special relevance for generic versions of TDS, which can contain different adhesives and/or excipients compared with those used in the reference listed drug (RLD), and a generic TDS may utilize an entirely different design than the RLD. Considering the growing body of evidence about heat effects on TDS performance, it is reasonable to expect that heat effect evaluations will continue to be needed. As such, the development of clinically relevant in vitro methods, perhaps combined with computational modeling of activation energies described later in this review, could greatly facilitate the routine evaluation of the comparative drug release and delivery profiles from generic TDS and their RLD products under conditions of elevated temperature exposure.

4.2. Effects of heat on skin permeation under steady-state conditions
Drug plasma concentrations are proportional to the rate of drug permeation across the skin at steady state in vivo, when the drug follows linear pharmacokinetics with zero-order delivery from a TDS. Hence, skin permeation rate or skin permeability can provide useful information as an initial estimate of the effect of skin permeability enhancement on plasma concentration in the context of transdermal delivery. The effects of heat on skin permeability were investigated as early as the 1960s. Scheuplein investigated the effects of temperature on the permeation of water through skin and noted the different permeation behaviors of water at different temperatures.[40] Blank et al. examined the effects of temperature on the transport of nonelectrolytes across the skin and found that polar and nonpolar molecules appeared to diffuse through the epidermis by different molecular mechanisms characterized by different activation energies.[41] Cornwell and Barry studied temperature dependence of skin conductivity and permeation and found significant temperature effects influencing these two properties.[42] In that study, two distinctive skin transport mechanisms were observed: (a) the activation energy of ion permeation across the skin was consistent with a mechanism whereby the ions primarily diffuse across an aqueous polar pathway in the skin and (b) the activation energy of 5-fluorouracil diffusion across the skin was consistent with a mechanism of solute transport across a lipid barrier. Later, Peck et al. compared the temperature dependence of skin permeation of urea, as a model polar permeant, with that of corticosterone, as a model lipophilic permeant, and showed a higher activation energy of skin transport for corticosterone than for urea.[43]

It is generally accepted that the increased skin permeation observed in situations of elevated temperature is primarily related to the increased diffusivity, partitioning, and solubility of drugs in the SC at the elevated temperatures. Both increased partitioning of lidocaine base into the epidermis and increased epidermal diffusion at 45°C as compared with that at 32°C were observed in a study attempting to elucidate how drug release, partitioning, and epidermal diffusion responded to changes in local temperature.[11] Additionally, heat may “dilate’ the skin penetration pathways and increase drug solubility in the skin, leading to enhanced skin absorption.[44] Recently, Mitragotri summarized the activation energies of more than 30 molecules in the literature and analyzed their relationships with the molecular properties.[45] The activation energies describe the nature of the transport barrier of a membrane and correspond to the changes in membrane diffusivity and membrane partitioning of the permeants under the influence of temperature. The activation energies for various permeants in accordance with the Arrhenius equation are listed in Table 2, and the changes in permeability coefficients as ratios from 32°C to 37°C and 42°C were calculated using the activation energies of the permeants presented by Mitragotri. [45] Only human skin data are included in Table 2. The activation energy values range from 4 to 23 kcal/mol, and the permeability coefficients for these compounds of different molecular sizes and lipophilicities increase by as much as 1.9-fold with a 5°C increase above normal skin temperature of 32°C, and by as much as 3.4-fold with a 10°C increase from 32°C to 42°C. Similar results were reported for other compounds; e.g., with activation energies of 13–20 kcal/mol for methyl paraben, butyl paraben, and caffeine, approximately twofold increases in the epidermal fluxes of these compounds from their saturated suspensions were observed with an increase of 7–8°C in the temperature range of 23–45°C.[29]

Table 2
Calculated values of permeability enhancement due to changes in temperature based on activation energies of permeants.

Permeant Activation energy (kcal/mol)a Ratio of permeability at 37°C to 32°C Ratio of permeability at 42°C to 32°C
Acetylsalicylic acid 20.3 1.7 2.9
Butanol (n-butanol) 16.7 1.6 2.4
Butanone (2-butanone) 16.1 1.5 2.3
Butyl paraben 20.3 1.7 2.9
p-Bromophenol 8.8 1.3 1.6
Caffeine 12.7 1.4 1.9
Carbon disulfide 16.9 1.6 2.4
Chlorocresol 10.3 1.3 1.7
o-Chlorophenol 9.6 1.3 1.7
Corticosterone 23.2 1.9 3.4
m-Cresol 13.6 1.4 2.0
o-Cresol 12.8 1.4 2.0
p-Cresol 13.7 1.4 2.1
1,1-Dichloropropanone 11.2 1.3 1.8
Ethyl ether 16.1 1.5 2.3
Ethanol 19.6 1.7 2.8
Ethoxy ethanol 20.1 1.7 2.9
5-Fluorouracil 23.4 1.9 3.4
Glycopyrrolate 17.7 1.6 2.5
Heptanol 9.9 1.3 1.7
Hexanol 10.9 1.3 1.8
Ion conductivity 4.1 1.1 1.2
Mannitol 8.8 1.3 1.6
Methyl paraben 15.5 1.5 2.3
Methylsalicylic acid 13.7 1.4 2.1
Naphthol 9.8 1.3 1.7
m-Nitrophenol 13.3 1.4 2.0
Octanol 10.0 1.3 1.7
Pentanol 16.5 1.6 2.4
Phenol 14.4 1.5 2.1
Propanol 16.5 1.6 2.4
Resorcinol 17.8 1.6 2.5
Sarin 16.9 1.6 2.4
Tetraethylammonium 8.3 1.2 1.5
Thiourea 16.2 1.5 2.3
Thymol 12.6 1.4 1.9
2,4,6-Trichlorophenol 9.1 1.3 1.6
Urea 7.1 1.2 1.4
Water 14.6 1.5 2.1
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aData from [45] in accordance with the Arrhenius equation.
4.3. Effects of heat on transdermal and topical drug delivery systems
4.3.1. Effects of heat on transdermal drug delivery in vivo
Myriad studies of the effects of heat application on in vivo drug absorption from TDS and their findings are summarized in Table 3. In these studies, the plasma or serum peak drug concentrations and areas under the curve (AUCs) were often increased under conditions of elevated temperature. However, significant heat effects were not always observed. For example, in one study with an ethinyl estradiol and norelgestromin TDS, no significant heat effect was observed.[46] Likewise, the evaluation of a granisetron TDS using a heating pad indicated that although there was a small enhancement in flux, no significant changes were noted in the pharmacokinetics of the drug in humans.[27]

Table 3
Summary of in vivo studies for transdermal and topical delivery systems under conditions of elevated temperature.

Reference Drug name Heat application Results
Transdermal delivery systems
[47] Clonidine Bath 40°C 5 min daily; hot weather (summer versus winter) Hot bath had no effects on peak plasma concentrations or AUC; however, peak plasma concentrations and AUC tended to be higher in the summer trial
[48] Ethinyl estradiol/ levonorgestrel Dry sauna 76–82°C 10 min/day for 7 days; whirlpool 39–41°C 10 min/day for 7 days; treadmill 20–30 min/day for 7 days Decreased the mean peak concentration and AUC; slightly lower mean drug concentrations
[46] Ethinyl estradiol/norelgestromin Sauna 76–82°C 10 min daily for 7 days; whirlpool 39–41°C 10 min daily for 7 days; treadmill 20–30 min daily for 7 days Plasma concentrations remained within the reference range; no heat effect was observed
[27] Granisetron A heating pad was applied over the patch during either first or second patch application; 4.5 h daily for 5 days No overall effects of heat on pharmacokinetics of transdermal granisetron; while small increases in granisetron concentration during heat application were observed, the concentration quickly returned to without heat levels once the heat was removed
[22] Fentanyl CHADD 4 h Increased mean peak concentration and AUC for the 4 h period of heat application
[26] Fentanyl Electric heating pad to produce skin temperature 36–37°C, 0–10 h and 26–36 h post-dosing A similar effect on both matrix and reservoir systems: increased serum concentrations and AUC for the first 10 h
[49] Fentanyl Controlled heat to produce temperature 42 ± 2°C for 60 min; 0–4 h application During the first 4 h, three times higher peak concentration and AUC for the heated group than for the control without heat
[24] Glyceryl trinitrate Exercise 20 min; sauna 20 min at sauna air temperature 90°C Increased mean plasma concentrations
[50] Glyceryl trinitrate Exercise 20 min three times after patch application, renewal, and removal Increased peak plasma concentrations
[38] Nitroglycerin Local heating 15 min with an infrared bulb About twofold increase in mean plasma concentration
[12] Nicotine Local controlled heat 43°C 1 min every 5 min intervals for 30 min Up to 13-fold increase in nicotine uptake
[51] Nicotine Sauna bath 82°C, 28% RH, three 10 min periods separated by two 5 min breaks Increased peak plasma concentrations, AUC between 0 and 1 h, nicotine absorbed, and mean plasma concentrations; no significant difference in AUC between 0 and 3 h
[52] Nicotine Exercise 1 h at 8 h after patch application Exercise increased tissue concentration but had no effect on plasma concentration. A similar effect was observed for two patch products
[53] Nicotine Exercise 20 min at 11 h after patch application Increased plasma concentration during exercise
[23] Testosterone CHADD 4 h Significant increases in peak concentration, AUC with heat application
Topical delivery systems
[54] Lidocaine/tetracaine Four heated patches for 2, 4, and 12 h Increased plasma concentrations during the first 2 hours of application; time-normalized AUC showed no difference or lower between 2 and 12 h of application
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AUC: areas under the curve; CHADD: controlled heat-aided drug delivery.

The fentanyl TDS is one of the most widely investigated transdermal products, and a relatively large body of in vivo data characterizing heat effects with fentanyl TDS is available in the literature. The scientific interest in characterizing heat effects with fentanyl TDS is, in part, because heat may be used in combination with the fentanyl TDS for the treatment of pain, and particularly because fentanyl has a narrow therapeutic index and elevated fentanyl delivery could be toxic or fatal. The CHADD system contains a heat-generating element and produces heat when exposed to air. It can be applied on a transdermal or topical system to enhance drug delivery. The impact of local heat on the systemic delivery of fentanyl from TDS was previously assessed using a CHADD patch as a heat source.[22] The CHADD patch is designed to produce heat for 4 h and the heat passing through the fentanyl TDS increases skin temperature to 41 ± 1°C. The results...

the way i would try it is...first clean wrist or whatever part of body you intend transdermal aplication with alcohol..

Then after cleaning area apply apply your prepaired solution to skin ..then wrap or cover area with thin ...[cling plastic wrap].. around or over area of aplication.


Then use a heating pad over the plastic wrap..see what hapens ..

this could be tryed different ways...the thinner the skin...the easier and faster the transdermal penetration.. is a theory..


one example....the arm pits already...[ a warm spot on the body]... that have open pores that often sweat...
skin also appears thin on the wrists....

who knows till its tryed? can something penetrate under finger nails?..how about the skin on outer lips?

example ..[lidocaine] topical... enters through a transdermal route pretty easy

and i read a report where a woman coated a large part her body with lidocaine [about 70 percent!] then wrapped plastic cling wrap over the lidocaine....
and almost over dosed on lidocaine!

using a thin plastic wrap over skin with a topical medicine... locks in the medicine and if its molecular size is small enough.. it will pass through the skin layers...

but ...[the area on the body]...[the thinnesss of the skin]...it all has an effect.. when trying transdermal aplication....

I think dmt would have a better chance of working sublingually... though...

it all takes testing...

i think that DMSO stuff can be un safe...

i just found this on line discussion about transdermal aplication...


read below... .. [the tops of your feet]..... is a location i never concidered...

the skin there is fairly thin!




Groin should be obvious: you don't want transdermal on your member, that **** burns

Neck should be avoided because of dermal thickness, the fact that there's usually hair on the back, and the fact that transdermal application often burns here too.

Best places, in my humble opinion, are:

- The tops of your feet
- Calves
- Delts
- Upper-arms
- Fore-arms

Last night i did a transdermal test for first time using the top of my foot ..
[just above the anterior tibial artery]] [as i think its called]..the .area marked with an x on the photo below...

[At bedtime...and drinking a hot cup of lemon grass tea] i then applyed my home made transdermal patch...


I didnt use any spice this time... but i crushed half of a ... [50 mcg Huperzene A tablet]....equaling about ..[25 micrograms]...then i put the crushed ...[Hupe A powder].. in a narrow tubular lab flask ..then added grain alcohol.. because it huperzene is readily soluble in methanol..

I shook up the lab vile then let contents settle for over an hour and observed that the clear alcohol was now cloudy ...and the tablet [non active] filler setteled to the bottom of flask..

The huperzene had migrated into the alcohol very easily .. i then used a dropper to remove about
1 ml of huperzene laden alcohol..

the alcohol only filled a small dropper half way up...and i then mixed the pill extract into some target store aloe vera ..into 97.5 purity 190 proof grain alcohol...

i mixed the huperzene into the aloe vera gell very compleatly..

I allowed some of the alcohol to evaporate out of the gel ..then i used a large sized adhesive bandage...i placed the aloe vera gel W/ huperzene in it..onto the the bandage pad and after cleaning off top of foot ..put the bandage on my foot...

the adhesive borders on bandage stuck very well on top of foot..and sealed the contents onto the pad in middle of bandage...

I sometimes use ...Huperzene A..for lucid dreaming...as it is an acetylcholine booster that is also used for people with memory decline...

When i put the transdermal patch on my foot it was an hour befor bed...and the results were..It did work transdermally on top of my foot ..because it released huperzeen transdermally i know because it kept mr semi awake most of the whole night..

In the early deep sleep stages i could feel the effects of the huperzene and the magic of the LG tea...

durring the first 3 to 4 hours i was only semi asleep but observed a constant imagry show in my head..it was like dreams were trying to constantly materialize but i wasnt deep enough asleep to go into a fully emersed dream state...

i should have never taken that type of supplument before bed.. because it can cause insomnia!

I knew better ..but i did it any way..

thinking that the transdermal effect would be so light it shouldent cause me any insomnia?...
but i was wrong it did! and the patch worked pretty well on top of foot!

And very late in the morning [ last night] i had a short ..but nice lucid dream!]

So i know it worked transdermally because of the insomnia..and visions...and the later lucid dream..that i had and was flying around the dream scape!

I didnt try any spice yet...but am incouraged by how well it worked transdermally on the top of my foot just over and close to a foot blood artery..

There are atleast two main arterys on top of foot.. one on top center of fllot that i used ..and it worked with ...a small amount of...Huperzene A ..the other artery is near the big knuckel on side of foot...

there are also a lot of smaller blood vessels all through the foot....

Will this work with DMT/? i dont know yet... but because of how thin the skin is on the foot ant the arangement of arterys and blood vessels so close to the skin ..it looks possible!

I didnt even use all natural aloe vera,,and it still worked!

will add two photos below...

Ava69, just read your recommendations with the recent update, could you substitute the | High Pobability of Braindamage by Creepy non tested Drugs (forced by scammer 69ron) | with Aloe Vera sublingually? (or rather the Aloe Vera/ Everclear combo)?

Is this something you would recommenced, especially if one can't acquire | High Pobability of Braindamage by Creepy non tested Drugs (forced by scammer 69ron) |?

so far...
just applying the topical on top of foot is FASTER!.. absorbtion than most other parts of body.. [ i also suspect the back or top of the hand may also work this way transdermally]

And because of this....This discovery in itself is a noteable one ...besides i havent tryed spice yet with this method and cant condem it untill its tryed and fails..

One area this method could be an improvement ..is its use for lucid dreaming..

Most people take ...huperzene A or galantamine with choline orally after sleeping for 4 or 5 hours ..then wake breifly and take the suppliment...during higher REm sleep[..

Although a tryed and proven method...This method doesnt work well for everyone .. for dreaming because everyones sleep habits arent the same...[some people sleep deeply and others sleep more shallower...and are prone to insomnia..

Being able to take natural huperzene or galantamine [for lucid dreaming] transdermally can be an advantage for orionauts .. because ..transdermal application].. on a chart shows a stable constant level in the bloodstream with a very gradual decline untill hitting baseline..

Taking these dream supliments orally.. shows a sharp fast rise untell it peaks in bloodstream..then a sudden sharp fast decline untill it hits baseline...

So one benifit with transdermal ..[for lucid dreaming].. is it keeps a more constant level in bloodstream only dropping towards baseline very gradually..

And the speed of transdermal absorbtion.. isnt as important with lucid dream supliments.
[as it would be with DMT]

Because a gradual transdermal absorbtion causing an increased level of..[ huperzene A] in the bloodstream is all thats needed...for use some hours later.. while asleep.. for dreaming and increased dream awareness during the dream so that..[ the brain switch] is switched on..
that allows critical awareness during the dream state..[during most ordinary dreams this critical awareness switch is .[shut off].. during common nightly dreams.. causing the dreamer to see everything going on in the dream as real!
But once the higher brain functions in the frontal lobe of brain that controls critical thought is activated [from the acetylcholine boost] caused by the.. Huperzene A..you realize [its a dream] and have more of a chance to manipulate what happens in the dream to do anything you want.
.fly. walk through walls... create or distroy dream carectors ..you want a beautyfull woman?
she is suddenly there!...you want to fly to planet mars..its easy...ive even swam in
..[ swimming pools in dreams].. filled with pure sparkling energy...not water!

anything in a drug experiance can be recreated in a dream! especially a [WILD] .. [wake initiated lucid dream]!

in the highest quality dream state...there are no limits to the adventures one can have...dreams are the highest experiances on earth a human can have!


so its possible that people with sleep problems may be able to take hupe A or galantamine...several hours before bed time.. without it destroying their sleep...

I dont know if transdermall will work with dmt..[it probibly wont] but i wont condem it untill i try it... but still i see a benifit in this type of application for lucid dreaming supliments! and im also in to lucid dreaming.